Microsoft Word - Supplement_R2_FinalSubmission_031710_clean.doc 1 New Loci Associated with Kidney Function and Chronic Kidney Disease Supplement Anna Köttgen*, Cristian Pattaro*, Carsten A. Böger *, Christian Fuchsberger *, Matthias Olden, Nicole L. Glazer, Afshin Parsa, Xiaoyi Gao, Qiong Yang, Albert V. Smith, Jeffrey R. O’Connell, Man Li, Helena Schmidt, Toshiko Tanaka, Aaron Isaacs, Shamika Ketkar, Shih-Jen Hwang, Andrew D. Johnson, Abbas Dehghan, Alexander Teumer, Guillaume Paré, Elizabeth J. Atkinson, Tanja Zeller, Kurt Lohman, Marilyn C. Cornelis, Nicole M. Probst-Hensch, Florian Kronenberg, Anke Tönjes, Caroline Hayward, Thor Aspelund, Gudny Eiriksdottir, Lenore Launer, Tamara B. Harris, Evadnie Rampersaud, Braxton D. Mitchell, Dan E. Arking, Eric Boerwinkle, Maksim Struchalin, Margherita Cavalieri, Andrew Singleton, Francesco Giallauria, Jeffery Metter, Ian de Boer, Talin Haritunians, Thomas Lumley, David Siscovick, Bruce M. Psaty, M. Carola Zillikens, Ben A. Oostra, Mary Feitosa, Michael Province, Mariza de Andrade, Stephen T. Turner, Arne Schillert, Andreas Ziegler, Philipp S. Wild, Renate B. Schnabel, Sandra Wilde, Thomas F. Muenzel, Tennille S Leak, Thomas Illig, Norman Klopp,Christa Meisinger, H.-Erich Wichmann, Wolfgang Koenig, Lina Zgaga, Tatijana Zemunik, Ivana Kolcic, Cosetta Minelli, Frank B. Hu, Åsa Johansson, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Stefan Schreiber, Yurii S Aulchenko, Janine F. Felix, Fernando Rivadeneira, Andre G Uitterlinden, Albert Hofman, Medea Imboden, Dorothea Nitsch, Anita Brandstätter, Barbara Kollerits, Lyudmyla Kedenko, Reedik Mägi, Michael Stumvoll, Peter Kovacs, Mladen Boban, Susan Campbell, Karlhans Endlich, Henry Völzke, Heyo K. Kroemer, Matthias Nauck, Uwe Völker, Ozren Polasek, Veronique Vitart, Sunita Badola, Alexander N. Parker, Paul M. Ridker, Sharon L. R. Kardia, Stefan Blankenberg, Yongmei Liu, Gary C. Curhan, Andre Franke, Thierry Rochat, Bernhard Paulweber, Inga Prokopenko, Wei Wang, Vilmundur Gudnason, Alan R. Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, Michael G. Shlipak, Cornelia M. van Duijn, Ingrid Borecki, Bernhard K. Krämer, Igor Rudan, Ulf Gyllensten, James F. Wilson, Jacqueline C. Witteman, Peter P. Pramstaller, Rainer Rettig, Nick Hastie, Daniel I. Chasman **,W. H. Kao **, Iris M. Heid ** Caroline S. Fox ** *These co-authors contributed equally to this work **These senior authors jointly oversaw this work 2 TABLE OF CONTENTS 1. Supplementary Note a. Study-specific Methods and Full Acknowledgements Page 3 2. Supplementary Tables a. Supplementary Table 1a: Study Design and Sample sizes Page 21 b. Supplementary Table 1b: Genotyping and Imputation Platforms Page 23 c. Supplementary Table 2: Genome-wide Significant Loci: SNP Imputation Quality in Stage 1 Discovery Cohorts Page 27 d. Supplementary Table 3: Genome-Wide Significant Loci: SNP Association Across Renal Traits in Stage 1 Discovery and Stage 2 Replication Meta-Analyses Page 30 e. Supplementary Table 4: Additional Gene Biology of Novel Loci Page 34 f. Supplementary Table 5: Effect sizes of association with eGFRcrea across strata of diabetes and hypertension Page 37 g. Supplementary Table 6: Expression Associated SNP Analysis Page 39 h. Supplementary Table 7: Additional SNPs associated with eGFRcrea and CKD at an FDR of 0.05 Page 48 3. Reference List Page 49 4. Supplementary Figures a. Supplementary Figure 1: Quantile-quantile plots of observed vs. expected -log10(p-values) from discovery analyses of eGFRcrea (A), CKD (B), and eGFRcys (C). Page 54 b. Supplementary Figure 2: Locus-specific regional association plots for susceptibility loci for reduced renal function and CKD. Page 55 3 Supplementary Note – Study-specific Methods and Full Acknowledgements Discovery Cohorts Age Gene/Environment Susceptibility Reykjavik Study (AGES): The AGES-Reykjavik Study represents a sample drawn from the established prospective population-based cohort, the Reykjavik Study.1 Between 2002 and 2006, the AGES-Reykjavik study re-examined 5764 survivors of the original cohort. Serum creatinine was measured at the Icelandic Heart Association using the Roche-Hitachi P-Module instrument with Roche Creatininase Plus assay. The coefficient of variation (CV) for the creatinine assay was 2.5%. Covariates were obtained at examination. Genotyping was performed at the Molecular Genetics Section and Laboratory of Neurogenetics, NIA, NIH, using using the Illumina 370CNV BeadChip array on 3664 participants. Standard protocols for working with Illumina data were followed, with clustering score greater than 0.4. Amish Studies (Amish): Old Order Amish individuals included in this study were participants of several ongoing studies of cardiovascular health carried out at the University of Maryland. Participants were relatively healthy volunteers from the Old Order Amish community of Lancaster County, Pennsylvania and their family members.2, 3 Study participants were enrolled within the 2000-2008 timeperiod. Serum creatinine was measured using a modified kinetic Jaffé reaction. Cystatin C measured using a particle-enhanced immunonephelometric method BNII, (Dade-Behring). Covariates were obtained at the index examination. Atherosclerosis Risk in Communities Study (ARIC): The ARIC Study is an ongoing prospective population-based cohort study to investigate the etiology of atherosclerosis. The study started in 1987-89 with the enrollment of 15,792 adults aged 45-64 years in four US communities; participants mostly self-identified as black or white.4 Participants for the current 4 study included those with measures of serum creatinine from visits 1, 2 (1990-92), or 4 (1996- 98) for the analyses of eGFRcrea and CKD, and from visit 4 for the analyses of eGFRcys. Serum creatinine was measured using a modified kinetic Jaffé reaction. CKD was defined as cumulative CKD prevalence for individuals with eGFRcrea <60 ml/min/1.73m2 at ARIC visits 1, 2, or 4. Individuals were not counted as CKD cases if CKD at an earlier study exam was not apparent at a later study exam, unless there was also a CKD related hospitalization from continuously collected hospitalization discharge records.5 Serum cystatin C was measured by a particle enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring). Covariates were obtained at the visit from which eGFR was used in analyses. Austrian Stroke Prevention study (ASPS): The Austrian Stroke Prevention study is a single center prospective follow-up study on the effects of vascular risk factors on brain structure and function in the normal elderly population of the city of Graz, Austria. The procedure of recruitment and diagnostic work-up of study participants has been described previously.6, 7 A total of 2007 European Caucasian participants were randomly selected from the official community register stratified by gender and 5 year age groups. Individuals were excluded from the study if they had a history of neuropsychiatric disease, including previous stroke, transient ischemic attacks, and dementia, or an abnormal neurologic examination determined on the basis of a structured clinical interview and a physical and neurologic examination. Since 1992, blood was drawn from all study participants for DNA extraction; covariates were obtained at the index examination. Serum creatinine was measured. Baltimore longitudinal study of Aging (BLSA): The Baltimore Longitudinal Study of Aging (BLSA) is an observational study that began in 1958 to investigate normative aging in community dwelling adults who were healthy at study entry.8 Participants are examined every one to four years depending on their age. Currently there are approximately 1100 active participants enrolled in the study. Serum and urinary creatinine was measured by an enzymatic 5 method using the Vitros 750 analyzer (Johnson & Johnson Co., Rochester, NY). The Modification of Diet in Renal Disease (MDRD) Study equation was used to calculate eGFRcrea. The analysis was restricted to subjects with European ancestry. Each analysis was further adjusted for the top two principal components derived from an EIGENSTRAT analysis utilizing ~10,000 randomly selected SNPs from the 550K SNP panel. Cardiovascular Health Study (CHS): The Cardiovascular Health Study (CHS) is a population- based longitudinal study of risk factors for cardiovascular disease and stroke in adults 65 years of age or older, recruited at four field centers (Forsyth County, NC; Sacramento County, CA; Washington County, MD; Pittsburgh, PA).9 5201 individuals of predominantly European ancestry were recruited in 1989-1990 from random samples of Medicare eligibility lists, followed by an additional 687 African-Americans recruited in 1992-1993 (total n=5888). A total of 1908 persons were excluded from the GWAS study sample due to the presence at study baseline of coronary heart disease, congestive heart failure, peripheral vascular disease, valvular heart disease, stroke or transient ischemic attack or lack of available DNA. African American participants were excluded from this analysis since the other cohorts were predominantly of European ancestry. Using a particle-enhanced immunonephelometric method, Cystatin C was measured (BNII, Dade-Behring). Covariates were obtained at baseline. Erasmus Rucphen Family study (ERF): The Erasmus Rucphen Family (ERF) study is comprised of a family-based cohort embedded in the Genetic Research in Isolated Populations (GRIP) program in the Southwest of the Netherlands. Descriptions of ERF’s design have been previously published.10 Briefly, twenty-two families that had a minimum of five children baptized in the community church between 1850 and 1900 were identified with the help of detailed genealogical records. All living descendants of these couples, and their spouses, were invited to take part in the study. Participants included in the current study total 2079 individuals for whom 6 complete phenotypic and genotypic information was available. Covariates were obtained during the baseline examination. Family Heart Study (FamHS): In 1992, the Family Heart Study began with the ascertainment of 1200 families, half due to excess of coronary heart disease (CHD) or abnormal risk factors as compared with sex- and age-specific population, the other half randomly selected.11 These families, including about 6000 individuals, were sampled from four geographically diverse field centers: the Framingham Heart Study, the Utah Family Tree Study, and two ARIC centers (Minneapolis, and Forsyth County, NC). After about 8 years, a total of 2767 participants of European ancestry in 510 extended pedigrees were invited for a second clinical exam. A two- stage design was used for the GWAS conducted for this study. In the first stage, 1016 individuals chosen to be largely unrelated were selected, half from the highest quartile and half from the lowest quartile of sex- and age-adjusted coronary artery calcification values. The results presented here were derived using the first stage case-control sample. We did not observe association of eGFRcrea with the first ten principal components derived from the GWAS genotypes using Eigenstrat.12 Framingham Heart Study (FHS): In 1948, the Framingham Heart Study began when the Original Cohort was enrolled.13 Beginning in 1971, the Offspring Cohort was enrolled (5124 participants); the methodology and design has been described.14, 15 In 2002, the Third Generation cohort was enrolled (n=4095).16 Participants for the current study include individuals from the original cohort who attended cohort exam 15 (1977 to 1979) or exam 24 (1995 to 1998) [n=2338], as well as participants from the offspring cohort who attended the second exam (1979 - 1983) or the seventh exam (1998-2001) [n=4182], and individuals from the Third Generation first examination (for eGFR only). CKD was defined as cumulative CKD prevalence for individuals with eGFR <60 ml/min/1.73m2 at exam cycle 15 (original cohort) and exam cycle 2 (offspring cohort) for the earlier exams and exam 24 (original cohort) and exam 7 (offspring 7 cohort) for the later exam cycles. Using a particle-enhanced immunonephelometric method, Cystatin C was measured (BNII, Dade-Behring). Covariates were obtained at the index examination. We observed no association with CKD with the 10 principal components estimated using Eigenstrat.12 Significant association between eGFR and the 10 principle components was observed, therefore principle components were included in the analysis for association between genotype and eGFR. KORA Studies (KORA F3 and KORA F4): The KORA surveys for genetic research have been described in detail previously17 and have been initiated as part of the MONICA (Monitoring of Trends of Cardiovascular Diseases) multi-center study. The third KORA survey (KORA S3) is a population-based sample from the general population of the South-German city of Augsburg and surrounding counties, recruited 1994/1995. A subsample consisting of 1644 individuals from this survey with 10-year follow-up (KORA F3) information available was successfully genotyped..The fourth KORA survey (KORA S4) is a sample recruited 1999-2002 independent from KORA S3 using the same platform with the same standard operating procedures and based on the same population. From the sample with a 10-year follow-up (KORA F4), 1814 subjects were available for the GWA analysis. All participants had a German passport and were of European origin. Serum creatinine in KORA F3 and F4 was measured using a modified kinetic Jaffé reaction. Using a particle-enhanced immunonephelometric method, serum cystatin C was measured (BNII, Dade-Behring). Korcula Study (KORCULA): The Korcula Study (KORCULA) is a family-based, cross-sectional study on the Dalmatian island of Korcula.18 Data for participants aged 18 years and over were used for this analysis. Fasting blood samples were collected and over 200 health-related phenotypes and environmental exposures were measured in each individual. Plasma creatinine was measured with the Jaffé rate method. 8 KORCULA, MICROS, NSPHS, ORCADES, and VIS used a polygenic linear model fitted to the residuals of log(eGFRcrea) on age for estimating the inverse of the variance/covariance matrix, which accounts for the inter-individual relatedness and is based upon a genomic kinship matrix19 implemented in GenABEL. Genome-wide association between SNPs and the residuals was assessed by means of an approximate score test statistic20. For CKD, relatedness was accounted for by estimating the first three principal component of the genomic kinship matrix by multidimensional scaling. A genome-wide association scan was performed by means of a logistic regression model adjusted for age, sex, and the first three principal components. Microisolates in South Tyrol Study (MICROS): The MICROS study is part of the genomic health care program 'GenNova' and was carried out in three villages of the Val Venosta, South Tyrol (Italy), in 2001-03. It comprised members of the populations of Stelvio, Vallelunga and Martello. A detailed description of the MICROS study is available elsewhere.21 Information on the participant’s health status was collected through a standardized questionnaire. Laboratory data were obtained from standard blood analyses. Serum creatinine was measured by an enzymatic photometric assay using an ADVIA1650 clinical chemistry analyzer (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany) (PMID 3806017) and cystatin C was measured on a BN-ProSpec analyzer (Dade Behring, Marburg, Germany). Covariates were obtained during the interview phase. For study-specific statistical methods, see above page 8. Northern Swedish Population Health Study (NSPHS): The Northern Swedish Population Health Study (NSPHS) is a family-based study including a comprehensive health investigation and the collection of data on family structure, lifestyle, diet, medical history and of samples for laboratory analyses.22, 23 Participants came from the northern part of the Swedish mountain region (County of Norrbotten, Parish of Karesuando). Historic population accounts show that little migration or other dramatic population changes have occurred in this area over the last 200 years. Plasma creatinine was measured by an enzymatic photometric assay using an 9 ADVIA1650 clinical chemistry analyzer (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany).24 For study-specific statistical methods, see above page 8. Orkney Complex Disease Study (ORCADES): The Orkney Complex Disease Study (ORCADES) is an ongoing family-based, cross-sectional study in the isolated Scottish archipelago of Orkney.25 Genetic diversity in this population is decreased compared to Mainland Scotland, consistent with high levels of historical endogamy. Participants were aged 18-100 years and came from a subgroup of ten islands. Fasting blood samples were collected and over 200 health-related phenotypes and environmental exposures were measured in each individual. Plasma creatinine was measured by an enzymatic photometric assay using an ADVIA1650 clinical chemistry analyzer (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany).24 For study-specific statistical methods, see above page 8. Rotterdam Study I (RSI) and Rotterdam Study II (RSII): The RS is a population-based cohort study aimed at assessing the occurrence of and risk factors for chronic diseases in the elderly. In brief, all inhabitants of Ommoord, a district of Rotterdam in the Netherlands, who were 55 years or older were invited and 7983 (RSI) agreed to participate (78% response rate).26-28 The baseline visits took place between 1990-1993. In 1999, inhabitants who turned 55 years of age or moved into the study district since the start of the study were invited (RSII) of whom 3011 participated (67% response rate). Serum creatinine was assessed by a nonkinetic alkaline picrate (Jaffé) method (Kone Autoanalyzer; Kone Corp, Espoo, Finland, and Elan; Merck, Darmstadt, Germany). Covariates were obtained at baseline. Diabetes was defined as use of antidiabetes medication or abnormal nonfasting glucose or an abnormal oral glucose tolerance test. A nonfasting or post load glucose level 11.1 mmol/l was considered abnormal. Study of Health in Pomerania (SHIP): The Study of Health in Pomerania (SHIP) is a longitudinal population-based cohort study conducted in West Pomerania, the north-east area of 10 Germany.29 For the baseline examinations, a sample of 6267 eligible subjects aged 20 to 79 years was drawn from population registries. Only individuals with German citizenship and main residency in the study area were included. Baseline examinations were conducted between 1997 and 2001. Between 2002 and 2006 all participants were re-invited for an examination follow-up, in which 3300 subjects (83.5% of eligible persons) took part.29 Serum creatinine levels were determined according to the Jaffè method. Serum cystatin C levels were measured using the Siemens N Latex Cystatin C assay, a particle-enhanced nephelometric immunoassay, on the BN ProSpec® System. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Caché (InterSystems). Vis Study (VIS): The Vis Study (VIS) is a family-based, cross-sectional study on the Dalmatian island of Vis.30, 31 Data for participants aged 18 years and over were used for this analysis. Fasting blood samples were collected and over 200 health-related phenotypes and environmental exposures were measured in each individual. Serum creatinine was measured by an enzymatic photometric assay using an ADVIA1650 clinical chemistry analyzer (Siemens Healthcare Diagnostics GmbH, Eschborn, Germany). For study-specific statistical methods, see above page 8. Women’s Genome Health Study (WGHS): The Women’s Genome Health Study (WGHS) is a prospective cohort of female North American health care professionals representing participants in the Women’s Health Study (WHS) who provided a blood sample at baseline and consent for blood-based analyses.32 Participants in the WHS were 45 or older at enrollment and free of cardiovascular disease, cancer or other major chronic illness. Serum creatinine was measured in the baseline blood sample.32 Covariates were assessed at the index examination. The current data are derived from 22,054 WGHS participants for whom whole genome genotype information was available at the time of analysis and self-reported European ancestry could be 11 confirmed by multidimensional scaling analysis of 1443 ancestry informative markers in PLINK v. 1.06.33 In silico Replication Cohorts ARIC: Additional genotype data became available on 949 self-reported white ARIC participants over the course of this study. These individuals were not part of the discovery samples, did not have a first-degree relationship with any individual in the discovery sample, nor would they have been classified as an outlier based on allele sharing measures applied in data cleaning of the discovery sample. Family Heart Study: In the replication stage, 1753 family members with self-reported white ancestry are used for replication; 1486 and 249 participants were genotyped. We used field centers in regression models to account for potential population stratification. GENOA: The GENOA study of the Family Blood Pressure Program (FBPP) was initiated between 1995-2000 to identify genetic determinants of hypertension in multiple ethnic groups.34, 35 In Rochester, MN, the Mayo Clinic diagnostic index and medical record linkage system of the Rochester Epidemiology Project were used to identify non-Hispanic white (NHW) residents of Olmsted County with a diagnosis of essential hypertension made before age 60.36 Sibships in which either index hypertensive sibling was known to have impaired kidney function (e.g., serum creatinine 2.0 mg/dL) were not recruited, as impaired kidney function may cause secondary hypertension. A second stage of the FBPP was undertaken between 2000-2005 to identify genetic determinants of susceptibility to cardiac and renal complications of hypertension, consisting of 1239 whites in Rochester (76.6%), and 28 siblings of Rochester participants underwent an examination. Serum creatinine was measured using a modified kinetic Jaffé reaction. Covariates were obtained at the second stage examination. 12 Gutenberg Heart Study: The Gutenberg Heart Study began in 2007 as a community-based prospective study with participants ranging in age from 35 to 74 years. All participants have been drawn randomly from the local registry offices in the city of Mainz and the district of Mainz- Bingen. The present analysis was based on an initial sample of 3,500 subjects successively enrolled into the GHS from April 2007 to April 2008. Genomic DNA was isolated from all participants. Serum creatinine was measured in Heparin-Plasma using the Jaffe reaction method (Abbott Diagnostics; Delkenheim, Germany). Genotyping, imputation, and the statistical analysis were performed as indicated in Supplemental Table 1. Health ABC: The Health ABC Study is a community-based prospective cohort study that began in 1997, consisting of 3075 men and women in the original cohort. Participants of the cohort were recruited from Medicare listings in Pittsburgh, Pennsylvania and Memphis, Tennessee. Eligibility criteria included age 70–79 years, self-report of no difficulty walking one-quarter mile or climbing 10 steps, or with activities of daily living, no history of active treatment for cancer in the prior 3 years, and no plan to move out of the area. These analyses included only those Health ABC participants who reported their race/ethnicity as European-American. Serum creatinine was measured using a modified kinetic Jaffé reaction; serum cystatin C was measured using particle-enhanced immunonephelometric method (BNII, Dade-Behring). Covariates were obtained at baseline. Genomic DNA was extracted from buffy coat collected using PUREGENE® DNA Purification Kit during the baseline exam. In 2009, genotyping was performed by the Center for Inherited Disease Research (CIDR). Nurses Health Study/Health Professionals Follow-up Study (NHS/HPFS): The NHS was established in 1976 when 121,700 female registered nurses aged 30-55 years and residing in 11 large U.S. states completed a mailed questionnaire on their medical history and lifestyle characteristics.37 Every two years, follow-up questionnaires have been sent to update information on exposures and newly diagnosed illnesses. The HPFS was initiated in 1986 when 13 51,529 male U.S. health professionals aged 40-75 and residing in 50 U.S. states answered a detailed questionnaire that included a comprehensive diet survey, and items on lifestyle practice and medical history.38 The cohort is followed through biennial mailed questionnaire. Blood was collected from 32,826 NHS members between 1989 and 1990 and from 18,159 HPFS members between 1993 and 1999. Creatinine measures were performed on the samples from 1194 women and 1000 men with diabetes. Diabetes was defined as initially self-reported diabetes subsequently confirmed by a validated supplementary questionnaire.39, 40 Between 2008 and 2009, a subset of these men and women were genotyped as part of a GWAS of type 2 diabetes. Plasma creatinine was measured by a modified kinetic Jaffé reaction. Covariates were obtained from the questionnaire administered closest to the time creatinine was measured (1990 for NHS and 1994 for HPFS). Standardized protocols for the NHS and HPFS genome-wide scans were developed as part of the GENEVA consortium. In the initial GWAS, NHS (N=3529) and HPFS (N=2668) samples were genotyped approximately two months apart and underwent independent QC. POPGen: Using the POPGen biobank, data on healthy control individuals from Germany were obtained.41 As part of the GWAS initiative of the German National Genome Research Network (NGFN), genotyping was performed. Serum creatinine was measured with an enzymatic in vitro assay (CREAplus, Cobas®, Roche Diagnostics, Indianapolis, IN). SORBS: All participants are part of a sample from an extensively phenotyped self-contained population from Eastern Germany, the Sorbs.42 Sampling comprised unrelated subjects as well as families; 888 participants were available for the present study. Serum creatinine was measured using a kinetic enzymatic method (Roche Inc). Covariates were obtained at the index examination. Adjustment for genomic control was used to control for increased genetic sharing due to long term isolation of this population. 14 SPLIT: The Split Study (SPLIT) is a population-based, cross-sectional study in the Dalmatian city of Split. Data for participants aged 18 years and over were used for this analysis. Fasting blood samples were collected and over 200 health-related phenotypes and environmental exposures were measured in each individual. Serum creatinine was measured using the photometric Jaffé method. De novo genotyped replication cohorts Genotyping methods of these four cohorts are described above (Replication Analysis). KORA F3/F4: The subjects of KORA F3 and KORA F4 who had not been genotyped genome wide as described under “discovery cohorts” were used as replication samples including 1498 and 1202 subjects from KORA F3 and F4, respectively. Covariates were obtained at the index examination. In KORA F3, the mean call rate was 99.4%, the concordance among samples genotyped in duplicate across SNPs was 99.1%. In KORA F4, the mean call rate was 99.1%, the concordance among samples genotyped in duplicate across SNPs was 100%. SAPALDIA: The SAPALDIA study was originally designed to investigate the effects of air pollutants on respiratory health in a random sample of the adult population of Switzerland.43, 44 The original study consisted of 9651 adults as described elsewhere.43 Of the surviving 9368 participants, 93% (n = 8715) could be traced between 2001 and 2003, and were re-contacted for SAPALDIA 2.44 In the second survey, there was additionally a collection of blood specimens for analysis of blood and DNA markers.44 Included in this study are subjects with blood and DNA samples available (n=6031) who had consented to the general blood marker and DNA analyses. Blood samples were processed and stored in a standardized fashion according to the SAPALDIA protocol.44 Serum creatinine was measured using the Jaffé reaction (Roche) and calibrated to the Roche enzymatic gold standard reference. DNA was extracted as previously 15 described.44 The mean call rate was 98.0%, the concordance among samples genotyped in duplicate across SNPs was 98.1%. SAPHIR Study: The "Salzburg Atherosclerosis Prevention Program in subjects at High Individual Risk" (SAPHIR) is an observational study conducted in the years 1999-2002 involving healthy unrelated subjects: 641 females from 39 to 67 years of age and 1092 males from 39 to 66 years of age. Study participants were recruited by health screening programs in large companies in and around the city of Salzburg as described recently.45 All individuals were of West-European origin. Participants with established coronary artery, cerebrovascular or peripheral arterial disease, congestive heart failure, valvular heart disease, chronic alcohol (more than three drinks a day) or drug abuse, severe obesity (BMI>40 kg/m ) and pregnant women were excluded. Serum creatinine (mg/dl) was measured using a modified kinetic Jaffé reaction (CREA , Roche Diagnostics GmbH, Mannheim, Germany). Among the total of 1733 phenotyped participants, a total of 1733 had eGFR and genotype information, and 1733 had CKD status and genotype data. However, there were too few cases with CKD (n=19) to warrant analysis of this trait. Covariates were obtained at the index examination. The mean call rate was 98.7%, the concordance among samples genotyped in duplicate across SNPs was 99.1%. 16 Supplementary Note – Full Acknowledgements Discovery Cohorts AGES: We thank all participants in the study and the study staff for their invaluable contribution. The Age, Gene/Environment Susceptibility Reykjavik Study has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). AMISH: The Amish studies are supported by grants and contracts from the NIH including R01 AG18728 (Amish Longevity Study), R01 HL088119 (Amish Calcification Study), U01 GM074518-04 (PAPI Study), U01 HL072515-06 (HAPI Study), U01 HL084756 and NIH K12RR023250 (University of Maryland MCRDP), NIH P30 DK072488 (Clinical Nutrition Research Unit of Maryland) and NIH P60 DK079637 DRTC (Baltimore Diabetes Research and Training Center), the University of Maryland General Clinical Research Center, grant M01 RR 16500, the Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center and the Paul Beeson Physician Faculty Scholars in Aging Program. We thank our Amish research volunteers for their long-standing partnership in research, and the research staff at the Amish Research Clinic for their hard work and dedication. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. ASPS: The research reported from the Austrian Stroke Prevention study (ASPS) in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. The authors thank the staff and the participants of the ASPS for their valuable contributions. We thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler and Irmgard Poelzl for the technical assistance at creating the DNA-bank. BLSA: The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. CHARGe Consortium: We acknowledge the individual participating studies and investigators of the CHARGe (Cohorts for Heart and Aging Research in Genome Epidemiology) consortium (AGES, ARIC, CHS, Framingham Heart Study, Rotterdam Study). CHS: The CHS research reported in this article was supported by contract numbers N01-HC- 85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC- 75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652, and R01 AG027002 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was 17 supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. ERF: The ERF study was supported by grants from The Netherlands Organisation for Scientific Research, Erasmus MC and the Centre for Medical Systems Biology (CMSB). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. Family Heart Study: This research was conducted in part using data and resources from the NHLBI Family Heart Study supported in part by NIH grant 5R01HL08770002. Framingham Heart Study: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC- 25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. KORA: The genetic epidemiological work was funded by the NIH subcontract from the Children’s Hospital, Boston, US, (H.E.W., I.M.H, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.W. 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (H.E.W.), and by the Else Kröner-Fresenius Stiftung (P48/08//A11/08; C.A.B., B.K.K.). The kidney parameter measurements in F3 were funded by the Else Kröner-Fresenius Stiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W.K.). Genome wide genotyping costs in F3 and F4 were in part funded by the Else Kröner- Fresenius-Stiftung (C.A.B., B.K.K.). Denovo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Research Center München for Environmental Health, by the German Federal Ministry of Education and Research and the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computations were funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center. KORCULA: The Korcula study in the Croatian island of Vis was supported through the grants from the Medical Research Council UK to H.C., A.F.W. and I.R.; and Ministry of Science, Education and Sport of the Republic of Croatia to I.R. (number 108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh (Rosa Bisset) and the people of Korcula. MICROS: We owe a debt of gratitude to all participants. We thank the primary care practitioners Raffaela Stocker, Stefan Waldner, Toni Pizzecco, Josef Plangger, Ugo Marcadent 18 and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. We thank Dr. Peter Riegler (Hemodialysis Unit, Hospital of Merano) for the important discussions. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006- 018947). NSPHS: The Northern Swedish Population Health Study was supported by grants from the Swedish Natural Sciences Research Council, the European Union through the EUROSPAN project (contract no. LSHG-CT-2006-018947), the Foundation for Strategic Research (SSF) and the Linneaus Centre for Bioinformatics (LCB). We are also grateful for the contribution of samples from the Medical Biobank in Umeå and for the contribution of the district nurse Svea Hennix in the Karesuando study. ORCADES: ORCADES was supported by the the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson, the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. ROTTERDAM STUDY: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research; The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. The genome-wide association database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr. 175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank Michael Moorhouse, PhD, Department of Bioinformatics, and Pascal Arp, BSc, Mila Jhamai, BSc, Marijn Verkerk, BSc, and Sander Bervoets, BSc, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands, for their help in creating the database. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. VIS: The Vis study in the Croatian island of Vis was supported through the grants from the Medical Research Council UK to H.C., A.F.W. and I.R.; and Ministry of Science, Education and Sport of the Republic of Croatia to I.R. (number 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). We would like to acknowledge the invaluable contributions of the recruitment team (including those from the 19 Institute of Anthropological Research in Zagreb) in Vis, the administrative teams in Croatia and Edinburgh (Rosa Bisset) and the people of Vis. WGHS: The WGHS is supported by HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. Replication Cohorts GENOA: This research was conducted in part using data and resources from the Genetic Epidemiology Network of Atherosclerosis (GENOA) study. The analyses reflect intellectual input and resource development from the GENOA study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute grant (HL-87660) and its contract with Mayo Clinic College of Medicine for genotyping services and statistical analyses. GUTENBERG HEART STUDY: The Gutenberg Heart Study is funded through the government of Rheinland-Pfalz (“Stiftung Rheinland Pfalz für Innovation”, contract number AZ 961- 386261/733), the research programs “Wissen schafft Zukunft” and “Schwerpunkt Vaskuläre Prävention” of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems including an unrestricted grant for the Gutenberg Heart Study. Specifically, the research reported in this article was supported by the National Genome Network “NGFNplus” (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany. HEALTH ABC: This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging NHS/HPFS: The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease”(HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845, R01DK066574). M.C.C is a 20 recipient of a Canadian Institutes of Health Research Fellowship. We thank the staff and participants of the NHS and HPFS for their dedication and commitment. POPGen: The POPGen study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN). It is currently funded by the Ministry of Science, Commerce and Transportation of the State of Schleswig- Holstein. The project has also received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces”. SAPALDIA: The SAPALDIA cohort study is supported by the Swiss National Science Foundation (grants 4026-28099, 3347CO-108796, 3247BO-104283, 3247BO-104288, 3247BO- 104284, 32-65896.01, 32-59302.99, 32-52720.97, 32-4253.94), the Federal Office for Forest, Environment and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the Canton's Government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Zürich, the Swiss Lung League, the Canton's Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino and Zürich. De novo genotyping was in part contributed to by the NHLBI Intra-mural research program and the Center for Population Studies, and by the Else Kröner-Fresenius-Stiftung (P48/08//A11/08; C.A.B., B.K.K.). SAPHIR: The SAPHIR-study was partially supported by a grant from the Kamillo Eisner Stiftung to B. Paulweber and by grants from the "Genomics of Lipid-associated Disorders – GOLD" of the "Austrian Genome Research Programme GEN-AU" to F. Kronenberg. De novo genotyping was in part contributed to by the NHLBI Intra-mural research program and the Center for Population Studies, and by the Else Kröner-Fresenius-Stiftung (P48/08//A11/08; C.A.B., B.K.K.). SORBS: This work was supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to M.S., P.K. and A.T.; N06 to P.K.) and from the German Diabetes Association (to A.T. and P.K.). MS is supported by a grant from the DFG (KFO 152). We would like to thank Knut Krohn from the Microarray Core Facility of the Interdisciplinary Centre for Clinical Research (IZKF), University of Leipzig, Germany, Nigel William Rayner from the Wellcome Trust Centre for Human Genetics, University of Oxford, UK and John Broxholm from the Bioinformatics Core Unit of the Wellcome Trust Centre for Human Genetics for their excellent support. The research of Inga Prokopenko and Reedik Magi is funded in part through the European Community's Seventh Framework Programme (FP7/2007- 2013), ENGAGE project, grant agreement HEALTH-F4-2007- 201413. SPLIT: The Split study in the Croatian city of Split was supported through the grants from the Medical Research Council UK to H.C., A.F.W. and I.R.; and Ministry of Science, Education and Sport of the Republic of Croatia to I.R. (number 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). We would like to acknowledge the invaluable contributions of the recruitment team from the Croatian Centre for Global Health, University of Split, the administrative teams in Croatia and Edinburgh (Rosa Bisset) and the people of Split. 21 Supplementary Table 1a- Study Design and Sample sizes Study design Overall sample size Analyzed sample size eGFRcrea / CKD/ eGFRcys Stage 1 discovery AGES Population-based prospective 5764 3,219 / 3,219/NA Amish Amish founder "healthy"population 1611 1211 / NA/ 783 ARIC Population-based 15792 8069/8069/6430 ASPS Community-based prospective longitudinal 2007 850/850/NA BLSA Prospective population-based cohort 848 723 / 723 / NA CHS Population-based 5888 3259 / 3259 / 2820 ERF Cross-sectional population- based study with pedigree information 2313 2079 / 2079 / NA Family Heart Study Case-Control 2756 883 / 883 / NA Framingham Heart Study Community-based family multi-generation 6520 7782 / 4140 / 2992 KORA F3 General population, unrelated, age-range 35- 84yrs 3006 1641 / 1641 / 1642 KORA F4 General population, unrelated, age 32-81 yrs 3080 1814 / 1814 / 1811 Korcula Croatia Cross-sectional population- based study with pedigree information 909 888 / 888 / NA MICROS Cross-sectional population- based study with pedigree information 1287 1201 / 1201/ 1248 NSPHS Cross-sectional population- based study with pedigree information 720 565 / 565 / NA ORCADES Cross-sectional population- based study with pedigree information 1019 704 / 704 / NA RS 1 Population-based 6239 4390/4390/NA RS2 Population-based 2020 1863 / 1863 / NA SHIP Population-based 3300 3231 / 3228/ 3231 Vis Croatia Cross-sectional population- based study with pedigree information 795 768 / 768 / NA WGHS Population-based, women only 22054 21953 / 21953 / NA Stage 2 replication, in silico ARIC* Population-based 15792 944/944/751 Family Heart Study* Family-based cohort 2756 1537/1537/NA GENOA Community-based sibships 1605 1056/1056/NA Gutenberg Heart Study Community-based Prospective Cohort 5000 3180/3180/NA Health ABC Population-based elderly cohort 1663 1663/1663/1663 22 HPFS Health Professional –based cohort study 51,529 818/818/X Nurses Health Study Health Professional –based cohort study 121,700 786/786/NA Popgen Population-based biobank 1241 1163/1163/NA Sorbs Self-contained population 1047 888/888/NA SPLIT Community-based cohort 499 479/NA/NA Stage 2 replication, de novo genotyped KORA F3* General population, unrelated, age-range 35- 84yrs 3006 1498/1498/1498 KORA F4* General population, unrelated, age 32-81 yrs 3080 1202/1202/1202 SAPALDIA Random Sample, Switzerland 9651 6031/6031/NA SAPHIR Health Working Cohort 1733 1733/1733/NA * subjects independent from subjects contributing to discovery analyses 23 Supplementary Table 1b - Genotyping and Imputation Platforms Array type Genotype calling QC filters for genotyped SNPs used for imputation # SNPs used for imputati on Imputation Imputation Backbone for phased CEU haplotypes (NCBI build) Filtering of imputed genotypes Data management and statistical analysis Stage 1: Discovery AGES Illumina 370CNV BeadStudio call rate <97%, MAF <1%, pHWE <1e-6, Mishap p <1e-9, A/T and G/C SNPs, Mismatches between Illumina, dbSNP and/or HapMap position 308,340 MACH v1.0.16 HapMap release 22 (build 36) none PLINK, R Amish Affymetrix 500K BRLMM call rate <95%, MAF <1%, pHWE <1e-6, SNPs not in HapMap 338,598 MACH v1.0.15 HapMap release 22 (build 36) MAPP, mixed model to account for relatedness ARIC Affymetrix 6.0 Birdseed call rate <95%, MAF<1%, pHWE<10E-5 602,642 MACH v1.0.16 HapMap release 21 (build 35) none ProbABEL, PLINK, R ASPS Illumina Human610- Quad BeadChip® BeadStudio call rate <98%, pHWE<10E-6 550,635 MACH v1.0.15 HapMap release 22 (build 36) none ProbABEL BLSA Illumina HumanHap 550K Beadstudio call rate <99%, MAF <1%, pHWE <10E-4 501,764 MACH v1.0.15 HapMap release 21 (build 35) MAF<1%, r <0.3 SAS,MERLIN (fastAssoc option),R CHS Illumina 370CNV BeadStudio call rate <97%, heterozygotes=0, pHWE<10E-5, SNP not in HapMap 306,655 BimBam HapMap release 21A (build 36) dosage variance <0.01 R, robust variance option ERF Illumina, 300K Illumina MAF 1% , pHWE 1e-6 , call rate 98% 460,584 MACH v1.0.15 HapMap release 22 (build 36) none R, GenABEL , ProbABEL, GC correction to account for relatedness Family Heart Study Illumina550 K BeadStudio- Gencall v3.0 call rate <98%, MAF <1%, pHWE<10E-6 456,293 MACH v1.0.15 HapMap release 22 (build 36) none SAS, linear mixed effect and logistic models Framingham Heart Study Affymetrix 500K Affymetrix 50K supplement al Affymetrix pHWE<1e-6, call rate<97%, mishap p<1e-9, MAF<0.01, Mendelian errors>100, SNPs not in Hapmap or strandedness issues merging with Hapmap 378,163 MACH v1.0.15 HapMap release 22 (build 36) none R, linear mixed effect models and GEE models, robust variance option to account for relatedness 24 KORA F3 Affymetrix 500K BRLMM per-chip call rate <93%, MAF <5%, discrepancy for one of the 50 SNPs common on both chips, gender checks 380,407 MACH HapMap release 22, (build 35) none MACH2QTL, ProbABEL, R, Visual basic KORA F4 Affymetrix 6.0 BRLMM per-chip call rate <93%, per-SNP call rate <93%, MAF<1%, gender checks 629,893 MACH HapMap release 22, (build 36) none ProbABEL, R, Visual basic Korcula Illumina, 370K Beadstudio call rate <98%, MAF < 1%, pHWE<10E-6 317,896 MACH v1.0.16 HapMap release 22 (build 36) none R , ProbABLE MICROS Illumina, 300K Beadstudio call rate <98%, MAF < 1%, pHWE<10E-6 292,917 MACH v1.0.16 HapMap release 22 (build 36) none R, GenABEL, ProbABEL; details in Study-Specific Methods NSPHS Illumina, 300K Beadstudio MAF 1%, pHWE 1e-6 , call rate 98% 318,049 MACH v1.0.15 HapMap release 22 (build 36) none R, GenABEL, ProbABEL; details in Study-Specific Methods ORCADES Illumina, 300K Beadstudio MAF 1%, pHWE 1e-6 , call rate 98% 306,207 MACH v1.0.15 HapMap release 22 (build 36) none R, GenABEL, ProbABEL; details in Study-Specific Methods RS-I, RS-II Illumina 550K Beadstudio call rate <90%, MAF<1%, pHWE<10E-5 530,683 MACH v1.0.15 HapMap release 22 (build 36) none Linear and logistic regression using ProbABEL, R SHIP Affymetrix 6.0 Birdseed V2 per-chip call rate <92% 869,224 IMPUTE v0.5.0 HapMap release 22 (build 36) none SNPTEST v1.1.5, QUICKTEST v0.94 Vis Illumina, 300K Beadstudio MAF 1% , pHWE 1e-6 , call rate 98% 305,068 MACH v1.0.15 HapMap release 22 (build 36) none R, GenABEL, ProbABEL; details in Study-Specific Methods WGHS Illumina HumanHap 300 Duo "+" BeadStudio 3.3 call rate < 98% on SNPs; pHWE < 10-6 317,186 MACH HapMap release 21 (build 35), SNP positions updated to build 36 none R, ProbABEL, bash scripting Array type Genotype calling QC filters for genotyped SNPs used for imputation # SNPs used for imputati on Imputation Imputation Backbone (NCBI build) Filtering of imputed genotypes Data management and statistical analysis Stage 2: in silico replication ARIC* Affymetrix 6.0 Birdseed call rate <95%, MAF<1%, pHWE <10E-5 669,450 MACH v1.0.16 HapMap release 22 (build 36) none ProbABEL, PLINK, R 25 Family Heart Study* Illumina Human 1M GenomeStudio call rate <97%, MAF< 1%, pHWE <10E-6 682,874 MACH v1.0.16 HapMap release 22 (build 36) none SAS, linear mixed effect models GENOA Affymetrix 6.0 Birdseed v2 call rate < 95%, pHWE <10E-6 MACH v1.0.16 HapMap release 22 (build 36) none PLINK; linear mixed models (R multic); GEE models (R gee glm); robust variance option to account for relatedness Gutenberg Heart Study Affymetrix 6.0 Birdseed v2 call rate <98%, maf <1%, pHWE <10E-4 608,203 IMPUTE v1.0.0 HapMap release 22 (build 36) none R Health ABC Illumina Human1M- Duo Illumina BeadStudio call rate < 97%, HWE p<10E-06, MAF<1% 914,263 MACH v1.0.16 Hapmap release 22 build 36 none R HPFS Affymetrix 6.0 Birdseed call rate <97%, pHWE<10E-4, MAF<2%, >1 discordance/29 replicates, significant plate associations 607,569 MACH v1.0.15 HapMap release 22 (build 36) none ProbABEL (R), SAS 9.0 Nurses Health Study Affymetrix 6.0 Birdseed call rate <97%, pHWE <10E-4, MAF <2%, >1 discordance/12 replicates, significant plate associations 606,626 MACH v1.0.15 HapMap release 22 (build 36) none ProbABEL (R), SAS 9.0 popgen Affymetrix 6.0 Birdseed v2 per-person-call rate <0.90, per-SNP call rate <0.95, pHWE<10E-4, MAF <1% 709,003 MACH v1.0.16 HapMap release 22 (build 36) none PLINK, R Sorbs 500K Affymetrix, Affymetrix 6.0 BRLMM; Birdseed call rate <95%, pHWE<10E-4, MAF 1% 378,513 IMPUTE HapMap release 21 (build 35) Proper- info>0.4, MAF>1%, HWE<10-4 SNPTEST, GC correction to account for relatedness SPLIT Illumina 370CNV Illumina GenTrain Algorithm call rate <98%, pHWE<1E-10 NA NA NA NA R, GenAbel Genotypin g platform Quality control of genotyped SNPs # SNPs genotype d Data management and statistical analysis Stage 2: De novo genotyping replication KORA F3* Sequenom, TaqMan mean call rate 99.4%, concordance of duplicates 99.1%, pHWE > 0.05 22 NA NA NA ProbABEL (R) 26 KORA F4* Sequenom, TaqMan mean call rate 99.1%, concordance of duplicates 100%, pHWE > 0.05 22 NA NA NA ProbABEL (R) SAPALDIA Sequenom, TaqMan mean call rate 98.0%, concordance of duplicates 98.1%, pHWE > 0.001 22 NA NA NA ProbABEL (R) SAPHIR Sequenom, TaqMan mean call rate 98.7%, concordance of duplicates 99.1%, pHWE > 0.05 22 NA NA NA SAS 9.1.3. * subjects independent from subjects contributing to discovery analyses 27 Supplementary Table 2- Genome-wide Significant Loci: SNP Imputation Quality in Stage 1 Discovery Cohorts. Study rs16864170 (CKD) rs1933182 rs267734 rs1260326 rs13538 rs7422339 rs347685 rs17319721 rs11959928 rs6420094 rs881858 AGES 0.99 0.96 0.99 1.00 0.94 0.79 1.00 0.99 0.97 1.00 0.87 Amish 1.00 0.98 1.00 0.96 0.95 0.50 1.00 0.99 0.81 0.37 0.66 ARIC 0.99 0.99 1.00 0.98 1.00 0.66 1.00 1.00 0.98 0.61 0.95 ASPS 0.99 0.98 0.97 1.00 1.00 0.80 1.00 0.98 0.98 1.00 0.75 BLSA 0.96 0.98 0.99 0.96 0.98 0.60 1.00 0.99 0.97 0.99 0.89 CHS 0.51 0.80 0.95 1.01 0.45 0.23 1.02 0.74 0.87 0.99 0.83 ERF 0.94 0.97 0.98 0.98 0.94 0.81 1.00 0.99 0.95 0.95 0.77 FamHS 0.99 0.96 0.49 0.98 0.91 0.80 0.95 1.07 1.00 1.03 0.92 FHS 0.92 1.00 0.98 0.99 0.99 0.99 1.03 1.01 0.99 0.48 0.69 KORA F3 0.88 1.00 1.00 0.96 0.95 0.54 1.00 0.96 0.89 0.51 0.73 KORA F4 0.98 0.97 1.00 0.96 0.98 0.60 1.00 1.00 0.93 0.62 0.93 Korcula 0.97 0.94 0.99 0.99 0.99 0.82 1.00 0.95 0.93 1.00 0.69 Micros 0.83 0.94 0.99 0.95 0.91 0.74 1.00 0.97 0.95 0.99 0.85 Orcades 0.98 0.98 1.00 0.96 0.89 0.78 0.99 0.97 0.96 1.00 0.80 RS-1 0.98 0.98 0.99 0.96 0.99 0.82 1.00 0.99 0.98 1.00 0.88 RS-11 0.99 0.99 1.04 1.00 1.00 0.78 0.98 0.98 0.99 0.98 0.91 NHSPH 0.77 0.97 1.00 0.99 0.88 0.82 1.00 0.94 0.95 1.00 0.89 SHIP 0.98 0.99 1.00 0.99 0.99 0.88 1.00 1.00 0.99 0.70 0.95 Vis 0.98 0.96 0.94 0.96 0.91 0.76 0.99 0.96 0.95 0.99 0.84 WGHS 0.90 0.94 0.97 0.97 0.72 0.99 1.00 0.91 0.92 1.00 0.86 median imputation quality 0.98 0.97 0.99 0.98 0.95 0.78 1.00 0.98 0.96 0.99 0.86 28 Study rs2279463 rs6465825 rs7805747 rs10109414 rs4744712 rs10794720 rs4014195 rs10774021 rs626277 rs2453533 AGES 0.99 1.00 0.53 0.99 1.00 0.99 1.00 1.00 0.99 1.00 Amish 0.98 0.92 0.44 0.88 0.95 0.98 0.93 0.83 0.46 0.98 ARIC 0.99 0.99 0.57 0.99 1.00 1.00 0.99 0.98 0.99 1.00 ASPS 1.00 1.00 0.94 0.99 1.00 1.00 0.99 1.00 1.00 1.00 BLSA 0.99 1.00 0.93 0.99 1.00 1.00 0.99 1.00 1.00 1.00 CHS 0.95 0.96 0.43 0.85 0.96 1.01 0.96 1.01 0.98 0.95 ERF 0.96 1.00 0.56 0.99 1.00 1.00 1.00 0.98 0.99 1.00 FamHS 1.00 0.95 0.94 0.97 0.94 1.04 0.42 1.00 0.98 1.00 FHS 1.01 1.00 0.50 0.99 1.00 0.99 0.99 0.94 0.78 0.98 KORA F3 0.95 0.98 0.54 1.00 1.00 1.00 0.99 0.84 0.58 1.00 KORA F4 0.98 0.97 0.52 0.98 0.98 1.00 1.00 0.92 1.00 0.99 Korcula 0.97 1.00 0.52 0.97 0.99 1.00 0.98 1.00 1.00 1.00 Micros 0.98 1.00 0.56 0.99 1.00 0.99 0.99 1.00 0.99 1.00 Orcades 0.97 1.00 0.60 1.00 1.00 1.00 0.97 1.00 1.00 1.00 RS-1 0.99 1.00 0.92 0.99 1.00 1.00 1.00 1.00 1.00 1.00 RS-11 1.02 1.04 0.95 0.99 1.00 1.01 1.02 1.00 1.01 0.98 NHSPH 0.97 1.00 0.43 0.98 0.99 0.99 0.98 1.00 0.99 1.00 SHIP 0.97 0.99 0.51 1.00 0.99 1.00 1.00 0.96 1.00 1.00 Vis 0.96 1.00 0.51 0.99 1.00 0.97 0.96 1.00 1.00 1.00 WGHS 0.99 1.00 0.99 0.91 0.99 1.00 0.98 1.00 1.00 0.97 median imputation quality 0.98 1.00 0.55 0.99 1.00 1.00 0.99 1.00 1.00 1.00 29 Study rs491567 rs1394125 rs12917707 rs9895661 rs12460876 eGFRcys: rs653178 AGES 1.00 0.97 0.98 0.79 1.00 1.00 Amish 0.91 0.56 0.90 0.65 0.81 0.50 ARIC 0.99 0.68 0.94 1.00 0.99 0.99 ASPS 0.99 0.96 0.96 0.86 1.00 1.00 BLSA 1.00 0.94 0.96 0.99 0.99 1.00 CHS 0.92 1.01 0.96 0.68 0.87 1.05 ERF 0.99 0.91 0.89 0.72 0.98 1.00 FamHS 0.93 0.95 1.03 0.97 0.96 1.00 FHS 1.00 0.71 0.96 0.70 0.98 0.99 KORA F3 1.00 0.54 0.86 0.70 0.93 0.79 KORA F4 0.99 0.67 0.87 1.00 0.94 1.00 Korcula 0.99 0.96 0.96 0.84 0.98 1.00 Micros 0.98 0.95 0.95 0.72 0.98 1.00 Orcades 0.98 0.95 0.98 0.72 0.99 1.00 RS-1 1.00 0.94 0.98 1.00 1.00 1.00 RS-11 1.01 0.96 0.94 1.00 1.02 1.00 NHSPH 0.99 0.98 0.91 0.81 0.93 1.00 SHIP 0.99 0.79 0.99 1.00 0.98 1.00 Vis 0.99 0.96 0.92 0.75 0.97 1.00 WGHS 0.98 0.99 0.95 0.80 0.95 1.00 median imputation quality 0.99 0.95 0.95 0.81 0.98 1.00 30 Supplementary Table 3 - Genome-Wide Significant Loci: SNP Association Across Renal Traits in Stage 1 Discovery and Stage 2 Replication Meta-Analyses. eGFRcrea (n=67093), CKD (n=62237) or eGFRcys (n=20907) Chr position (b36) Genes Nearby modeled allele# eGFRcre a beta eGFRcrea SE p-value eGFRcrea beta eGFRcrea SE 1-sided p- value Renal Function Loci, Association with eGFRcrea Discovery Replication rs1933182 1 109801361 SYPL2;ATXN7L2,CYB561D 1,PSMA5,AMIGO1,SORT1 a -0.008 0.001 1.3E-08 -0.002 0.002 1.9E-01 rs267734 1 149218101 ANXA9;FAM63A,PRUNE,B NIPL,LASS2,SETDB1 c 0.010 0.002 5.2E-09 0.008 0.002 1.1E-04 rs16864170 (CKD) 2 5825331 SOX11 c -0.011 0.003 6.9E-04 0.000 0.004 4.8E-01 rs1260326 2 27584444 GCKR;IFT172,FNDC4 t 0.009 0.001 1.3E-10 0.007 0.002 1.1E-04 rs13538 2 73721836 NAT8;NAT8B,ALMS1 g 0.009 0.002 2.6E-08 0.010 0.002 7.2E-07 rs347685 3 143289827 TFDP2 c 0.009 0.001 7.0E-09 0.006 0.002 1.4E-03 rs11959928 5 39432889 DAB2;C9 a -0.009 0.001 1.8E-11 -0.009 0.002 5.6E-07 rs6420094 5 176750242 SLC34A1;GRK6,RGS14,LM AN2,PRR7,F12,PFN3 g -0.011 0.002 3.8E-12 -0.006 0.002 6.6E-04 rs881858 6 43914587 VEGFA g 0.011 0.002 2.2E-11 0.006 0.002 7.7E-04 rs7805747 7 151038734 PRKAG2 a -0.012 0.002 5.1E-11 -0.012 0.002 1.8E-08 rs4744712 9 70624527 PIP5K1B;FAM122A a -0.008 0.001 7.2E-10 -0.007 0.002 6.6E-05 rs4014195 11 65263398 RNASEH2C;DKFZp761E19 8,HTATIP,OVOL1 g -0.008 0.001 3.3E-08 -0.002 0.002 1.4E-01 rs653178 12 110492139 ATXN2 t 0.003 0.001 3.0E-02 0.005 0.002 2.9E-03 rs626277 13 71245697 DACH1 c 0.009 0.001 2.9E-10 0.004 0.002 1.0E-02 rs1394125 15 73946038 UBE2Q2;FBXO22 a -0.009 0.001 3.7E-10 -0.010 0.002 4.7E-08 rs12460876 19 38048731 SLC7A9;CCDC123,ECAT8 c 0.008 0.001 5.5E-09 0.009 0.002 2.5E-07 Creatinine Production Loci, Association with eGFRcrea rs7422339 2 211248752 CPS1 a -0.009 0.002 2.4E-09 -0.010 0.002 2.6E-07 rs2279463 6 160588379 SLC22A2 g -0.013 0.002 8.7E-10 -0.008 0.003 1.7E-03 rs6465825 7 77254375 TMEM60;RSBN1L,PHTF2 c -0.008 0.001 3.5E-09 -0.003 0.002 3.5E-02 rs10794720 10 1146165 WDR37 t -0.014 0.002 2.1E-08 -0.006 0.003 4.7E-02 31 rs10774021 12 219559 SLC6A13;JARID1A,SLC6A1 2 c 0.008 0.001 6.7E-09 0.004 0.003 7.1E-02 rs491567 15 51733885 WDR72 c 0.009 0.002 1.3E-08 0.009 0.002 1.0E-05 rs9895661 17 56811371 BCAS3;TBX2,C17orf82 c -0.011 0.002 1.4E-08 -0.012 0.002 3.0E-08 Chr position (b36) Genes Nearby modeled allele# OR CKD 95% CI p-value OR CKD 95% CI 1-sided p-value Renal Function Loci, Association with CKD Discovery Replication rs1933182 1 109801361 SYPL2;ATXN7L2,CYB561D1, PSMA5,AMIGO1,SORT1 a 1.06 1.01 - 1.10 2.3E-02 1.00 0.91-1.10 4.9E-01 rs267734 1 149218101 ANXA9;FAM63A,PRUNE, BNIPL,LASS2,SETDB1 c 0.93 0.88 - 0.98 5.3E-03 0.94 0.85-1.05 1.5E-01 rs16864170 (CKD) 2 5825331 SOX11 c 1.30 1.18 - 1.43 4.5E-08 1.04 0.84-1.28 3.5E-01 rs1260326 2 27584444 GCKR;IFT172,FNDC4 t 0.97 0.93 - 1.01 1.8E-01 0.95 0.87-1.04 1.3E-01 rs13538 2 73721836 NAT8;NAT8B,ALMS1 g 0.95 0.91 - 1.01 8.4E-02 0.87 0.78-0.97 5.0E-03 rs347685 3 143289827 TFDP2 c 0.92 0.88 - 0.96 3.3E-04 1.01 0.91-1.11 4.6E-01 rs11959928 5 39432889 DAB2;C9 a 1.11 1.06 - 1.15 4.6E-06 0.99 0.90-1.07 3.7E-01 rs6420094 5 176750242 SLC34A1;GRK6,RGS14, LMAN2,PRR7,F12,PFN3 g 1.09 1.05 - 1.15 1.6E-04 1.03 0.93-1.14 3.0E-01 rs881858 6 43914587 VEGFA g 0.93 0.88 - 0.98 4.4E-03 0.97 0.88-1.06 2.4E-01 rs7805747 7 151038734 PRKAG2 a 1.18 1.12 - 1.25 8.6E-09 1.24 1.11-1.38 7.7E-05 rs4744712 9 70624527 PIP5K1B;FAM122A a 1.06 1.02 - 1.11 6.6E-03 1.10 1.01-1.20 1.9E-02 rs4014195 11 65263398 RNASEH2C;DKFZp761E198, HTATIP,OVOL1 g 1.10 1.05 - 1.14 4.1E-05 1.07 0.98-1.17 7.7E-02 rs653178 12 110492139 ATXN2 t 0.97 0.93 - 1.01 1.2E-01 0.95 0.87-1.04 1.3E-01 rs626277 13 71245697 DACH1 c 0.93 0.89 - 0.97 1.4E-03 1.01 0.93-1.10 4.1E-01 rs1394125 15 73946038 UBE2Q2;FBXO22 a 1.07 1.02 - 1.12 3.2E-03 1.15 1.05-1.27 1.8E-03 rs12460876 19 38048731 SLC7A9;CCDC123,ECAT8 c 0.94 0.90 - 0.98 7.9E-03 0.88 0.81-0.96 2.6E-03 Creatinine Production Loci, Association with CKD rs7422339 2 211248752 CPS1 a 1.12 1.07 - 1.18 8.0E-06 1.15 1.04-1.27 2.5E-03 rs2279463 6 160588379 SLC22A2 g 1.11 1.04 - 1.18 1.1E-03 1.07 0.94-1.23 1.5E-01 32 rs6465825 7 77254375 TMEM60;RSBN1L,PHTF2 c 1.04 1.00 - 1.09 4.7E-02 1.04 0.95-1.13 2.0E-01 rs10794720 10 1146165 WDR37 t 1.16 1.08 - 1.26 1.5E-04 1.09 0.93-1.27 1.5E-01 rs10774021 12 219559 SLC6A13;JARID1A,SLC6A12 c 0.95 0.91 - 0.99 2.4E-02 1.00 0.90-1.10 4.7E-01 rs491567 15 51733885 WDR72 c 0.94 0.89 - 0.98 1.1E-02 0.84 0.75-0.93 6.3E-04 rs9895661 17 56811371 BCAS3;TBX2,C17orf82 c 1.07 1.01 - 1.13 2.6E-02 1.17 1.05-1.31 2.0E-03 Chr position (b36) Genes Nearby modeled allele# eGFRcys beta eGFRcys SE p-value eGFRcys beta eGFRcys SE 1-sided p- value Renal Function Loci, Association with eGFRcys Discovery Replication rs1933182 1 109801361 SYPL2;ATXN7L2,CYB561D1, PSMA5,AMIGO1,SORT1 a -0.006 0.003 1.6E-02 0.002 0.005 3.4E-01 rs267734 1 149218101 ANXA9;FAM63A,PRUNE, BNIPL,LASS2,SETDB1 c 0.004 0.003 1.5E-01 0.016 0.006 2.3E-03 rs16864170 (CKD) 2 5825331 SOX11 c -0.010 0.005 6.8E-02 -0.013 0.011 1.2E-01 rs1260326 2 27584444 GCKR;IFT172,FNDC4 t 0.006 0.002 6.4E-03 0.004 0.004 1.6E-01 rs13538 2 73721836 NAT8;NAT8B,ALMS1 g 0.010 0.003 5.0E-04 0.007 0.005 7.9E-02 rs347685 3 143289827 TFDP2 c 0.008 0.003 1.5E-03 -0.001 0.005 4.3E-01 rs11959928 5 39432889 DAB2;C9 a -0.007 0.002 2.6E-03 -0.010 0.004 1.0E-02 rs6420094 5 176750242 SLC34A1;GRK6,RGS14, LMAN2,PRR7,F12,PFN3 g -0.009 0.003 1.6E-03 -0.014 0.005 8.7E-04 rs881858 6 43914587 VEGFA g 0.011 0.003 6.4E-05 0.018 0.005 9.0E-05 rs7805747 7 151038734 PRKAG2 a -0.014 0.004 4.5E-04 -0.018 0.005 2.7E-04 rs4744712 9 70624527 PIP5K1B;FAM122A a -0.006 0.002 1.8E-02 -0.006 0.004 1.1E-01 rs4014195 11 65263398 RNASEH2C;DKFZp761E198, HTATIP,OVOL1 g -0.005 0.002 4.3E-02 -0.004 0.005 1.9E-01 rs653178 12 110492139 ATXN2 t 0.013 0.002 3.8E-08 0.016 0.004 1.4E-04 rs626277 13 71245697 DACH1 c 0.006 0.002 2.4E-02 0.013 0.004 1.7E-03 rs1394125 15 73946038 UBE2Q2;FBXO22 a -0.009 0.003 8.3E-04 -0.004 0.005 1.7E-01 rs12460876 19 38048731 SLC7A9;CCDC123,ECAT8 c 0.006 0.002 8.2E-03 0.001 0.004 3.9E-01 Creatinine Production Loci, Association with eGFRcys 33 rs7422339 2 211248752 CPS1 a 0.003 0.003 3.9E-01 0.005 0.005 1.3E-01 rs2279463 6 160588379 SLC22A2 g -0.001 0.004 7.7E-01 -0.007 0.007 1.6E-01 rs6465825 7 77254375 TMEM60;RSBN1L,PHTF2 c 0.000 0.002 9.5E-01 0.004 0.004 1.9E-01 rs10794720 10 1146165 WDR37 t -0.006 0.004 1.1E-01 -0.005 0.008 2.8E-01 rs10774021 12 219559 SLC6A13;JARID1A,SLC6A12 c 0.000 0.002 9.3E-01 0.005 0.008 2.8E-01 rs491567 15 51733885 WDR72 c 0.003 0.003 2.3E-01 0.008 0.005 7.3E-02 rs9895661 17 56811371 BCAS3;TBX2,C17orf82 c -0.004 0.003 1.8E-01 0.001 0.006 4.1E-01 #The minor allele based on sample size weighted mean allele frequency in the discovery cohorts is modeled. Genes within 60 kb were based on RefSeq genes (b36). The gene closest to the SNP is listed first and bold if the SNP is located within the gene. Other genes in the region are listed after ";". Betas for eGFR refer to age-adjusted sex-specific residuals of natural log transformed eGFR. P-values in discovery analyses are corrected for genomic control before and after meta-analysis. 34 Supplementary Table 4 - Additional Gene Biology. This table lists additional genes in associated regions containing a gene highlighted in Box 1, as well as genes in other associated regions. For novel regions associated with both eGFRcrea and eGFRcys, the gene(s) in closest physical proximity and/or in strong LD (r2>0.8) with the lead SNP is presented. For novel regions association with eGFRcrea only, the gene in closest physical proximity is presented. Location Gene Function 1q21 LASS2 LAG1 homolog, ceramide synthase 2 (LASS2) is highly expressed in the kidney and may be involved in cell growth.46 A non-synonymous coding SNP in LASS2, rs267738 (E115A), was in perfect LD with the lead SNP in the region and of predicted damaging function.47 LASS2 has been implicated in the synthesis of specific ceramides.48 Ceramides and their product sphingolipids are important in genetic diseases of the kidney,49 and have a role in aging mechanisms. 1q21, LASS2 region ANXA9 Annexin A9 (ANXA9) is expressed in kidney and functions as a calcium-sensitive protein. 50 1q21, LASS2 region SETDB1 SET domain, bifurcated 1 (SETDB1) is a key histone methyltransferase important in chromatin homeostasis and thus epigenetic regulation of gene expression.51 It is expressed in numerous tissues including the kidney (UniGene). 2p23.3, GCKR region FNDC4 Encodes fibronectin type III domain containing 4 gene. This gene shows low expression in the kidney,52 and is involved in cell adhesion activity. 2q35 CPS1 Encodes carbamoyl-phosphate synthetase 1. Has 3 isoforms and is involved in the hepatic urea cycle and in production of arginine, a precursor to creatine production that could potentially affect serum creatinine levels. Moreover, CPS1 is associated with hyperammonemia, which has been shown to decrease creatine synthesis.53 The associated SNP causes a nonsynonymous amino acid change. 3q23 TFDP2 TFDP2 encodes E2F dimerization partner (DP) 2. Dimerization of DP proteins with E2F proteins increases the transcription activity of E2F. The role of TFDP2 has mainly been studied in the context of tumorigenesis via its known interaction with E2F54 and with the TGF signaling pathway,55 and not in the context of renal disease. 35 3q23, TFDP2 region ATP1B3 Encodes ATPase, Na+/K+ transporting, beta 3 polypeptide. eSNP data points to this gene (Table 4). It contains a highly conserved actin nucleation and is involved in membrane growth and polarity. It is expressed in numerous tissues, including kidney (UniGene). 6q26 SLC22A2 SLC22A2 encodes solute carrier family 22, member 2 which functions as an organic cation transporter and mediates the uptake of a variety of organic cations, including creatinine in the basolateral membrane of renal tubular epithelial cells.56 Neighboring genes are SLC22A1 and SLC22A3, which have similar function. 7q11.23 TMEM60 Encodes transmembrane protein 60. It is expressed in many tissues including the kidney and muscle. Its biological function in unknown. 9q13 PIP5K1B PIP5K1B encodes phosphatidylinositol-4-phosphate 5-kinase, type 1 with a possible role in cell polarization.57 The lead SNP we identified is an intronic SNP in a region with high conservation across species. Expression is complex, with multiple transcripts detected in a wide variety of tissues, including the kidney. No publications connecting this gene and kidney function. 9q21.11, PIP5K1B region FAM122A Encodes the protein family with sequence similarity 122A. No known association with kidney disease. 10p15.3 WDR37 Encodes WD repeat domain 37. Members of this protein family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Specific biological function is unknown. 12p13.3 SLC6A13 Encodes solute carrier family 6 (neurotransmitter transporter, betaine/GABA), member 13, which is expressed in the kidney. It is induced by hypertonicity and mediates chloride- and sodium- dependent transport of both betaine and the neurotransmitter GABA, and shows high homology to a known creatinine transporter encoded by SLC8A13.58 12q24, ATXN2 region BRAP In a monocyte differentiation model, BRAP (BRCA-associated protein) interacts directly with CDKN1A.59 Knockout of CDKN1A ameliorates the development of chronic renal failure in a mouse model.60 15q21.3 WDR72 WD repeat-containing protein 7 (WDR72) is a protein of unknown function. The SNP rs17730281 is a coding SNP in WDR72 with predicted damaging function (SIFT) and in LD with the lead SNP we identified (r2=0.75). It is highly expressed in the kidney. 15q24.2 UBE2Q2 Ubiquitin-conjugating enzyme E2Q family member 2 is reported to catalyze the covalent attachment of ubiquitin to other proteins. UBE2Q2 has a role in the cell cycle.61 It is expressed in 36 the kidney. 15q24.2, UBE2Q2 region FBXO22 Encodes F-box protein 22, which contains an F box motif (OMIM). It constitutes one of four parts of the ubiquitin protein ligase complex with a role in ubiquitination (www.genecards.org) It is expressed in kidney. 17q23 BCAS3 Encodes breast carcinoma amplified sequence 3. Involves a functional estrogen response element. It is ubiquitously expressed, and has been associated with human height, which could secondarily be associated with muscle mass.62 Our identified SNP was also in strong LD with the TBX2 gene. 19q13.11, SLC7A9 region CCDC123 Coiled-coil domain containing 123 (CCDC123) encodes a mitochondrial protein. It is expressed in the kidney (www.genecards.org). 37 Supplementary Table 5: Effect sizes of association with eGFRcrea across strata of diabetes and hypertension. Results are presented for the lead SNP at known and novel loci related to renal function. Diabetes No Diabetes SNPID locus chr pos A1 A2 Freq1 Beta SE pval Beta SE pval pval diff rs267734 ANXA9 1 149218101 t c 0.79 -0.011 0.007 1.2E-01 -0.009 0.002 7.9E-08 8.0E-01 rs1260326 GCKR 2 27584444 t c 0.41 0.015 0.006 1.2E-02 0.009 0.001 3.8E-10 3.2E-01 rs13538 ALMS1 2 73721836 a g 0.77 0.001 0.007 9.4E-01 -0.010 0.002 6.7E-09 1.5E-01 rs347685 TFDP2 3 143289827 a c 0.72 -0.010 0.006 1.1E-01 -0.009 0.001 2.4E-09 8.5E-01 rs17319721 SHROOM3 4 77587871 a g 0.43 -0.025 0.006 1.3E-05 -0.012 0.001 2.8E-17 2.3E-02 rs11959928 DAB2 5 39432889 a t 0.44 -0.012 0.006 4.6E-02 -0.009 0.001 4.1E-10 6.3E-01 rs6420094 SLC34A1 5 176750242 a g 0.66 0.020 0.007 3.1E-03 0.010 0.002 3.9E-11 1.7E-01 rs881858 VEGFA 6 43914587 a g 0.72 -0.018 0.007 8.3E-03 -0.010 0.002 2.1E-10 2.8E-01 rs7805747 PRKAG2 7 151038734 a g 0.25 0.004 0.008 6.6E-01 -0.013 0.002 9.2E-13 4.8E-02 rs10109414 STC1 8 23807096 t c 0.42 -0.005 0.006 3.6E-01 -0.008 0.001 1.3E-09 6.0E-01 rs4744712 PIP5K1B 9 70624527 a c 0.39 -0.008 0.006 1.9E-01 -0.009 0.001 2.4E-10 8.4E-01 rs10794720 WDR37 10 1146165 t c 0.08 -0.015 0.011 1.6E-01 -0.014 0.002 5.7E-08 9.1E-01 rs653178 ATXN2 12 110492139 t c 0.51 0.012 0.006 4.1E-02 0.003 0.001 4.8E-02 1.3E-01 rs626277 DACH1 13 71245697 a c 0.60 -0.012 0.006 3.9E-02 -0.008 0.001 9.1E-09 5.1E-01 rs491567 WDR72 15 51733885 a c 0.78 -0.012 0.007 6.9E-02 -0.009 0.002 3.4E-08 6.3E-01 rs1394125 UBE2Q2 15 73946038 a g 0.35 -0.016 0.006 1.2E-02 -0.009 0.002 5.0E-09 2.8E-01 rs12917707 UMOD 16 20275191 t g 0.18 0.033 0.007 1.4E-05 0.015 0.002 1.3E-17 2.3E-02 rs12460876 SLC7A9 19 38048731 t c 0.60 0.000 0.006 1.0E+00 -0.009 0.001 6.4E-10 1.5E-01 Hypertension No Hypertension SNPID locus chr pos A1 A2 Freq1 Beta SE pval Beta SE pval pval diff rs267734 ANXA9 1 149218101 t c 0.79 -0.008 0.003 6.1E-03 -0.010 0.002 6.1E-07 6.0E-01 rs1260326 GCKR 2 27584444 t c 0.41 0.009 0.002 2.4E-04 0.009 0.002 6.2E-09 7.7E-01 rs13538 ALMS1 2 73721836 a g 0.77 -0.007 0.003 1.0E-02 -0.010 0.002 4.5E-07 4.2E-01 rs347685 TFDP2 3 143289827 a c 0.72 -0.011 0.003 2.4E-05 -0.007 0.002 2.3E-05 2.8E-01 rs17319721 SHROOM3 4 77587871 a g 0.43 -0.010 0.002 6.8E-06 -0.014 0.002 2.7E-18 2.0E-01 rs11959928 DAB2 5 39432889 a t 0.44 -0.010 0.002 2.1E-05 -0.009 0.002 1.2E-07 6.4E-01 rs6420094 SLC34A1 5 176750242 a g 0.66 0.012 0.003 7.4E-06 0.010 0.002 6.9E-08 5.8E-01 rs881858 VEGFA 6 43914587 a g 0.72 -0.012 0.003 1.8E-05 -0.011 0.002 1.2E-08 8.0E-01 rs7805747 PRKAG2 7 151038734 a g 0.25 -0.016 0.003 2.6E-07 -0.010 0.002 4.6E-06 8.1E-02 rs10109414 STC1 8 23807096 t c 0.42 -0.010 0.002 1.5E-05 -0.007 0.002 3.4E-06 3.7E-01 38 rs4744712 PIP5K1B 9 70624527 a c 0.39 -0.008 0.002 5.8E-04 -0.009 0.002 7.8E-08 8.0E-01 rs10794720 WDR37 10 1146165 t c 0.08 -0.010 0.004 1.8E-02 -0.016 0.003 2.6E-08 2.1E-01 rs653178 ATXN2 12 110492139 t c 0.51 0.004 0.002 7.7E-02 0.001 0.002 3.8E-01 3.3E-01 rs626277 DACH1 13 71245697 a c 0.60 -0.007 0.002 2.0E-03 -0.009 0.002 3.9E-08 5.4E-01 rs491567 WDR72 15 51733885 a c 0.78 -0.010 0.003 2.4E-04 -0.009 0.002 5.5E-06 6.8E-01 rs1394125 UBE2Q2 15 73946038 a g 0.35 -0.010 0.003 5.5E-05 -0.009 0.002 2.5E-07 7.2E-01 rs12917707 UMOD 16 20275191 t g 0.18 0.023 0.003 4.7E-15 0.012 0.002 1.6E-09 1.8E-03 rs12460876 SLC7A9 19 38048731 t c 0.60 -0.007 0.002 4.0E-03 -0.009 0.002 5.6E-09 3.2E-01 P-value for difference are from a t-test for independent samples (b1hat -b2hat ~ N(b1-b2,SE1^2+SE2^2)): under the null hypothesis, the difference between the effects in the two groups follows a normal distribution N(0, 2), with 2 estimated as the sum of the squares of the standard errors. Differences were considered significant if p<5.6*10E-03 (0.1/18) and are indicated in bold font. All discovery studies contributed to the meta-analyses of eGFR among those without diabetes and without hypertension. The BLSA Study did not contribute to the meta-analysis among those with hypertension, and theAmish, the BLSA, and the Family Heart Study did not contribute to the meta-analysis among those with diabetes. Sample sizes for hypertension and diabetes are presented in Table 1. 39 Supplementary Table 6: Expression Associated SNP Analysis. SNPs significantly associated with eGFRcrea, CKD or eGFRcys in Stage 1 discovery analyses that are associated with gene expression in liver, lymphoblastoid cell lines (LCL) or lymphocytes. Starred loci (*) were also detected in association with eGFRcrea using the FDR method. Tissue: LIVER p-value Closest gene Second closest gene SNP e G F R c y s C K D e G F R c re a eSNP inGene Genes within 60kb Name D is ta n c e (b p ) Name D is ta n c e (b p ) Expressed Gene Expressed Probe r2 t o t o p S N P top SNP n o te s rs10857787 2.4E-02 4.5E-02 6.2E-08 2.8E-35 SYPL2 ATXN7L2; CYB561D1; SYPL2; PSMA5; AMIGO1 SYPL2 1190 ATXN7L2 16271 SYPL2 0.92 rs1933182 rs8076494 3.8E-01 2.5E-02 4.2E-07 7.9E-07 FBXL20 MED1; FBXL20 FBXL20 41154 MED1 43815 PERLD1 * rs2268755 2.2E-01 1.6E-02 2.9E-06 5.5E-08 ACVR2B ACVR2B; XYLB; ENDOGL1 ACVR2B 6127 ENDOGL1 35916 HSS00051291 * rs7374458 2.4E-01 7.2E-03 4.4E-06 2.4E-06 ACVR2B SCN5A; ACVR2B; ENDOGL1 ACVR2B 3420 ENDOGL1 6621 XYLB * rs4256249 2.7E-01 8.0E-02 1.0E-05 4.3E-06 SHROOM3 SHROOM3 SHROOM3 102327 FLJ25770 130121 SHROOM3 0.06 rs17319721 rs11070327 5.5E-03 1.6E-03 1.9E-05 5.3E-06 OIP5 NUSAP1; OIP5; CHP OIP5 1399 NUSAP1 22202 Contig53488 * rs1589576 6.5E-05 4.0E-02 1.9E-05 5.0E-11 ALMS1 ALMS1 ALMS1 98242 NAT8 129045 ALMS1 0.85 rs13538 rs11078895 7.6E-01 1.0E-02 2.3E-05 2.0E-11 FBXL20; RPL19; CACNB1; STAC2 FBXL20 15789 STAC2 19077 CRKRS * rs3372 3.0E-01 4.9E-03 3.9E-05 2.2E-08 HTATIP; RNASEH2 C DKFZp761E198; HTATIP; RELA; RNASEH2C RNASEH2C 73 HTATIP 1856 RNASEH2C 0.26 rs4014195 rs7035163 8.0E-01 2.4E-02 4.0E-05 2.4E-11 PIP5K1B FAM122A; PIP5K1B FAM122A 8922 PIP5K1B 65426 FAM122A 0.19 rs4744712 rs12113119 1.1E-02 2.5E-01 4.6E-05 6.0E-08 RSBN1L; PTPN12 RSBN1L 10941 PTPN12 45432 BC037783 0.21 rs6465825 rs2593280 2.9E-01 3.4E-03 6.1E-05 2.1E-07 UBE2Q2 UBE2Q2; FBXO22 UBE2Q2 15166 FBXO22 45234 UBE2Q2 0.00 rs1394125 rs6762208 3.1E-01 7.6E-01 6.9E-05 5.2E-09 SENP2 IGF2BP2; SENP2 SENP2 17718 IGF2BP2 30362 HSS00090370 40 rs17350188 2.5E-04 8.2E-02 7.0E-05 4.4E-06 TPRKB; FLJ43987; DUSP11; NAT8B TPRKB 329 DUSP11 24488 TPRKB 0.39 rs13538 rs16967572 5.3E-02 1.9E-01 7.2E-05 9.6E-13 CCDC123 RHPN2; SLC7A9; C19orf40; CCDC123 CCDC123 42608 C19orf40 50664 SLC7A9 0.58 rs12460876 rs2927743 3.2E-01 3.0E-01 7.6E-05 7.3E-11 ZFP30 ZNF571; ZFP30; ZNF781; ZNF607; ZNF540 ZFP30 8946 ZNF781 26315 ZFP30 rs10838738 1.7E-01 2.9E-03 8.7E-05 1.8E-11 MTCH2 C1QTNF4; MTCH2; AGBL2; NDUFS3 MTCH2 1015 AGBL2 18095 CUGBP1 rs3887266 7.9E-01 4.0E-02 1.0E-04 2.3E-06 SLC17A1; SLC17A3 SLC17A3 1581 SLC17A1 11459 SLC17A1 rs164749 1.8E-01 9.0E-01 1.3E-04 2.5E-09 C16orf55; CHMP1A; CDK10; DPEP1; SPATA2L; CPNE7 CHMP1A 2619 DPEP1 3387 C16orf55 rs1103851 8.0E-03 2.4E-02 1.9E-04 1.3E-06 ANKRD27 ANKRD27; RGS9BP; NUDT19 ANKRD27 19688 RGS9BP 19898 SNORA68 rs409783 1.3E-02 4.2E-01 3.1E-04 5.5E-07 STC1 STC1 3530 NKX3-1 155453 C2orf29 0.29 rs10109414 rs2734974 2.9E-01 1.9E-04 4.1E-03 2.5E-10 HLA-G HLA-G 34902 HLA-A 76551 HLA-A rs3768439 2.2E-04 1.8E-01 2.3E-01 3.6E-06 C1orf164 C1orf164; TMEM53 C1orf164 4070 TMEM53 6175 C1orf164 Tissue: Lymphoblastoid Cell Lines (LCL) p-value Closest gene Second closest gene SNP e G F R c y s C K D e G F R c re a eSNP inGene Genes within 60kb Name D is ta n c e (b p ) Name D is ta n c e (b p ) Expressed Gene Expressed Probe r2 t o t o p S N P top SNP n o te s rs6955503 2.9E-01 9.2E-02 1.5E-07 5.3E-09 PTPN12 PTPN12 PTPN12 42145 RSBN1L 98518 PTPN12 244356_at 0.35 rs6465825 rs4390625 3.5E-01 2.0E-02 3.6E-07 6.2E-10 CRKRS MED1; CRKRS CRKRS 2056 MED1 12820 225697_at * rs867282 6.6E-02 1.2E-01 4.4E-07 1.1E-07 MRPL33; SLC4A1AP; RBKS SLC4A1AP 33811 MRPL33 42925 209313_at rs1544457 2.9E-01 1.8E-01 4.4E-07 2.9E-08 TMEM60; RSBN1L; PHTF2 TMEM60 3755 RSBN1L 10287 PTPN12 244356_at 0.72 rs6465825 rs12450559 3.7E-01 2.1E-02 4.4E-07 3.3E-10 CRKRS CRKRS 6191 NEUROD2 65312 225697_at * 41 rs6685648 1.4E-03 1.6E-01 4.5E-07 7.4E-12 CASP9 ELA2B; ELA2A; CTRC; CASP9; DNAJC16 CASP9 6399 ELA2B 7301 221648_s_at * rs7503705 3.6E-01 2.0E-02 4.7E-07 2.8E-10 CRKRS CRKRS CRKRS 18814 MED1 62177 225697_at * rs2338800 3.9E-01 2.4E-02 5.2E-07 4.8E-10 FBXL20 FBXL20 FBXL20 59727 MED1 62388 225697_at * rs2338755 4.1E-01 2.9E-02 6.0E-07 4.8E-10 FBXL20 FBXL20; RPL19; STAC2 FBXL20 2477 STAC2 37343 225697_at * rs588193 4.1E-01 3.1E-02 6.5E-07 4.8E-10 FBXL20 FBXL20; STAC2 FBXL20 23599 STAC2 58465 225697_at * rs2061342 4.6E-01 2.6E-02 6.9E-07 4.6E-10 FBXL20; RPL19; CACNB1; STAC2 FBXL20 11183 STAC2 23683 225697_at * rs2868813 1.8E-01 1.8E-01 9.8E-07 1.1E-08 RSBN1L TMEM60; RSBN1L RSBN1L 3262 TMEM60 17304 PTPN12 244356_at 0.69 rs6465825 rs711309 3.3E-01 2.1E-01 1.3E-06 4.3E-09 PHTF2 PHTF2 PHTF2 46795 MAGI2 106629 PTPN12 244356_at 0.69 rs6465825 rs1619021 2.4E-01 4.8E-02 1.5E-06 3.2E-10 PPP1R1B; NEUROD2; STARD3; CRKRS NEUROD2 20747 PPP1R1B 43904 225697_at * rs848493 2.8E-01 2.3E-01 1.6E-06 4.9E-08 PHTF2 PHTF2 PHTF2 54018 TMEM60 104774 PTPN12 244356_at 0.66 rs6465825 rs4795369 3.9E-01 2.2E-02 4.9E-06 1.1E-09 MED1; FBXL20; CRKRS MED1 1593 CRKRS 9171 225697_at * rs522063 1.7E-01 4.2E-03 5.6E-06 3.5E-08 EXDL1 EXDL1; CHP EXDL1 1278 CHP 47227 204125_at * rs535211 6.7E-01 1.8E-01 5.7E-06 1.9E-15 RBM14; CCDC87; RBM4; SPTBN2; RBM4B; CCS RBM4 5657 RBM14 5669 203522_at rs6956726 2.1E-01 2.8E-01 6.1E-06 2.7E-09 RSBN1L TMEM60; RSBN1L RSBN1L 34157 TMEM60 48199 PTPN12 244356_at 0.67 rs6465825 rs10441228 2.3E-01 2.9E-01 6.5E-06 2.1E-10 RSBN1L TMEM60; RSBN1L RSBN1L 38341 TMEM60 52383 PTPN12 244356_at 0.67 rs6465825 rs521890 1.9E-01 5.2E-03 6.7E-06 1.4E-07 EXDL1; CHP EXDL1 1788 CHP 50293 204125_at * rs3811644 2.1E-02 2.4E-01 1.3E-05 6.5E-09 C2orf16 GCKR; XAB1; CCDC121; ZNF512; C2orf16 C2orf16 2784 ZNF512 3087 GPN1 209313_at 0.03 rs1260326 rs6503513 6.6E-01 3.3E-02 1.4E-05 7.6E-08 MED1 MED1; FBXL20; CRKRS MED1 1076 FBXL20 3737 225697_at * rs6734059 2.1E-02 2.4E-01 2.0E-05 2.1E-10 ZNF512 XAB1; CCDC121; ZNF512; C2orf16 ZNF512 2262 C2orf16 2565 GPN1 209313_at 0.04 rs1260326 rs618838 6.2E-01 2.3E-02 2.0E-05 1.4E-12 ACTN3 RBM14; CCDC87; BBS1; ZDHHC24; CCS; CTSF; ACTN3; DPP3 ACTN3 2078 CTSF 2216 203522_at 42 rs1815739 6.5E-01 2.6E-02 2.2E-05 3.2E-13 ACTN3 RBM14; CCDC87; BBS1; ZDHHC24; CCS; CTSF; ACTN3; DPP3 ACTN3 2702 CTSF 2840 203522_at rs1324087 1.9E-01 4.7E-03 2.4E-05 3.5E-13 SLC17A1; SLC17A3 SLC17A3 3919 SLC17A1 9121 209846_s_at rs1881396 2.2E-02 2.3E-01 2.6E-05 4.7E-09 ZNF512 XAB1; SLC4A1AP; CCDC121; SUPT7L; ZNF512; C2orf16 ZNF512 1357 CCDC121 3904 GPN1 209313_at 0.03 rs1260326 rs2295626 9.6E-04 3.3E-01 3.1E-05 9.5E-13 DNAJC16 ELA2B; AGMAT; CASP9; DNAJC16 DNAJC16 21610 CASP9 24171 221648_s_at * rs2290999 1.8E-01 2.0E-01 3.4E-05 5.1E-08 ZFP30 ZNF571; ZFP30; ZNF781; ZNF607; ZNF540 ZFP30 7426 ZNF781 19762 235373_at rs241935 1.6E-01 2.7E-01 3.5E-05 7.9E-08 ZNF573 ZNF573 23763 ZNF607 83272 235373_at rs316611 3.4E-02 8.9E-04 4.1E-05 1.0E-15 RTF1 LTK; NDUFAF1; RTF1; RPAP1; ITPKA RTF1 24076 ITPKA 34443 204125_at * rs7810273 1.2E-02 2.4E-01 4.7E-05 1.4E-10 RSBN1L; PTPN12 RSBN1L 11115 PTPN12 45258 PTPN12 244356_at 0.21 rs6465825 rs4727461 1.5E-02 2.5E-01 4.8E-05 1.4E-10 RSBN1L; PTPN12 RSBN1L 5371 PTPN12 51002 PTPN12 244356_at 0.19 rs6465825 rs7254809 1.8E-01 2.8E-01 4.9E-05 9.2E-08 SIPA1L3 SIPA1L3 32172 ZNF573 95495 235373_at rs1725745 3.4E-01 1.8E-01 5.7E-05 2.5E-08 MAGI2; PHTF2 PHTF2 11999 MAGI2 47835 PTPN12 244356_at 0.45 rs6465825 rs1377416 7.6E-02 1.0E-05 5.8E-05 2.5E-08 RAPSN; PSMC3; MYBPC3; SLC39A13; SPI1 SLC39A13 13435 SPI1 16619 229272_at rs4752801 2.8E-01 1.1E-03 6.0E-05 2.4E-12 NUP160 NUP160 37584 PTPRJ 94468 229272_at rs3766160 9.4E-03 4.7E-01 6.8E-05 3.0E-08 ELA2B ELA2B; ELA2A; CTRC; CASP9; EFHD2; DNAJC16 ELA2B 6277 CASP9 9924 221648_s_at * rs3820071 1.0E-02 4.7E-01 6.9E-05 1.4E-08 ELA2B ELA2B; ELA2A; CTRC; CASP9; EFHD2; DNAJC16 ELA2B 6172 CASP9 10029 221648_s_at * rs896817 1.3E-01 3.0E-05 7.1E-05 4.6E-09 SPI1 PSMC3; MYBPC3; SLC39A13; MADD; SPI1 SPI1 5822 MYBPC3 20052 229272_at 43 rs10769258 1.4E-01 1.6E-03 8.1E-05 3.2E-10 SPI1 PSMC3; SLC39A13; MADD; MYBPC3; SPI1 SPI1 9088 MYBPC3 16786 229272_at rs1757468 1.1E-01 6.9E-04 8.4E-05 8.7E-15 RTF1 LTK; NDUFAF1; RTF1; ITPKA RTF1 32180 ITPKA 42547 204125_at * rs10838738 1.7E-01 2.9E-03 8.7E-05 9.0E-11 MTCH2 C1QTNF4; MTCH2; AGBL2; NDUFS3 MTCH2 1015 AGBL2 18095 229272_at rs1768808 6.4E-05 9.3E-02 1.2E-02 8.5E-28 MAST2; PIK3R3 MAST2 1421 PIK3R3 2596 1560263_at rs11211152 6.8E-05 1.9E-01 2.7E-02 1.3E-44 GPBP1L1 GPBP1L1; NASP; IPP; TMEM69; CCDC17 GPBP1L1 12654 CCDC17 24484 1560263_at rs3811436 7.2E-05 1.9E-01 2.8E-02 8.4E-52 GPBP1L1 GPBP1L1; NASP; IPP; TMEM69; CCDC17 GPBP1L1 931 TMEM69 27966 1560263_at rs10430105 7.3E-05 1.9E-01 2.8E-02 1.3E-44 GPBP1L1; NASP; IPP; TMEM69; CCDC17 GPBP1L1 12065 TMEM69 14970 1560263_at Tissue: LYMPHOCYTE p-value Closest gene Second closest gene SNP e G F R c y s C K D e G F R c re a eSNP inGene Genes within 60kb Name D is ta n c e ( b p ) Name D is ta n c e ( b p ) Expressed Gene Expressed Probe r2 t o t o p S N P top SNP n o te s rs1346268 8.3E-01 2.8E-06 2.1E-19 8.4E-24 C15orf48; SPATA5L1; GATM GATM 2049 SPATA5L 1 21556 SPATA5L1 GI_13129039-S 0.44 rs2453533 rs9806699 8.4E-01 1.8E-04 2.6E-13 5.6E-19 SPATA5L1; C15orf48; SLC30A4 C15orf48 14747 SPATA5L 1 26781 SPATA5L1 GI_13129039-S 0.35 rs2453533 rs1260326 6.4E-03 1.8E-01 1.3E-10 7.0E-12 GCKR GCKR; IFT172; FNDC4 GCKR 11235 FNDC4 12854 IFT172 GI_37546863-S top SN P rs835223 5.5E-03 2.2E-05 1.7E-10 4.7E-04 DAB2 C9; DAB2 DAB2 9578 C9 16702 DAB2 GI_4503250-S 0.93 rs11959928 rs700221 1.1E-03 3.1E-05 1.8E-10 7.0E-05 C9 C9; DAB2 C9 7480 DAB2 14604 DAB2 GI_4503250-S 0.84 rs11959928 rs700233 1.2E-03 3.7E-05 2.5E-10 1.0E-03 C9 C9; DAB2 C9 101 DAB2 7225 DAB2 GI_4503250-S 0.84 rs11959928 44 rs950027 8.0E-01 4.5E-03 4.1E-10 2.7E-10 SLC30A4 C15orf21; SLC30A4 C15orf21 2298 SLC30A4 13967 SPATA5L1 GI_13129039-S 0.62 rs2453533 rs1421095 2.1E-03 2.6E-04 6.8E-10 8.8E-04 C9 C9; DAB2 C9 9007 DAB2 16131 DAB2 GI_4503250-S 0.81 rs11959928 rs10512696 5.9E-03 6.4E-06 1.4E-09 9.3E-04 DAB2 C9; DAB2 DAB2 1428 C9 59252 DAB2 GI_4503250-S 0.72 rs11959928 rs3737267 3.2E-01 4.8E-04 3.2E-09 5.9E-05 SPATA5L1 C15orf48; SPATA5L1; GATM SPATA5L1 8214 C15orf48 19963 SPATA5L1 GI_13129039-S 0.13 rs2453533 rs335675 2.0E-04 4.3E-01 9.4E-08 2.1E-03 FBXO22 NRG4; UBE2Q2; FBXO22 FBXO22 3028 NRG4 15558 FBXO22 GI_22547148-I 0.01 rs1394125 rs6546838 4.0E-05 1.9E-01 1.1E-07 1.8E-04 ALMS1 ALMS1 ALMS1 66395 EGR4 158607 ALMS1 GI_27436958-S 0.95 rs13538 rs2901438 6.5E-05 1.8E-01 1.2E-07 7.0E-05 ALMS1 ALMS1 ALMS1 52771 EGR4 144983 ALMS1 GI_27436958-S 0.95 rs13538 rs6546835 6.6E-05 1.8E-01 1.3E-07 4.8E-05 ALMS1 ALMS1 ALMS1 51830 EGR4 144042 ALMS1 GI_27436958-S 0.95 rs13538 rs10496191 6.0E-05 1.8E-01 1.3E-07 6.7E-05 ALMS1 ALMS1 ALMS1 60913 EGR4 153125 ALMS1 GI_27436958-S 0.95 rs13538 rs13384952 2.6E-05 1.1E-01 1.3E-07 5.8E-08 ALMS1 ALMS1 ALMS1 111074 NAT8 143890 ALMS1 GI_27436958-S 0.95 rs13538 rs3813227 9.2E-05 1.8E-01 1.5E-07 8.6E-05 ALMS1 ALMS1 ALMS1 39082 EGR4 131294 ALMS1 GI_27436958-S 0.95 rs13538 rs10193972 7.4E-05 1.7E-01 1.5E-07 2.8E-04 ALMS1 ALMS1 ALMS1 104771 NAT8 150193 ALMS1 GI_27436958-S 0.95 rs13538 rs2056486 8.5E-05 1.9E-01 1.6E-07 7.5E-05 ALMS1 ALMS1 ALMS1 104682 NAT8 150282 ALMS1 GI_27436958-S 0.95 rs13538 rs335684 2.4E-04 4.3E-01 2.2E-07 2.1E-03 NRG4; UBE2Q2; FBXO22 UBE2Q2 924 FBXO22 1895 FBXO22 GI_22547148-I rs13538 rs10198549 9.1E-04 1.4E-01 3.8E-07 4.8E-09 ALMS1 ALMS1 ALMS1 42642 NAT8 73445 ALMS1 GI_27436958-S 1.00 rs13538 rs4645989 1.3E-03 1.5E-01 4.2E-07 1.5E-14 CASP9 ELA2B; AGMAT; ELA2A; CASP9; DNAJC16 CASP9 447 DNAJC16 3008 GI_14790127-A * rs12450559 3.7E-01 2.1E-02 4.4E-07 6.0E-06 CRKRS CRKRS 6191 NEUROD 2 65312 GI_7706548-S * rs6685648 1.4E-03 1.6E-01 4.5E-07 9.5E-15 CASP9 ELA2B; ELA2A; CTRC; CASP9; DNAJC16 CASP9 6399 ELA2B 7301 GI_14790127-A * rs6440052 1.5E-02 3.0E-04 5.0E-07 5.2E-22 ATP1B3; TFDP2 TFDP2 12086 ATP1B3 13859 GI_4502280-S rs8025019 1.7E-01 2.2E-03 5.4E-07 1.4E-04 SPATA5L1; C15orf48; SLC30A4 C15orf48 10220 SPATA5L 1 22254 SPATA5L1 GI_13129039-S 0.21 rs2453533 rs12439639 7.7E-02 3.7E-02 9.2E-07 3.1E-10 C15orf21 C15orf21; SLC30A4; PLDN C15orf21 1848 SLC30A4 32078 SPATA5L1 GI_13129039-S 0.10 rs2453533 rs7216086 4.0E-01 3.2E-02 9.4E-07 3.8E-06 NEUROD2; CRKRS CRKRS 20904 NEUROD 2 50599 GI_7706548-S * 45 rs7116712 9.9E-02 9.9E-03 2.1E-06 1.2E-05 MAP3K11 LTBP3; MAP3K11; RELA; SIPA1; SSSCA1; FAM89B; KCNK7; EHBP1L1 MAP3K11 7292 KCNK7 9051 GI_21735553-S rs11062357 5.3E-01 1.9E-01 2.4E-06 5.5E-07 JARID1A JARID1A; SLC6A13 JARID1A 32172 SLC6A13 49392 JARID1A GI_4826967-S 0.37 rs10774021 rs1678750 2.3E-01 6.9E-04 2.9E-06 9.4E-04 INOC1 INOC1 2365 EXDL1 64226 GI_38570147-A * rs4407366 2.4E-01 7.2E-03 2.9E-06 7.8E-04 ACVR2B ACVR2B; ENDOGL1 ACVR2B 13206 ENDOGL1 16407 GI_10862697-S * rs3812042 1.7E-01 2.5E-03 3.0E-06 1.2E-08 C9; DAB2 DAB2 872 C9 6252 DAB2 GI_4503250-S 0.72 rs11959928 rs9838614 1.9E-01 8.1E-03 4.2E-06 8.2E-04 SCN5A; ACVR2B; ENDOGL1 ENDOGL1 161 ACVR2B 3040 GI_10862697-S * rs2297797 1.1E-01 1.2E-01 4.2E-06 2.7E-05 CYB561D1 ATXN7L2; CYB561D1; SYPL2; GNAI3; GPR61; AMIGO1 CYB561D1 797 ATXN7L2 5326 CYB561D GI_32698981-S 0.32 rs1933182 rs1132064 2.4E-01 9.3E-03 4.3E-06 4.4E-06 SCN5A; ACVR2B; ENDOGL1 ENDOGL1 340 SCN5A 23033 GI_4826713-S * rs7374458 2.4E-01 7.2E-03 4.4E-06 1.8E-05 ACVR2B SCN5A; ACVR2B; ENDOGL1 ACVR2B 3420 ENDOGL1 6621 GI_4826713-S * rs2300669 2.4E-01 7.5E-03 4.5E-06 7.3E-05 ENDOGL1 SCN5A; ACVR2B; ENDOGL1 ENDOGL1 3486 ACVR2B 6687 GI_4826713-S * rs4795369 3.9E-01 2.2E-02 4.9E-06 5.3E-07 MED1; FBXL20; CRKRS MED1 1593 CRKRS 9171 GI_7706548-S * rs3741414 2.7E-02 1.5E-01 5.2E-06 2.5E-06 INHBC INHBE; GLI1; ARHGAP9; MARS; INHBC INHBC 560 INHBE 5046 GI_14210509-S * rs4311394 9.6E-01 2.5E-02 5.5E-06 2.5E-03 ARL15 ARL15 ARL15 120049 NDUFS4 321495 Hs.306852-S * rs6546862 3.7E-03 1.2E-01 5.7E-06 5.7E-06 NAT8; ALMS1 NAT8 7501 ALMS1 23302 ALMS1 GI_27436958-S 0.57 rs13538 46 rs12472502 3.4E-03 1.2E-01 5.8E-06 8.3E-06 NAT8; ALMS1 NAT8 8665 ALMS1 22138 ALMS1 GI_27436958-S 0.57 rs13538 rs931127 1.8E-02 3.7E-04 8.6E-06 1.8E-03 MAP3K11; RELA; SIPA1; KCNK7; EHBP1L1 SIPA1 294 RELA 16516 hmm1261-S rs7736354 8.7E-01 3.5E-02 1.0E-05 3.0E-03 ARL15 ARL15 ARL15 116978 NDUFS4 318424 Hs.306852-S * rs2163294 7.1E-02 4.7E-02 1.0E-05 4.9E-08 ATP1B3; TFDP2 TFDP2 2874 ATP1B3 23071 GI_4502280-S rs11126414 3.7E-04 1.8E-01 1.0E-05 1.5E-05 TPRKB; DUSP11; NAT8B NAT8B 3577 TPRKB 24959 TPRKB GI_7705589-S 0.35 rs13538 rs4852976 4.3E-04 9.5E-02 1.5E-05 5.6E-06 TPRKB; DUSP11; NAT8B NAT8B 7855 TPRKB 20681 TPRKB GI_7705589-S 0.39 rs13538 rs12620091 2.9E-03 1.4E-01 1.8E-05 4.6E-06 TPRKB; NAT8; NAT8B NAT8B 20818 NAT8 37282 NAT8 GI_7705327-S 0.42 rs13538 rs7210 1.4E-04 5.3E-02 1.8E-05 9.8E-06 TPRKB TPRKB; FLJ43987; DUSP11; NAT8B TPRKB 121 NAT8B 28657 TPRKB GI_7705589-S 0.39 rs13538 rs1589576 6.5E-05 4.0E-02 1.9E-05 1.5E-12 ALMS1 ALMS1 ALMS1 98242 NAT8 129045 ALMS1 GI_27436958-S 0.85 rs13538 rs2141372 2.0E-02 2.5E-01 2.0E-05 9.4E-05 ZNF512 XAB1; SLC4A1AP; CCDC121; SUPT7L; ZNF512; C2orf16 ZNF512 18762 CCDC121 21309 GPN1 GI_14149628-S 0.04 rs1260326 rs618838 6.2E-01 2.3E-02 2.0E-05 6.0E-10 ACTN3 RBM14; CCDC87; BBS1; ZDHHC24; CCS; CTSF; ACTN3; DPP3 ACTN3 2078 CTSF 2216 GI_6042195-S rs1815739 6.5E-01 2.6E-02 2.2E-05 8.0E-10 ACTN3 RBM14; CCDC87; BBS1; ZDHHC24; CCS; CTSF; ACTN3; DPP3 ACTN3 2702 CTSF 2840 GI_6042195-S rs1881396 2.2E-02 2.3E-01 2.6E-05 4.1E-04 ZNF512 XAB1; SLC4A1AP; CCDC121; SUPT7L; ZNF512; C2orf16 ZNF512 1357 CCDC121 3904 GI_14149628-S rs12101934 2.0E-01 4.4E-03 2.8E-05 2.1E-03 INOC1 INOC1 INOC1 55261 CHAC1 104370 GI_38570147-A * 47 rs2051216 1.4E-01 7.7E-03 2.9E-05 2.4E-05 ENDOGL1 SCN5A; ACVR2B; ENDOGL1 ENDOGL1 3891 SCN5A 27264 GI_4826713-S * rs9933029 8.5E-01 2.2E-01 3.0E-05 2.1E-04 SLC7A6 SLC7A6; NFATC3; RBM35B; SLC7A6OS; LYPLA3; PRMT7 SLC7A6 4988 LYPLA3 8451 GI_4507052-S * rs816828 1.9E-01 2.8E-01 3.1E-05 2.6E-22 KCNMA1 KCNMA1 KCNMA1 105709 DLG5 258682 GI_26638649-S rs1065212 1.0E+0 0 1.2E-05 3.9E-01 6.8E-16 HSPC111 C5orf25; HIGD2A; KIAA1191; CLTB; HSPC111; ARL10 HSPC111 192 HIGD2A 4650 GI_20270388-S * rs10838702 7.6E-02 1.4E-05 4.6E-05 4.6E-04 RAPSN; PSMC3; MYBPC3; SLC39A13; MADD; SPI1 SPI1 10761 SLC39A1 3 19293 GI_4507174-S rs17751897 0.0E+0 0 4.4E-02 7.7E-02 3.1E-07 CST3; CST9L; CST9 CST9 6201 CST3 21579 GI_19882253-S rs13043610 0.0E+0 0 4.7E-02 1.0E-01 8.0E-08 CST3; CST9L; CST9 CST9 428 CST3 27352 GI_19882253-S rs6036478 0.0E+0 0 6.4E-02 6.1E-02 1.3E-07 CST3; CST4; CST9 CST3 2934 CST9 24846 GI_19882253-S 48 Supplementary Table 7 - Additional SNPs associated with eGFRcrea and CKD at an FDR of 0.05. Shown are SNPs with p-value >5x10E-08 in stage 1 discovery analyses that are associated with eGFRcrea and CKD at an FDR of 0.05 (p<4.8x10E-06) trait SNP^ chr pos beta se pval qval coded allele coded allele freq. eSNP**, (r2 to FDR SNP) beta cys pval eGFRcys genes eGFRcrea rs4233535 1 15717784 -0.008 0.001 1.9E-07 0.024 c 0.30 rs4645989 (1) -0.008 1.3E-03 CASP9; AGMAT, CTRC, DDI2, DNAJC16, EFHD2, ELA2A, ELA2B eGFRcrea rs6431731 2 15780453 -0.018 0.003 3.2E-07 0.024 t 0.94 -0.006 4.0E-01 DDX1; eGFRcrea rs7593901 2 205598761 0.012 0.002 1.6E-06 0.047 t 0.08 0.008 8.4E-02 PARD3B; eGFRcrea rs6893522 5 53335192 -0.015 0.003 1.5E-06 0.046 t 0.95 rs7736354 (0.18) -0.003 5.3E-01 ARL15; eGFRcrea rs963837 11 30705666 -0.007 0.001 5.3E-08 0.024 t 0.54 -0.006 1.1E-02 eGFRcrea rs2193172 12 15223609 0.008 0.002 1.7E-06 0.049 c 0.19 0.011 2.2E-04 RERG; eGFRcrea rs11845823 14 92623469 -0.008 0.002 1.6E-06 0.047 a 0.78 -0.006 1.9E-02 ITPK1; C14orf109, C14orf85, MOAP1 eGFRcrea rs2453583 17 19382628 0.007 0.001 5.8E-07 0.024 a 0.59 0.005 7.3E-02 SLC47A1; SNORA59A, SNORA59B eGFRcrea rs12936996 17 34919080 -0.008 0.002 2.8E-07 0.024 a 0.74 rs4390625 (1) -0.003 3.2E-01 CRKRS; MED1, NEUROD2 All SNPs within 10^6 bp of genomewide associations excluded from FDR analysis. ^Best (smallest p-value) SNP from each locus with at least one SNP reaching FDR < 0.05. **eSNPs were selected among those significant for the same trait listed in this table as the one with the highest r2 to the SNP presented in this table. 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A B C λmeta=1.04 λmeta=1.03 λmeta=1.09 λ individual studies AGES: 1.03 KORAF4: 1.01 Amish: 1.04 Korcula: 1.00 ARIC: 1.04 Micros: 1.01 ASPS: 1.01 NSPHS: 0.94 BLSA: 1.01 Orcades: 0.98 CHS: 1.03 RS-I: 1.01 ERF: 1.05 RS-II: 1.00 FamHS: 1.05 SHIP: 1.00 FHS: 1.04 Vis: 0.99 KORAF3: 0.98 WGHS: 1.06 λ individual studies AGES: 1.02 KORAF4: 1.00 Amish: NA Korcula: 1.04 ARIC: 1.03 Micros: 1.03 ASPS: 0.97 NSPHS: 0.97 BLSA: 1.02 Orcades: 1.15 CHS: 1.03 RS-I: 1.04 ERF: 1.06 RS-II: 1.02 FamHS: 0.98 SHIP: 0.99 FHS: 1.04 Vis: 0.99 KORAF3: 1.01 WGHS: 0.99 λ individual studies AGES: NA KORAF4: 1.00 Amish: 1.02 Korcula: NA ARIC: 1.00 Micros: 1.00 ASPS: NA NSPHS: NA BLSA: NA Orcades: NA CHS: 1.03 RS-I: NA ERF: NA RS-II: NA FamHS: NA SHIP: 0.99 FHS: 1.02 Vis: NA KORAF3: 0.98 WGHS: NA eGFRcrea, n=67093 CKD, n=62237 eGFRcys, n=20957 Expected –log10(P) Expected –log10(P) O bs er ve d –l og 10 (P ) O bs er ve d –l og 10 (P ) O bs er ve d –l og 10 (P ) 0 5 10 15 0 0 5 10 15 0 5 10 15 5 10 15 0 0 5 10 15 20 25 0 5 10 15 20 25 λmeta represents the genomic control parameters after discovery meta-analysis, and the λ for the individuals studies is reported next to each trait. The graphs present p-values corrected for inflation at the study-specific level before meta-analysis as well as after meta- analysis for the meta-analysis genomic control parameter. No correction was applied to data from studies with λ<1.The graph for eGFRcys is cut off; all SNPs with lower p-values are located at the CST locus on chromosome 20. NA denotes phenotype unavailability. Black: results from meta-analysis, orange: null hypothesis. Suppl. Figure 1: Quantile-quantile plots of observed vs. expected -log10(p-values) from discovery analyses of eGFRcrea (A), CKD (B), and eGFRcys (C). Expected –log10(P) 54 Regional Association Plots - Susceptibility Loci for Reduced Renal Function and Chronic Kidney Disease O b se rv e d ( -l o g 10 P) Supplementary Figure 2 -log10 p-values are plotted versus genomic position (build 36). The lead SNP in each region is labeled. Other SNPs in each region are color-coded based on their LD to the lead SNP (LD based on the HapMap CEU, see color legend). Gene annotations are based on UCSC Genome Browser (RefSeq Genes, b36) and arrows indicate direction of transcription. Graphs were generated using the software SNAP (http://www.broadinstitute.org/mpg/snap/index.php). Chromosome 1 position (hg18) (kb) 148900 149200 149500 0 2 4 6 8 10 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs267734 0.8 0.5 r2 TARS2 ECM1 ADAMTSL4 MCL1 ENSA GOLPH3L HORMAD1 CTSS CTSK ARNT SETDB1 LASS2 ANXA9 FAM63A PRUNE BNIPL C1orf56 CDC42SE1 MLLT11 RP11-68I18.1 SEMA6C TNFAIP8L2 LYSMD1 SCNM1 TMOD4 VPS72 PIP5K1APSMD4 ZNF687 PI4KB RFX5 SELENBP1 PSMB4 POGZ Chromosome 2 position (hg18) (kb) 27300 27600 27900 0 3 6 9 12 0 20 40 60 80 R e co m b in a tio n ra t e (cM /M b ) rs1260326 0.8 0.5 r2 MAPRE3TMEM214 AGBL5 EMILIN1 KHK CGREF1 ABHD1 PREB C2orf53 TCF23 SLC5A6 C2orf28 CAD SLC30A3 DNAJC5G TRIM54 UCN MPV17 GTF3C2 EIF2B4 SNX17 ZNF513 PPM1G NRBP1 KRTCAP3 IFT172 FNDC4 GCKR C2orf16 ZNF512 CCDC121 GPN1 SUPT7L SLC4A1AP MRPL33 RBKS BRE chromosome 2, rs1260326, GCKR region chromosome 1, rs267734, LASS2 region 55 O b se rv e d ( -l o g 10 P) O b se rv e d ( -l o g 10 P) chromosome 2, rs13538, ALMS1 region chromosome 3, rs347685, TFDP2 region Chromosome 3 position (hg18) (kb) 143000 143300 143600 0 2 4 6 8 10 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs347685 0.8 0.5 r2 RASA2 RNF7 GRK7 ATP1B3 TFDP2 GK5 XRN1 ATR O b se rv e d ( -l o g 10 P) Chromosome 2 position (hg18) (kb) 73400 73700 74000 0 2 4 6 8 10 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs13538 0.8 0.5 r2 SMYD5 C2orf7 CCT7 FBXO41 EGR4 ALMS1 NAT8 NAT8B TPRKB DUSP11 FLJ43987 STAMBP ACTG2 DGUOK TET3 BOLA3 O b se rv e d ( -l o g 10 P) 56 chromosome 5, rs11959928, DAB2 region chromosome 5, rs6420094, SLC34A1 region Chromosome 5 position (hg18) (kb) 39100 39400 39700 0 3 6 9 12 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs11959928 0.8 0.5 r2 OSMR RICTOR FYB C9 DAB2 Chromosome 5 position (hg18) (kb) 176400 176700 177000 0 3 6 9 12 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs6420094 0.8 0.5 r2 HK3 UIMC1 ZNF346FGFR4 NSD1 RAB24 PRELID1 MXD3 LMAN2 RGS14 SLC34A1 PFN3 F12 GRK6 PRR7 DBN1 PDLIM7 DOK3 DDX41 FLJ10404 TMED9 B4GALT7 FAM153A O b se rv e d ( -l o g 10 P) O b se rv e d ( -l o g 10 P) 57 chromosome 6, rs881858, VEGFA region Chromosome 6 position (hg18) (kb) 43600 43900 44200 0 3 6 9 12 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs881858 0.8 0.5 r2 ZNF318 ABCC10 DLK2 TJAP1 C6orf154 YIPF3 POLR1C XPO5 POLH GTPBP2 MAD2L1BP C6orf206 MRPS18A VEGFA C6orf223 MRPL14 TMEM63B CAPN11 SLC29A1 HSP90AB1 SLC35B2 NFKBIE TCTE1 AARS2 O b se rv e d ( -l o g 10 P) Chromosome 7 position (hg18) (kb) 150700 151000 151300 0 3 6 9 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs7805747 0.8 0.5 r2 ABCF2 CSGlcA-T SMARCD3 NUB1 WDR86 CRYGN RHEB PRKAG2 GALNTL5 GALNT11 MLL3 O b se rv e d ( -l o g 10 P) chromosome 7, rs7805747, PRKAG2 region 58 chromosome 9, rs4744712, PIP5K1B region chromosome 12, rs653178, ATXN2 region Chromosome 9 position (hg18) (kb) 70300 70600 70900 0 3 6 9 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs4744712 0.8 0.5 r2 PGM5 C9orf71 PIP5K1BFAM122A PRKACG FXN TJP2 C9orf61 O b se rv e d ( -l o g 10 P) Chromosome 12 position (hg18) (kb) 110200 110500 110800 0 2 4 6 8 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs653178 0.8 0.5 r2 CUX2 FAM109A SH2B3 ATXN2 BRAP ACAD10 ALDH2 MAPKAPK5 TMEM116 ERP29 C12orf30 O b se rv e d ( -l o g 10 P) 59 chromosome 13, rs626277, DACH1 region Chromosome 15 position (hg18) (kb) 73600 73900 74200 0 3 6 9 12 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs1394125 0.8 0.5 r2 SIN3A PTPN9 SNUPN IMP3 SNX33 CSPG4 ODF3L1 UBE2Q2FBXO22 NRG4 C15orf27 ETFA ISL2 SCAPER O b se rv e d ( -l o g 10 P) Chromosome 13 position (hg18) (kb) 70900 71200 71500 0 3 6 9 12 0 20 40 60 80 R e co m b in a tio n ra te (cM /M b ) rs626277 0.8 0.5 r2 DACH1 chromosome 15, rs1394125, UBE2Q2 region O b se rv e d ( -l o g 10 P) 60 chromosome 19, rs12460876, SLC7A9 region Chromosome 19 position (hg18) (kb) 37700 38000 38300 0 2 4 6 8 10 0 20 40 60 80 R e co m b in a tio n ra t e (cM /M b ) rs12460876 0.8 0.5 r2 ZNF507 DPY19L3 PDCD5 ANKRD27 RGS9BP NUDT19 TDRD12 SLC7A9 CCDC123 C19orf40 RHPN2 GPATCH1 WDR88 LRP3 SLC7A10 CEBPA O b se rv e d ( -l o g 10 P) 61 Supplement_R2_FinalSubmission_031710_clean.doc [Compatibility Mode] Supplement_R2_FinalSubmission_031710_clean2a Supplement_R2_FinalSubmission_031710_clean.2 QQ_multipanel_022210 Regional_plots_022610_page1 Regional_plots_022610_page2 Regional_plots_022610_page3 Regional_plots_022610_page4 Regional_plots_022610_page5 Regional_plots_022610_page6 Regional_plots_022610_page7