key: cord-0317174-5uolezav
authors: Liu, L.; Khan, A.; Sanchez-Rodriguez, E.; Zanoni, F.; Li, Y.; Steers, N.; Balderes, O.; Zhang, J.; Krithivasan, P.; LeDesma, R. A.; Fischman, C.; Hebbring, S. J.; Harley, J. B.; Moncrieffe, H.; Kottyan, L. C.; Namjou-Khales, B.; Walunas, T. L.; Knevel, R.; Raychaudhuri, S.; Karlson, E. W.; Denny, J. C.; Stanaway, I. B.; Crosslin, D.; Rauen, T.; Floege, J.; Eitner, F.; Moldoveanu, Z.; Reily, C.; Knoppova, B.; Hall, S.; Sheff, J. T.; Julian, B. A.; Wyatt, R. J.; Suzuki, H.; Xie, J.; Chen, N.; Zhou, X.; Zhang, H.; Hammarstrom, L.; Viktorin, A.; Magnusson, P. K. E.; Shang, N.; Hripcsak, G.; Weng,
title: Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
date: 2021-11-20
journal: nan
DOI: 10.1101/2021.11.19.21265524
sha: 2333a93ea21436339a9c3b9c74552935b779b1bd
doc_id: 317174
cord_uid: 5uolezav

Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and has a known role in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed genetic analyses of serum IgA levels in 41,263 individuals of diverse ancestries. We observed unexpected variability in IgA levels across major ancestral populations, with African ancestry being reproducibly associated with higher serum IgA levels compared to other ancestries. The trans-ethnic GWAS analysis identified 20 genome-wide significant loci associated with serum IgA levels, including nine known and 11 novel loci. Systematic co-localization analysis with blood and primary immune cell expression QTLs prioritized candidate genes for 14 of 20 loci. Most GWAS loci encoded genes that produce immune defects and IgA abnormalities when genetically manipulated in mice. We uncovered positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes and body mass index, as well as negative genetic correlations with celiac disease, inflammatory bowel disease, several infections, and intestinal microbiome diversity. Our findings provide novel insights into the genetic regulation of IgA production and its potential role in human disease.

Immunoglobulin A (IgA) provides protection against mucosal infections and contributes to the pathogenesis of 73 autoimmune and inflammatory disorders 1,2 . Most of the IgA production occurs at the mucosal surfaces along 74 the gastrointestinal and respiratory tracts, but a large portion of circulating IgA is contributed by bone-marrow 

In this study, we conducted a multiethnic GWAS meta-analysis for serum IgA levels in 41,263 85 individuals across 17 international cohorts of diverse ancestries, maximizing power for genetic discovery. We 86 identified novel genetic determinants of serum IgA levels and, through comprehensive functional annotations, 87 we prioritized candidate causal genes at each of the IgA-associated loci. We then investigated the shared 88 genetic architecture between serum IgA levels and other human traits using several approaches, including five of the 20 loci had at least two independently genome-wide significant variants underlying their association 123 signal ( Table 2 and Supplementary Table 1 ). The conditionally independent genome-wide significant SNPs 124 jointly explained approximately 2% of the overall phenotypic variance. In addition, we identified eight 125 suggestive signals with P<1x10 -6 (Supplementary Table 2) , including the TNFSF13 locus previously reported 126 in a GWAS performed in a Han Chinese cohort 19 . Using linkage disequilibrium (LD)-score regression method 21 , 127 we estimated the genome-wide SNP-based heritability of age-and sex-adjusted IgA levels at approximately 128 7% (95%CI: 2%-11%).

As expected, the effect sizes of independently associated variants were inversely related to their minor 130 allelic frequencies (Figure 2b) . Two relatively rare genome-wide significant variants exhibited the largest 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. to non-coding regions, we evaluated their potential regulatory function by systematic eQTL co-localization 177 analyses using whole blood 28 and 13 primary immune cell types 29 . The co-localization probability (PP4)

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The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint exceeded 50% in at least one cell type for 14 of 20 GWAS loci, prioritizing biologically plausible candidate 179 genes at each of these loci (Figure 3a and 208 locus previously associated with IgA levels 20 . The top SNP is within the FADS2 gene, and the IgA-increasing 209 haplotype has previously been associated with ratio of arachidonic to linoleic acid reflective of fatty acid 210 desaturase activity and linked to the risk of coronary artery disease 35,36 . At the same time, the IgA-increasing 211 haplotype has previously been described as protective from rheumatoid arthritis (Figure 2c) . The second 212 independent signal centers on the TMEM258 gene, previously associated with the risk of Crohn's disease 37 .

The co-localization analyses of this locus across multiple immune cell types and whole blood suggested 214 several candidate genes, including FADS1 and FADS2 genes (fatty acid desaturases regulating unsaturation 215 of fatty acids, co-localized across most cell types) and the TMEM258 gene (co-localized specifically in T cells),

with the IgA-increasing allele (rs968567-T) associated with higher expression of all three transcripts. Rs968567 217 falls into a genetically regulated histone-modification peak (H3K4me1) for FADS2 in T cells, monocytes and 218 neutrophils 38 . TMEM258 is a particularly attractive candidate gene at this locus, because it appears to play an represented a monocyte-specific hQTL (H3K27ac) 38 , suggesting that it alters LITAF enhancer activity in the 228 monocytic lineage (Figure 3a and c) . The IgA-increasing allele (rs113962704-T) was associated with higher 229 mRNA expression of LITAF in monocytes, supporting the hypothesis that this transcription factor provides a 230 stimulus for IgA production by altering monocyte function.

The locus on chr.14q32.32 (rs12147883, Beta=0.05, P=5.42x10 -14 ) contains TRAF3 encoding TNF 232 Receptor Associated Factor 3, a protein participating in the CD40 signaling, inhibiting non-classical NF-κB 233 signaling, and participating in the regulation of class switch recombination in B cells [43] [44] [45] . Interestingly, this locus 234 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint co-localizes with eQTL for TRAF3 specifically in T cell lineage, where the IgA-increasing variant is associated 235 with higher TRAF3 expression. In contrast to its inhibitory functions in B-cells, TRAF3 is known to promote 236 many T-cell effector functions through enhancing signaling by the T-cell receptor-CD28 complex 46,47 .

The third locus on chr.12q13.11 (rs7487637, Beta=0.05, P=9.97x10 -15 ) contains HDAC7 encoding an CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint (P=3.1x10 -12 ), spleen (P=1.5x10 -6 ) and EBV-transformed lymphocytes (4.7x10 -9 ) with the IgA-increasing allele 263 (rs10896045-A) associated with high expression of OVOL1 gene in all three GTEx tissues. 

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The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint IL-6-type cytokine receptor ligand interactions and signaling (Figure 4a) . The CITED2 locus on chr.6q24.1 291 (rs17069163, Beta=0.05, P=5.94x10 -11 ) encodes a CBP/P300 interacting trans-activator, which functions as a 292 molecular switch of TGF-a and TGF-b induced signaling 60 and has previously been implicated in immune 293 homeostasis and tolerance 61 . The locus on chr.1q41 (rs73100295, Beta=0.36, P=3.91x10 -08 ) encodes the 294 GPATCH2 gene, but its role in the immune system regulation is unknown. The co-localization analysis of the 295 locus on chr.7q11.23 (rs55722505, Beta=0.048, P=8.61x10 -14 ) suggested several candidate effector genes 296 including SRCRB4D, DTX2 and YWHAG genes in whole blood, ZP3 and SSC4D in monocytes, and POMZP3 297 in naïve CD8 and B cells (Figure 3a) . Lastly, we confirmed the previously described effect of the HLA locus, 298 and our stepwise conditional analysis identified at least eight independent SNPs contributing to the HLA signal, Table 11 ). Among these, there were five genome-wide 319 significant loci with high probability of shared causal variants (PP4>0.7), TNFSF4/TNFSF18, ANKRD55/IL6ST, 320 OVOL1/RELA, SH2B3, and HORMAD2/LIF (Supplementary Table 12 ). There were also four loci with an 321 overlapping genomic position, but high probability of different causal variants between the two traits (PP3>0.7),

HLA, CTF1, TRAF3 and TNFSF8/TNFSF15. Between IgA levels and tonsillectomy, we observed two co-323 localized loci (SH2B3 and HORMAD2/LIF), both with concordant effects, and another two loci (HLA and CTF1) 324 with high probability of different causal variants (Supplementary Table 13 ). Remarkably, the HORMAD2/LIF 325 locus was genome-wide significant in all three GWAS and co-localized across all three traits, suggesting a 326 common genetic mechanism (Figure 5a and b) .

To further explore the genetic relationships between these traits, we performed two sample Mendelian 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table   365 15). In this analysis, we detected only two phenome-wide-significant associations: a protective association with 366 Celiac disease (OR per SD=0.86, P=4.6x10 -12 ) and a risk association with morbid obesity (ORSD=1.09, 367 P=3.0x10 -5 ). These associations were direction-consistent with our genome-wide genetic correlation analyses.

Given these results, we next applied Mendelian randomization approach to resolve potential causal 369 relationships between serum IgA levels, Celiac disease, and BMI. For instrumental variables, we used 370 independent genome-wide significant alleles (excluding HLA region) from this study, and from the largest 371 studies for Celiac disease 64 and BMI 65 . Interestingly, we detected no significant causal effects between serum 372 IgA levels and Celiac disease or BMI. In reverse causality analyses, however, we observed a highly significant 373 causal effect of BMI on serum IgA levels (inverse variance weighted effect = 0.12, 95%CI: 0.05-0.19, P<0.001).

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We also observed an inverse genetic correlation of serum IgA levels with intestinal microbiome 428 diversity, which may be related to the associations of IgA levels with obesity and inflammatory bowel disease.

The species abundance of Dorea longicatena in particular was most strongly correlated with GWAS loci for 

In summary, we identified 20 genome-wide significant loci associated with serum IgA levels, and we 

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Samples with an internal CV greater than 10% were re-run. Samples that fall outside of the standard range 465 (500 ng/mL -0.2 ng/mL) were re-run at appropriate dilutions. 

We measured serum IgA levels using standardized ELISA protocol (see above) in N=5420 participants, and 472 these individuals were included in the GWAS analysis. The standard genotype quality control (QC) filters 473 included per-SNP genotyping rate >95%, per-individual genotyping rate >90%, MAF >0.01, and HWE test p-

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We obtained summary statistics for GWAS for total IgA levels for 9,617 participants; the ascertainment, 526 genotyping, and analysis of this cohorts has been published previously 16 . In order to improve marker density, 527 we re-imputed this cohort based on association estimates of the genotyped markers from the summary 528 statistics using ImPG V1.0 82 software and the 1000 Genomes (Phase 3) European reference 76 . Using ImPG 529 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Genome-wide association studies and multiethnic meta-analysis

We conducted a multiethnic meta-analysis of 17 discovery cohorts including a total of 41,263 individuals.

Multiethnic cohorts were classified into ancestry-specific strata based on global PCA analysis. In each sub-549 cohort, serum IgA levels were log-transformed and expressed as standard-normalized residuals from 550 regression of log-transformed IgA levels against age and sex. We performed genome-wide association testing 551 in each cohort for the markers that were imputed at high quality (r " > 0.8) using a linear regression model 552 under additive coding of the dosage genotypes, and with adjustment for cohort-specific significant principal 553 components (PCs) of ancestry 85 . To quantify potential inflation of type I error due to stratification or technical 554 artifacts, we estimated the genomic inflation factor for each cohort but detected no substantial inflation with 555 lambda <1.05 in each individual study. We performed a fixed-effects meta-analysis to combine the results of 556 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Supplementary Figure 2) . The genome-wide significant signals were defined by the generally 559 accepted P<5.0x10 -8 and signals with P<1.0x10 -6 were considered as suggestive. 

We first defined each GWAS locus by +/-400kb of the genome-wide significant index SNP. We annotated all 583 transcripts within these intervals using the latest assembly of the human genome (hg19) to create sets of 584 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint positional candidate genes for each locus. Using ANNOVAR software 88 , we annotated all variants within the 585 region that were in LD (r 2 >0.5) with the top SNP, including all known coding, splicing, and 3'UTR and 5'UTR 586 variants. To prioritize the candidate genes at each of the GWAS loci, we next performed colocalization 587 analyses based on our meta-analysis statistics and gene expression QTLs in whole blood quantified from 

In addition, we used ToppGene Suite 91 to calculate interaction enrichment p-values for each gene. A

Bonferroni-corrected P<0.05 was used as enrichment significance cut-off.

Intersection with related mouse phenotypes

We evaluated genes that when knocked out cause abnormal immune phenotypes in mice based on the 608 comprehensive MGI phenotype ontology database. The following mouse phenotypes were evaluated: 

We calculated a maximum r 2 between SNPs associated with each catalogued trait and the independent SNPs 639 from our study based on 1000 Genomes Project Phase 3 data 93 . We defined shared susceptibility alleles if 640 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. available ICD-10 codes to ICD-9-CM system given that the great majority eMERGE-III diagnoses were coded 665 using ICD-9-CM. After the conversion, eMERGE participants had a total of 20,783 ICD codes that were then 666 mapped to 1,817 distinct phecodes. The 488,377 UKBB participants had a total of 10,221 ICD codes mapped 667 to 1,523 phecodes. Phenome-wide associations were then performed using the PheWAS R package 101 . The

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The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint case definition required a minimum of two ICD-9 codes from the "case" grouping of each phecode, while 669 "control" group had no ICD-9 codes relevant to the tested phecode. In total, 1,523 overlapping phecodes were 670 tested in both UKBB and eMERGE-III using logistic regression after adjusting each analysis for age, sex, study 671 site, genotyping batch, and 3 PCs of ancestry. The meta-PheWAS across both datasets was performed using 

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The copyright holder for this this version posted November 20, 2021. ; https://doi.org/10.1101/2021.11.19.21265524 doi: medRxiv preprint

summary statistics for the intestinal microbiome GWAS. This work was funded by the National 697

Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant numbers R01-DK105124 (KK)

with additional support 699 by R01-LM013061 (KK, CW), R01-LM006910 (GH)

K01-DK106341 (CR), and R03-DK122194 (CR). JF and FE were 701 funded by the Deutsche Forschungsgemeinschaft

TR is funded by R01-MD012467, R01-NS029993, R01-NS040807

U19-AG065169, UL1-TR002736, KL2-TR002737, and the Florida Department of Health. MESA and the

MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI)

in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001

N01-HC-95161, 75N92020D00005

75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166

Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping 711 was performed at Affymetrix

USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Parts of this study have been 713 conducted using the UKBB Resource under UKBB project ID number 41849. The eMERGE network is 714 funded by the National Human Genome Research Institute (NHGRI) through the following grants

U01HG008666 (Cincinnati Children's

U01HG008684 (Children's Hospital of Philadelphia)

U01HG008701 (Vanderbilt University Medical Center serving as the Coordinating 720

U01HG008676 (Partners Healthcare/Broad Institute)

and U54MD007593 (Meharry Medical College). The NIDDK, NHLBI, and NHGRI had no role in the design of InWeb

The function of immunoglobulin A in immunity

Impact of the molecular form of immunoglobulin A on functional 804 activity in defense against Streptococcus pneumoniae

Structure and function relationships in IgA

Role of secretory IgA in infection and maintenance of homeostasis

Distinct features of SARS-CoV-2-specific IgA response in COVID-19 810 patients

Serum IgA, IgM, and IgG responses in COVID-19

IgA dominates the early neutralizing antibody response to SARS-CoV-2

Significance of serum IgA levels and serum IgA/C3 ratio in diagnostic 816 analysis of patients with IgA nephropathy

Dysfunctions of the Iga system: a common link 818 between intestinal and renal diseases

High serum IgA concentrations in patients with diabetes 820 mellitus: agewise distribution and relation to chronic complications

Serum levels of immunoglobulins (IgG, IgA, IgM) in a general 823 adult population and their relationship with alcohol consumption, smoking and common 824 metabolic abnormalities

Genetic and environmental influences on serum levels of 826 immunoglobulins and complement components in monozygotic and dizygotic twins

Biologic variation of human 829 immunoglobulin concentration. I. Sex-age specific effects on serum levels of IgG, IgA, 830 IgM and IgD

Changes in human serum immunoglobulin levels with 832 age and sex

IgA1 Glycosylation Is Heritable in Healthy Twins

IgA measurements in over 12 000 Swedish twins reveal sex differential 836 heritability and regulatory locus near CD30L

Causal analysis of the variability of IgA, IgG, and 838 IgM immunoglobulin levels

Heritability estimates and genetic and environmental correlations for 840 the human immunoglobulins G, M, and A

Genome-wide association study identifies TNFSF13 as a susceptibility gene 842 for IgA in a South Chinese population in smokers

Identification of sequence variants influencing immunoglobulin levels

LD Score regression distinguishes confounding from 846 polygenicity in genome-wide association studies

Detection of human adaptation during the past 2000 years

ToppGene Suite for gene list 850 enrichment analysis and candidate gene prioritization

Biological interpretation of genome-wide association studies using 853 predicted gene functions

The NHGRI-EBI GWAS Catalog of published genome-wide association 855 studies, targeted arrays and summary statistics 2019

Toward Adenotonsillectomy in Children: A Review for the 858 General Pediatrician

ELL2, a new member of an ELL family of RNA polymerase II 860 elongation factors

Large-scale cis-and trans-eQTL analyses identify thousands of genetic loci 862 and polygenic scores that regulate blood gene expression

Impact of Genetic Polymorphisms on Human Immune Cell Gene 865 Expression

Genome-Wide Association Study on Immunoglobulin G Glycosylation 867 Patterns

Role of RUNX family members in transcriptional repression 869 and gene silencing

The RUNX family: developmental regulators in cancer

Requirement for Runx proteins in IgA class switching acting 873 downstream of TGF-beta 1 and retinoic acid signaling

Variants in ELL2 influencing immunoglobulin levels associate with 875 multiple myeloma

FADS genotypes and desaturase activity estimated by the ratio of 877 arachidonic acid to linoleic acid are associated with inflammation and coronary artery 878 disease

Genetic adaptation of fatty-acid metabolism: a human-specific 880 haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids

Genome-wide meta-analysis increases to 71 the number of confirmed 883

Crohn's disease susceptibility loci

Genetic Drivers of Epigenetic and Transcriptional Variation in Human 885 Immune Cells

LITAF mediation of increased TNF-alpha secretion from inflamed 889 colonic lamina propria macrophages

A new transcription factor that regulates TNF-alpha gene expression

LITAF, is increased in intestinal tissues from patients with CD and UC

LPS-induced TNF-alpha factor (LITAF)-894 deficient mice express reduced LPS-induced cytokine: Evidence for LITAF-dependent LPS 895 signaling pathways

Specificity of TRAF3 in its 897 negative regulation of the noncanonical NF-kappa B pathway

TRAF3 controls activation of the canonical and alternative NFkappaB by 900 the lymphotoxin beta receptor

TRAF3 Acts as a Checkpoint of B Cell Receptor Signaling to Control 902

Antibody Class Switch Recombination and Anergy

TNF receptor-associated factor 3 is 904 required for T cell-mediated immunity and TCR/CD28 signaling

TRAF3 in T Cells Restrains 907 Negative Regulators of LAT to Promote TCR/CD28 Signaling

Histone Deacetylase 7 mediates tissue-909 specific autoimmunity via control of innate effector function in invariant Natural Killer T 910 Cells

Genome-wide association analysis identifies variation in vitamin D 912 receptor and other host factors influencing the gut microbiota

Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and 915

Regulation and function of NF-kappaB transcription 917 factors in the immune system

Loci associated with N-glycosylation of human immunoglobulin G show 919 pleiotropy with autoimmune diseases and haematological cancers

Novel Insights into the Multiple Sclerosis Risk Gene 922 ANKRD55

Overview of the IL-1 family in innate inflammation and acquired 924 immunity

miRDB: an online database for prediction of functional microRNA 926 targets

Predicting effective microRNA target 928 sites in mammalian mRNAs

The IL-1 receptor 1 is critical for Th2 cell type airway 930 immune responses in a mild but not in a more severe asthma model

Regulation of normal B-cell differentiation and malignant B-cell 933 survival by OCT2

Mouse Genome Database (MGD) 2019

CITED2 functions as a molecular switch of cytokine-induced 937 proliferation and quiescence

Transforming Growth Factor-beta Signaling in Immunity and 939

Genome-wide association and HLA region fine-mapping studies identify 941 susceptibility loci for multiple common infections

An atlas of genetic correlations across human diseases and traits

Dense genotyping identifies and localizes multiple common and rare 945 variant association signals in celiac disease

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The effect of host genetics on the gut microbiome

An Update on the Current State of 951 Management and Clinical Trials for IgA Nephropathy

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Gut Microbiota Profile and Its Association with Clinical Variables and 955 Dietary Intake in Overweight/Obese and Lean Subjects: A Cross-Sectional Study

A comparative study of the gut microbiota in immune-mediated 958 inflammatory diseases-does a common dysbiosis exist? Microbiome

Diversity and dynamism of IgA-microbiota 960 interactions

Multi-Ethnic Study of Atherosclerosis: objectives and design

Whole genome sequence analysis of pulmonary function and COPD in 964 19,996 multi-ethnic participants

Next-generation genotype imputation service and methods

Reference-based phasing using the Haplotype Reference Consortium 968 panel

A global reference for human genetic variation

Fast Principal-Component Analysis Reveals Convergent Evolution of 972 ADH1B in Europe and East Asia

The eMERGE genotype set of 83,717 subjects imputed to ~40 974 million variants genome wide and association with the herpes zoster medical record 975 phenotype

Medical Records-Based Genetic Studies of the Complement System

Medical records-based chronic kidney disease phenotype for clinical care 979 and "big data" observational and genetic studies

GWAS for serum galactose-deficient IgA1 implicates critical genes of the 981 O-glycosylation pathway

Fast and accurate imputation of summary statistics enhances 983 evidence of functional enrichment

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Principal components analysis corrects for stratification in genome-wide 989 association studies

METAL: fast and efficient meta-analysis of 991 genomewide association scans

Conditional and joint multiple-SNP analysis of GWAS summary statistics 993 identifies additional variants influencing complex traits

ANNOVAR: functional annotation of genetic variants 996 from high-throughput sequencing data

Bayesian test for colocalisation between pairs of genetic 998 association studies using summary statistics

A scored human protein-protein interaction network to catalyze genomic 1000 interpretation

ToppCluster: a multiple 1002 gene list feature analyzer for comparative enrichment clustering and network-based 1003 dissection of biological systems

LD Hub: a centralized database and web interface to perform LD score 1005 regression that maximizes the potential of summary level GWAS data for SNP 1006 heritability and genetic correlation analysis

Discovery of new risk loci for IgA nephropathy implicates genes involved 1008 in immunity against intestinal pathogens

Cytoscape: a software environment for integrated models of 1010 biomolecular interaction networks

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic 1012 Risk Scores

Fast principal component analysis of large-scale genome-wide 1014 data

UK biobank: an open access resource for identifying the causes of a 1016 wide range of complex diseases of middle and old age

A global reference for human genetic variation

Fast and accurate 1020 genotype imputation in genome-wide association studies through pre-phasing

The UK Biobank resource with deep phenotyping and genomic data

PheWAS: demonstrating the feasibility of a phenome-wide scan to 1025 discover gene-disease associations

The MR-Base platform supports systematic causal inference across the 1027 human phenome

Figure 3 | Colocalization and enrichment analyses across different tissue/cell types

Colocalization analysis with gene expression QTLs (eQTLs) in whole blood and primary immune cells; each 1061 row indicates one gene and each column denotes one tissue/cell type; the color from red to white shows 1062 the probability of sharing the same causal variant between GWAS loci and eQTLs (PP4). (b) Tissue/cell 1063 type enrichment in DEPICT

MeSH tissue and cell type annotations. (c) Integrative analysis of eQTL and hQTL for LITAF locus. The 1065 upper and lower panels show the regional plots of the LITAF locus for IgA GWAS and eQTLs in monocyte, 1066 respectively

The lowest panel denotes the positions of LITAF gene and a hQTL peak (H3K27ac) in monocyte

Supplementary Table 14 provides a comparison of genetic 1094 correlations with and without HLA. (b) Meta-PheWAS of genome-wide polygenic score (GPS) for IgA levels 1095 across eMERGE-III and UKBB biobanks (total N=556,656). The y axis shows -log10 (P-value) and is 1096 truncated to accommodate the top association with celiac disease

Bonferroni-corrected significance threshold for 1,523 phecodes tested (alpha = 0.05/1,523 = 3.28 x 10 -5 )

Each triangle represents an individual phenotype (phecode) tested as an outcome against the GPS for IgA 1099 levels as a predictor; an upward triangle indicates a positive (risk) association, while a downward triangle 1100 indicates a negative (protective) association. All associations are adjusted for age, sex, site, genotyping 1101 batch, and principal components of ancestry. The phenotypes are grouped by organ system (or relevant 1102 disease category) and sorted based on their statistical significance within each group

We are grateful to all study participants for contributing DNA and serum samples for the purpose of our 693 genetic studies. We would also like to acknowledge Dr. Andre Franke, Institute of Clinical Molecular Biology,