Zeggini Genome Medicine 2014, 6:83 http://genomemedicine.com/content/6/10/83 RESEARCH HIGHLIGHT Using genetically isolated populations to understand the genomic basis of disease Eleftheria Zeggini Abstract Rare variation has a key role in the genetic etiology of complex traits. Genetically isolated populations have been established as a powerful resource for novel locus discovery and they combine advantageous characteristics that can be leveraged to expedite discovery. Genome-wide genotyping approaches coupled with sequencing efforts have transformed the landscape of disease genomics and highlight the potentially significant contribution of studies in founder populations. ways underpinning T2D were achieved through the Complex trait locus discovery in isolated populations Genetically isolated or founder populations have recently returned to the fore of genetic association studies as valuable resources for complex trait gene identification [1]. Population isolates have well-documented character- istics, including reduced phenotypic, environmental and genetic heterogeneity, that can aid in the detection of rare variants associated with complex traits. In isolated populations, where a relatively small number of individ- uals found a new population, rare variants that were present in the founders can drift up in frequency as the population expands, thus increasing power for genetic association studies. The small effective population size, which remains small over time, leads to increased levels of homozygosity and linkage disequilibrium. In addition, isolated population cohorts often provide the opportun- ity to recall subjects by genotype, access detailed genea- logical records, obtain linkage to health records and follow the cohort longitudinally. Recent successes in the literature have highlighted how these advantageous characteristics can help with disease gene mapping. Researchers studying the Ice- landic population have, in recent years, pioneered the Correspondence: Eleftheria@sanger.ac.uk Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK © 2014 Zeggini; licensee BioMed Central Ltd. months following its publication. After this time, t (http://creativecommons.org/licenses/by/4.0), whi the original work is properly credited. The Creativ publicdomain/zero/1.0/) applies to the data mad use of next-generation association studies, a hybrid of genome-wide genotyping and whole genome sequencing (WGS) approaches, for complex disease gene mapping [2,3]. In Iceland, numerous novel loci for complex dis- eases, such as type 2 diabetes (T2D) and prostate cancer [4,5], have been identified through a combination of WGS and long-range phasing-assisted imputation on a genome-wide genotype scaffold, together with calcula- tion of genotype probabilities in approximately 300,000 untyped individuals by making use of the extended ge- nealogical information available. More recently, novel insights into the biological path- study of a Greenlandic founder population [6]. A non- sense variant in the TBC1D4 gene was found to be strongly associated with postprandial hyperglycemia, im- paired glucose tolerance and T2D. These unique insights into the mechanism conferring muscle insulin resistance for this subset of T2D was afforded by studying the small Greenlandic population, which has experienced a dramatic increase in T2D prevalence, and recalling indi- viduals based on their TBC1D4 variant status. This poly- morphism is common in Greenland (17% minor allele frequency), but vanishingly rare in other global popula- tions (only encountered in one Japanese individual in the 1000 Genomes Project data). This work elegantly demonstrates the value of combining the genetic charac- teristics of founder populations with the potential to re- contact participants for further follow-up of promising results. Studies in extensively phenotyped founder popu- lation cohorts, such as the Amish, have also demon- strated the value of combining unique population characteristics with recall of subjects to increase our un- derstanding of disease etiopathology. The Old Order Amish are a cultural isolate and geographically localized, genetically homogeneous population with extensive ge- nealogical records available. This deeply phenotyped co- hort has been the subject of long-term genetic studies. For example, in 2008, Pollin et al. [7] reported a mis- sense variant (R19X) that abolishes expression of the The licensee has exclusive rights to distribute this article, in any medium, for 12 he article is available under the terms of the Creative Commons Attribution License ch permits unrestricted use, distribution, and reproduction in any medium, provided e Commons Public Domain Dedication waiver (http://creativecommons.org/ e available in this article, unless otherwise stated. mailto:Eleftheria@sanger.ac.uk http://creativecommons.org/licenses/by/4.0 http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/ Zeggini Genome Medicine 2014, 6:83 Page 2 of 3 http://genomemedicine.com/content/6/10/83 APOC3 gene and is strongly associated with a cardiopro- tective phenotype (higher high-density lipoprotein and lower blood triglyceride levels). Notably, the same missense cardioprotective variant was also found in an independent isolated population from Greece in the HELIC-MANOLIS study [8]. Resi- dents of the mountainous Mylopotamos villages on Crete have a high fat content diet but anecdotally display lower levels of, for example, T2D complications com- pared with the general population. The R19X APOC3 variant was carried by approximately 4% of the individ- uals studied and reached genome-wide statistical signifi- cance with a sample size of fewer than 1,300. Discovery of the same effect in the general population would have required over 50 times the number of subjects. Large- scale studies of over 110,000 individuals of European descent have recently also established an association of rare variants in the APOC3 locus with protection against high triglyceride levels and coronary artery disease [9]. APOC3 is now becoming a poster child for the power afforded by founder populations and clearly demon- strates the generalizability of findings in isolates into more cosmopolitan populations. A prime example of how founder population charac- teristics coupled with linkage to medical records can ac- celerate discovery was recently produced by studying the Finnish population [10]. In a whole exome sequencing study of about 3,000 Finns, Lim et al. first established that the Finns have fewer variable sites overall but more loss-of-function variants compared with non-Finnish European individuals, and subsequently identified robust associations with key traits of medical relevance. Linkage to national medical records resulted in the demonstra- tion that splice variants in the LPA gene that are associ- ated with low levels of plasma lipoprotein(a) confer protection against cardiovascular disease. Future directions Going forward, it is clear that founder populations can provide a unique and powerful resource for the identifi- cation of low frequency and rare variants of direct medical consequence. Power to detect association is demonstrably boosted for individual sequence variants that have drifted up in frequency. In addition, power to detect a significant accumulation of rare variants at par- ticular loci is further increased in founder populations as neutral rare variation may be lost from the haplotype pool. In this context, meta-analysis at the locus level across different isolates is posited to be important for establishing burden of proof, although this principle requires empirical substantiation. Historically, the trans- ferability of findings in isolates across to more cosmo- politan populations has been a topic of debate. However, there is an accrual of emerging examples of loci discovered in founder populations that are more widely generalizable, with replication of signals achieved in di- verse sample sets [4,5,7-9]. Furthermore, invaluable and unprecedented insights into disease pathogenesis can be afforded by findings restricted to genetically isolated populations, as exemplified by the elegant metabolic trait study in Greenland [6]. Decreasing costs for deep whole genome sequencing and the increasing availability of deeply phenotyped genetically isolated cohorts sets the scene for further success stories in the near future. Abbreviations T2D: Type 2 diabetes; WGS: Whole genome sequencing. Competing interests The author has no competing interests to declare. References 1. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E, Kathiresan S, Daly MJ, Neale BM, Sunyaev SR, Lander ES: Searching for missing heritability: designing rare variant association studies. 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Genome Medicine 2014 6:83. Abstract Complex trait locus discovery in isolated populations Future directions Abbreviations Competing interests References