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Exome sequencing of Finnish isolates enhances rare-variant association power.

ABSTRACT: Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

SUBMITTER: Locke AE

PROVIDER: S-EPMC6697530 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Exome sequencing of Finnish isolates enhances rare-variant association power.

Locke Adam E AE Steinberg Karyn Meltz KM Chiang Charleston W K CWK Service Susan K SK Havulinna Aki S AS Stell Laurel L Pirinen Matti M Abel Haley J HJ Chiang Colby C CC Fulton Robert S RS Jackson Anne U AU Kang Chul Joo CJ Kanchi Krishna L KL Koboldt Daniel C DC Larson David E DE Nelson Joanne J Nicholas Thomas J TJ Pietilä Arto A Ramensky Vasily V Ray Debashree D Scott Laura J LJ Stringham Heather M HM Vangipurapu Jagadish J Welch Ryan R Yajnik Pranav P Yin Xianyong X Eriksson Johan G JG Ala-Korpela Mika M Järvelin Marjo-Riitta MR Männikkö Minna M Laivuori Hannele H Dutcher Susan K SK Stitziel Nathan O NO Wilson Richard K RK Hall Ira M IM Sabatti Chiara C Palotie Aarno A Salomaa Veikko V Laakso Markku M Ripatti Samuli S Boehnke Michael M Freimer Nelson B NB

Nature 20190731 7769

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of ra ...[more]

PMID: 31367044

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Project description:Background:Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods:Using 11?990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Results:Strong signals were detected for CDKN2A (Pmin = 6.16?×?10-8) in the CM cohort (n?=?273) and BAP1 (Pmin = 3.83?×?10-6) in the OM (n?=?99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379?CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75?×?10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37?×?10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions:The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

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Exome sequencing of Finnish isolates enhances rare-variant association power.

Publications

Exome sequencing of Finnish isolates enhances rare-variant association power.

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