@article{db063b8184f04db390f918b1aab057ac,
title = "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.",
author = "{FinnGen Project} and Locke, {Adam E.} and Steinberg, {Karyn Meltz} and Chiang, {Charleston W.K.} and Service, {Susan K.} and Havulinna, {Aki S.} and Laurel Stell and Matti Pirinen and Abel, {Haley J.} and Chiang, {Colby C.} and Fulton, {Robert S.} and Jackson, {Anne U.} and Kang, {Chul Joo} and Kanchi, {Krishna L.} and Koboldt, {Daniel C.} and Larson, {David E.} and Joanne Nelson and Nicholas, {Thomas J.} and Arto Pietil{\"a} and Vasily Ramensky and Debashree Ray and Scott, {Laura J.} and Stringham, {Heather M.} and Jagadish Vangipurapu and Ryan Welch and Pranav Yajnik and Xianyong Yin and Eriksson, {Johan G.} and Mika Ala-Korpela and J{\"a}rvelin, {Marjo Riitta} and Minna M{\"a}nnikk{\"o} and Hannele Laivuori and Dutcher, {Susan K.} and Stitziel, {Nathan O.} and Wilson, {Richard K.} and Hall, {Ira M.} and Chiara Sabatti and Aarno Palotie and Veikko Salomaa and Markku Laakso and Samuli Ripatti and Michael Boehnke and Freimer, {Nelson B.}",
note = "Funding Information: Acknowledgements We thank T. Teshiba for coordinating ethical permissions and samples; S. Kerminen, D. Lawson and G. Busby for discussions and providing scripts to run fineSTRUCTURE. S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (312062), Academy of Finland (285380), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, Biocentrum Helsinki and University of Helsinki HiLIFE Fellow grant. V.R. acknowledges support by RFBR, research project 18-04-00789 A. V.S. was supported by the Finnish Foundation for Cardiovascular Research. C.S. and L.S. received funding from HG006695, HL113315 and MH105578. M.A.-K. is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1158958) and works in a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The Baker Institute is supported in part by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program. A.U.J., D.R., L.J.S., H.M.S., R.W., P.Y., X.Y. and M.B. received funding from DK062370. S.K.S., C.W.K.C. and N.B.F. received funding from HL113315 and NS062691. The METSIM study was supported by grants from Academy of Finland (321428), the Sigrid Juselius Foundation, the Finnish Foundation for Cardiovascular Research, Kuopio University Hospital and the Centre of Excellence of Cardiovascular and Metabolic Diseases is supported by the Academy of Finland (M.L.). Sequencing was funded by 5U54HG003079. A.E.L., K.M.S., H.J.A., C.C.C., C.J.K., K.L.K., D.C.K., D.E.L., J.N., T.J.N., S.K.D., N.O.S., I.M.H. and R.K.W. were funded by 5U54HG003079 and 5UM1HG008853-03. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = aug,
day = "15",
doi = "10.1038/s41586-019-1457-z",
language = "English",
volume = "572",
pages = "323--328",
journal = "Nature",
issn = "0028-0836",
number = "7769",
}