Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Lim, ET, Würtz, P, Havulinna, AS, Palta, P, Tukiainen, T, Rehnström, K, Esko, T, Mägi, R, Inouye, M, Lappalainen, T, Chan, Y, Salem, RM, Lek, M, Flannick, J, Sim, X, Manning, A, Ladenvall, C, Bumpstead, S, Hämäläinen, E, Aalto, K, Maksimow, M, Salmi, M, Blankenberg, S, Ardissino, D, Shah, S, Horne, B, McPherson, R, Hovingh, GK, Reilly, MP, Watkins, H, Goel, A, Farrall, M, Girelli, D, Reiner, AP, Stitziel, NO, Kathiresan, S, Gabriel, S, Barrett, JC, Lehtimäki, T, Laakso, M, Groop, L, Kaprio, J, Perola, M, McCarthy, MI, Boehnke, M, Altshuler, DM, Lindgren, CM, Hirschhorn, JN, Metspalu, A, Freimer, NB, Zeller, T, Jalkanen, S, Koskinen, S, Raitakari, O, Durbin, R, MacArthur, DG, Salomaa, V, Ripatti, S, Daly, MJ, Palotie, A |
Corporate Authors | Sequencing Initiative Suomi (SISu) Project |
Journal | PLoS Genet |
Volume | 10 |
Issue | 7 |
Pages | e1004494 |
Date Published | 2014 Jul |
ISSN | 1553-7404 |
Keywords | European Continental Ancestry Group, Exome, Female, Finland, Founder Effect, Gene Frequency, Genetic Diseases, Inborn, Genetic Drift, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Male, Phenotype |
Abstract | Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p |
URL | http://dx.plos.org/10.1371/journal.pgen.1004494 |
DOI | 10.1371/journal.pgen.1004494 |
Pubmed | |
Alternate Journal | PLoS Genet. |
PubMed ID | 25078778 |
PubMed Central ID | PMC4117444 |
Grant List | HL-103010 / HL / NHLBI NIH HHS / United States R01DK075787 / DK / NIDDK NIH HHS / United States R01 DK062370 / DK / NIDDK NIH HHS / United States HL-102926 / HL / NHLBI NIH HHS / United States RFA-HL-12-007 / HL / NHLBI NIH HHS / United States 090367 / / Wellcome Trust / United Kingdom DK085584 / DK / NIDDK NIH HHS / United States R01 HL113315 / HL / NHLBI NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States RC2 HL-102925 / HL / NHLBI NIH HHS / United States RC2-DK088389 / DK / NIDDK NIH HHS / United States DK062370 / DK / NIDDK NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States 098381 / / Wellcome Trust / United Kingdom 086596/Z/08/Z / / Wellcome Trust / United Kingdom U01-DK-085545 / DK / NIDDK NIH HHS / United States |
PLoS Genet DOI:10.1371/journal.pgen.1004494
Distribution and medical impact of loss-of-function variants in the Finnish founder population.
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