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PLoS Genet DOI:10.1371/journal.pgen.1004494

Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Publication TypeJournal Article
Year of Publication2014
AuthorsLim, 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 AuthorsSequencing Initiative Suomi (SISu) Project
JournalPLoS Genet
Date Published2014 Jul
KeywordsEuropean 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

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


Alternate JournalPLoS Genet.
PubMed ID25078778
PubMed Central IDPMC4117444
Grant ListHL-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