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

• Published in: PLoS genetics 2014-07, Vol.10 (7), p.e1004494-e1004494
• Main Authors: Lim, Elaine T, Würtz, Peter, Havulinna, Aki S, Palta, Priit, Tukiainen, Taru, Rehnström, Karola, Esko, Tõnu, Mägi, Reedik, Inouye, Michael, Lappalainen, Tuuli, Chan, Yingleong, Salem, Rany M, Lek, Monkol, Flannick, Jason, Sim, Xueling, Manning, Alisa, Ladenvall, Claes, Bumpstead, Suzannah, Hämäläinen, Eija, Aalto, Kristiina, Maksimow, Mikael, Salmi, Marko, Blankenberg, Stefan, Ardissino, Diego, Shah, Svati, Horne, Benjamin, McPherson, Ruth, Hovingh, Gerald K, Reilly, Muredach P, Watkins, Hugh, Goel, Anuj, Farrall, Martin, Girelli, Domenico, Reiner, Alex P, Stitziel, Nathan O, Kathiresan, Sekar, Gabriel, Stacey, Barrett, Jeffrey C, Lehtimäki, Terho, Laakso, Markku, Groop, Leif, Kaprio, Jaakko, Perola, Markus, McCarthy, Mark I, Boehnke, Michael, Altshuler, David M, Lindgren, Cecilia M, Hirschhorn, Joel N, Metspalu, Andres, Freimer, Nelson B, Zeller, Tanja, Jalkanen, Sirpa, Koskinen, Seppo, Raitakari, Olli, Durbin, Richard, MacArthur, Daniel G, Salomaa, Veikko, Ripatti, Samuli, Daly, Mark J, Palotie, Aarno
• Format: Article
• Language: English
• Subjects: Biology and Life Sciences; Biomarkers; Clinical Medicine; Comparative analysis; Disease; Endocrinology and Diabetes; Endokrinologi och diabetes; European Continental Ancestry Group; Exome - genetics; Female; Finland; Founder Effect; Gene Frequency; Genes; Genetic Diseases, Inborn; Genetic Drift; Genetic research; Genetic Variation; Genetics, Population; Genome-wide association studies; Genome-Wide Association Study; Genomics; Grants; Heart attacks; Humans; Klinisk medicin; Lipoprotein A; Male; Medical and Health Sciences; Medical records; Medicin och hälsovetenskap; Phenotype; Physiological aspects; Population
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004494

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