Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population

• DOI: 10.1371/journal.pgen.1004494
• Publication Date: 2014-07-31T19:42:43Z
• Authors: Elaine T. Lim; Peter Würtz; Aki S. Havulinna; Priit Palta; Taru Tukiainen; Karola Rehnström; Tõnu Esko; Reedik Mägi; Michael Inouye; Tuuli Lappalainen; Yingleong Chan; Rany M. Salem; Monkol Lek; Jason Flannick; Xueling Sim; Alisa Manning; Claes Ladenvall; Suzannah Bumpstead; Eija Hämäläinen; Kristiina Aalto; Mikael Maksimow; Marko Salmi; Stefan Blankenberg; Diego Ardissino; Svati Shah; Benjamin Horne; Ruth McPherson; Gerald K. Hovingh; Muredach P. Reilly; Hugh Watkins; Anuj Goel; Martin Farrall; Domenico Girelli; Alex P. Reiner; Nathan O. Stitziel; Sekar Kathiresan; Stacey Gabriel; Jeffrey C. Barrett; Terho Lehtimäki; Markku Laakso; Leif Groop; Jaakko Kaprio; Markus Perola; Mark I. McCarthy; Michael Boehnke; David M. Altshuler; Cecilia M. Lindgren; Joel N. Hirschhorn; Andres Metspalu; Nelson B. Freimer; Tanja Zeller; Sirpa Jalkanen; Seppo Koskinen; Olli Raitakari; Richard Durbin; Daniel G. MacArthur; Veikko Salomaa; Samuli Ripatti; Mark J. Daly; Aarno Palotie
• Keywords: Exome; Founder effect; Mendelian Randomization; Loss function

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk presence numbers neutral variants, even phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare as they have deleterious that present at higher frequencies well a substantial reduction variation. To explore potential Finnish founder population low-frequency (0.5–5%) diseases, we compared exome sequence data 3,000 Finns to same non-Finnish Europeans discovered that, despite having fewer variable sites overall, average Finn has more loss-of-function complete gene knockouts. We then used several well-characterized cohorts study phenotypic effects 83 enriched across 60 phenotypes 36,262 Finns. Using deep set quantitative traits collected these cohorts, show 5 associations (p<5×10−8) including splice LPA lowered plasma lipoprotein(a) levels (P = 1.5×10−117). Through accessing national medical records participants, evaluate finding via Mendelian randomization confirm confer protection from cardiovascular (OR 0.84, P 3×10−4), demonstrating first time correlation between very low humans therapeutic implications diseases. More generally, this articulates role variation like combining unique genetic history centralized research access National Health Registers.