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

PLoS Genet
Authors
Keywords
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 (p5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.

Year of Publication
2014
Journal
PLoS Genet
Volume
10
Issue
7
Pages
e1004494
Date Published
2014 Jul
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1004494
PubMed ID
25078778
PubMed Central ID
PMC4117444
Links
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