Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population
By Elaine T. Lim, P. Würtz, Aki S. Havulinna, P. Palta, T. Tukiainen, K. Rehnström, T. Esko, Reedik Mägi, Michael Inouye, Tuuli Lappalainen and 50 more. 2014
412 citations recorded by the source corpus.
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<5×10−8) 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.
Subfields: Cellular and Molecular Neuroscience, Economics and Econometrics, Psychiatry and Mental health
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Citations in the corpus
- Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA (2016, background): “3 10 9, where the standard genome-wide significance level (5 10 8) is divided by the number of principal components (22) that explain over 95% of variation in the metabolomics data.”
- A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. (2017, result): “Finally, there is evidence that some individuals have alleles that do not express apo(a); therefore, they have either very low or absent circulating Lp(a) levels, have a reduced risk of CVD, but they are not at increased risk for non-CVD events, which is consistent with the causality of Lp(a) for va”
- Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement (2022, background): “8 In contrast, rare loss-of-function variants 121 and very common splice site variants within the K-IV Type-2 region that associated with marked decreases in Lp(a) are protective against cardiovascular events.”
- FinnGen provides genetic insights from a well-phenotyped isolated population (2023, methodology): “LD lookup variants were chosen using the following criteria: (1) they were less than 1,500 kb away from the lead variant; (2) they had a P < 0.”