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

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 (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.

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

“…However, only one FA patient has been found to carry truncating FANCM mutation and this individual also carries biallelic mutations in the FANCA gene (33,38). Furthermore, homozygous carriers of FANCM loss-of-function mutations c.5101C>T and c.5791C>T observed in the Finnish population do not show symptoms of FA (39). Thus, FANCM may have tumor suppressor activity, but, despite its role in the FA pathway, it may not contribute to FA.…”

Identification of point mutations and large intragenic deletions in Fanconi anemia using next‐generation sequencing technology

“…2014; Lim et al. 2014). Identification of mutations in different genes could unveil puzzling questions about correct assignment of the complementation group.…”

Health and population effects of rare gene knockouts in adult humans with related parents

“…Of the possible allelic combinations of the mother and child at each site (Table S8) 4 combinations are informative if only the mother is phased while 8 are informative if both the mother and child are phased. We first obtained a gold standard phased set of calls for the NA12878 duo by using the CEPH 13 member pedigree and only considered sites for which the phase and genotype information are consistent across all members of the pedigree, who had been previously sequenced (59).…”