Finnish founding bottleneck leads to excess of damaging loss-of-function variants with medically relevant associations. E. T. Lim1,2,3, P. Würtz4,5, A. S. Havulinna5, P. Palta4,6, T. Tukiainen1,2,3, Sequencing Initiative Suomi (SISu) Project 1) Analytic and Translational Genetics Unit, Mass General Hospital, Boston, MA; 2) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; 3) Department of Genetics, Harvard Medical School, Boston, MA; 4) Institute for Molecular Medicine Finland, University of Helsinki, Finland; 5) Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; 6) Wellcome Trust Sanger Institute, Cambridge, United Kingdom.

   Exome sequencing has made it possible to identify rare variants that are associated with complex diseases. However, these association tests have proven to be challenged by the large sample sizes needed to achieve adequate power to identify alleles with modest effects. There has been recent success in discovering rare (1% allele frequency) and low-frequency (1-5% allele frequency) variants in various diseases such as Alzheimers disease and insulin processing by taking advantage of the genetics of founder populations, such as the Icelandic and Finnish populations. To further develop this strategy, an international collaboration called the SISu project (Sequencing Initiative Suomi), aims to construct near complete genome variant data from up to 200,000 Finnish genomes from the National Biobanks repository (www.nationalbiobanks.fi) and link genome variant data with multiple phenotypes, partially gathered from national health records. The SISu project includes groups from UCLA (NFBC study), University of Michigan (GoT2D study), the Broad Institute (GoT2D), Oxford University (GoT2D), The Wellcome Trust Sanger Institute (migraine, Finrisk), Lund University (GoT2D), National Institute for Health and Welfare (Finland, (Finrisk)) and University of Helsinki. As a part of the SISu project we assessed the potential of the Finnish founder population for studying low-frequency variants in complex diseases by comparing 3000 exome sequences from Finns to outbred non-Finnish Europeans (NFEs) from Germany, Britain and Sweden. We discovered that the bottleneck in Finland has driven the allele frequencies of some extremely rare and deleterious variants in NFEs to much higher allele frequencies (0.5-5%) in Finns. As a result, the average Finn has 1.4x more loss-of-function variants (nonsense and essential splice site) than an average NFE and 2x more rare complete knockouts. This suggests that rare and low-frequency variants with medically important consequences can be detected more easily using smaller sample sizes in Finns. To discover new associations, we applied a reverse genetics approach and genotyped 89 low-frequency loss-of-function variants that are at least 2x enriched across ~35,000 Finns. We report several medically important associations for these low-frequency loss-of-function variants with various complex diseases such as Vitamin B12 deficiency, lipids and blood pressure, emphasizing the utility of the Finnish population for rare variant association studies.

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