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dc.contributor.authorLim, Elaine T.en_US
dc.contributor.authorWürtz, Peteren_US
dc.contributor.authorHavulinna, Aki S.en_US
dc.contributor.authorPalta, Priiten_US
dc.contributor.authorTukiainen, Taruen_US
dc.contributor.authorRehnström, Karolaen_US
dc.contributor.authorEsko, Tõnuen_US
dc.contributor.authorMägi, Reediken_US
dc.contributor.authorInouye, Michaelen_US
dc.contributor.authorLappalainen, Tuulien_US
dc.contributor.authorChan, Yingleongen_US
dc.contributor.authorSalem, Rany M.en_US
dc.contributor.authorLek, Monkolen_US
dc.contributor.authorFlannick, Jasonen_US
dc.contributor.authorSim, Xuelingen_US
dc.contributor.authorManning, Alisaen_US
dc.contributor.authorLadenvall, Claesen_US
dc.contributor.authorBumpstead, Suzannahen_US
dc.contributor.authorHämäläinen, Eijaen_US
dc.contributor.authorAalto, Kristiinaen_US
dc.contributor.authorMaksimow, Mikaelen_US
dc.contributor.authorSalmi, Markoen_US
dc.contributor.authorBlankenberg, Stefanen_US
dc.contributor.authorArdissino, Diegoen_US
dc.contributor.authorShah, Svatien_US
dc.contributor.authorHorne, Benjaminen_US
dc.contributor.authorMcPherson, Ruthen_US
dc.contributor.authorHovingh, Gerald K.en_US
dc.contributor.authorReilly, Muredach P.en_US
dc.contributor.authorWatkins, Hughen_US
dc.contributor.authorGoel, Anujen_US
dc.contributor.authorFarrall, Martinen_US
dc.contributor.authorGirelli, Domenicoen_US
dc.contributor.authorReiner, Alex P.en_US
dc.contributor.authorStitziel, Nathan O.en_US
dc.contributor.authorKathiresan, Sekaren_US
dc.contributor.authorGabriel, Staceyen_US
dc.contributor.authorBarrett, Jeffrey C.en_US
dc.contributor.authorLehtimäki, Terhoen_US
dc.contributor.authorLaakso, Markkuen_US
dc.contributor.authorGroop, Leifen_US
dc.contributor.authorKaprio, Jaakkoen_US
dc.contributor.authorPerola, Markusen_US
dc.contributor.authorMcCarthy, Mark I.en_US
dc.contributor.authorBoehnke, Michaelen_US
dc.contributor.authorAltshuler, David M.en_US
dc.contributor.authorLindgren, Cecilia M.en_US
dc.contributor.authorHirschhorn, Joel N.en_US
dc.contributor.authorMetspalu, Andresen_US
dc.contributor.authorFreimer, Nelson B.en_US
dc.contributor.authorZeller, Tanjaen_US
dc.contributor.authorJalkanen, Sirpaen_US
dc.contributor.authorKoskinen, Seppoen_US
dc.contributor.authorRaitakari, Ollien_US
dc.contributor.authorDurbin, Richarden_US
dc.contributor.authorMacArthur, Daniel G.en_US
dc.contributor.authorSalomaa, Veikkoen_US
dc.contributor.authorRipatti, Samulien_US
dc.contributor.authorDaly, Mark J.en_US
dc.contributor.authorPalotie, Aarnoen_US
dc.date.accessioned2014-09-08T15:37:33Z
dc.date.issued2014en_US
dc.identifier.citationLim, E. T., P. Würtz, A. S. Havulinna, P. Palta, T. Tukiainen, K. Rehnström, T. Esko, et al. 2014. “Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.” PLoS Genetics 10 (7): e1004494. doi:10.1371/journal.pgen.1004494. http://dx.doi.org/10.1371/journal.pgen.1004494.en
dc.identifier.issn1553-7390en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12785953
dc.description.abstractExome 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.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pgen.1004494en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117444/pdf/en
dash.licenseLAAen_US
dc.subjectBiology and Life Sciencesen
dc.subjectComputational Biologyen
dc.subjectGenome Analysisen
dc.subjectGenome-Wide Association Studiesen
dc.subjectEvolutionary Biologyen
dc.subjectPopulation Geneticsen
dc.subjectGeneticsen
dc.subjectGenetics of Diseaseen
dc.subjectGenetic Disordersen
dc.subjectHeredityen
dc.subjectQuantitative Traitsen
dc.subjectHuman Geneticsen
dc.subjectGenetic Association Studiesen
dc.subjectGene Disruptionen
dc.subjectGenomicsen
dc.subjectPhenotypesen
dc.titleDistribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Populationen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS Geneticsen
dash.depositing.authorTukiainen, Taruen_US
dc.date.available2014-09-08T15:37:33Z
dc.identifier.doi10.1371/journal.pgen.1004494*
dash.authorsorderedfalse
dash.contributor.affiliatedTukiainen, Taru
dash.contributor.affiliatedFlannick, Jason
dash.contributor.affiliatedLek, Monkol
dash.contributor.affiliatedAltshuler, David
dash.contributor.affiliatedEsko, Tõnu
dash.contributor.affiliatedMacArthur, Daniel
dash.contributor.affiliatedDaly, Mark
dash.contributor.affiliatedPalotie, Aarno
dc.identifier.orcid0000-0003-1982-6569


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