The Contribution of GWAS Loci in Familial Dyslipidemias

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dc.contributor University of Helsinki, Institute for Molecular Medicine Finland en
dc.contributor University of Helsinki, Institute for Molecular Medicine Finland en
dc.contributor University of Helsinki, Clinicum en
dc.contributor University of Helsinki, Institute for Molecular Medicine Finland en
dc.contributor University of Helsinki, Marja-Riitta Taskinen Research Group en
dc.contributor University of Helsinki, Institute for Molecular Medicine Finland en
dc.contributor University of Helsinki, Institute for Molecular Medicine Finland en
dc.contributor University of Helsinki, Medicum en
dc.contributor University of Helsinki, Institute for Molecular Medicine Finland en
dc.contributor University of Helsinki, Research Programs Unit en
dc.contributor University of Helsinki, Clinicum en
dc.contributor.author Ripatti, Pietari
dc.contributor.author Ramo, Joel T.
dc.contributor.author Soderlund, Sanni
dc.contributor.author Surakka, Ida
dc.contributor.author Matikainen, Niina
dc.contributor.author Pirinen, Matti
dc.contributor.author Pajukanta, Paivi
dc.contributor.author Sarin, Antti-Pekka
dc.contributor.author Service, Susan K.
dc.contributor.author Laurila, Pirkka-Pekka
dc.contributor.author Ehnholm, Christian
dc.contributor.author Salomaa, Veikko
dc.contributor.author Wilson, Richard K.
dc.contributor.author Palotie, Aarno
dc.contributor.author Freimer, Nelson B.
dc.contributor.author Taskinen, Marja-Riitta
dc.contributor.author Ripatti, Samuli
dc.date.accessioned 2016-07-08T07:47:02Z
dc.date.available 2016-07-08T07:47:02Z
dc.date.issued 2016-05
dc.identifier.citation Ripatti , P , Ramo , J T , Soderlund , S , Surakka , I , Matikainen , N , Pirinen , M , Pajukanta , P , Sarin , A-P , Service , S K , Laurila , P-P , Ehnholm , C , Salomaa , V , Wilson , R K , Palotie , A , Freimer , N B , Taskinen , M-R & Ripatti , S 2016 , ' The Contribution of GWAS Loci in Familial Dyslipidemias ' , PLoS Genetics , vol. 12 , no. 5 , 1006078 . https://doi.org/10.1371/journal.pgen.1006078 en
dc.identifier.issn 1553-7404
dc.identifier.other PURE: 65791445
dc.identifier.other PURE UUID: e3943eb6-ac42-4c1e-9902-f4ac009bcc22
dc.identifier.other WOS: 000377197100067
dc.identifier.other Scopus: 84974530357
dc.identifier.other ORCID: /0000-0002-1664-1350/work/29075052
dc.identifier.other ORCID: /0000-0002-6429-5149/work/31319966
dc.identifier.uri http://hdl.handle.net/10138/164672
dc.description.abstract Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined. en
dc.format.extent 14
dc.language.iso eng
dc.relation.ispartof PLoS Genetics
dc.rights en
dc.subject CORONARY-HEART-DISEASE en
dc.subject COMBINED HYPERLIPIDEMIA en
dc.subject ARTERY-DISEASE en
dc.subject HEPATIC LIPASE en
dc.subject LIPID-LEVELS en
dc.subject PHENOTYPE en
dc.subject RARE en
dc.subject HYPERCHOLESTEROLEMIA en
dc.subject HYPERTRIGLYCERIDEMIA en
dc.subject DEFICIENCY en
dc.subject 3142 Public health care science, environmental and occupational health en
dc.subject 3121 Internal medicine en
dc.subject 3111 Biomedicine en
dc.title The Contribution of GWAS Loci in Familial Dyslipidemias en
dc.type Article
dc.description.version Peer reviewed
dc.identifier.doi https://doi.org/10.1371/journal.pgen.1006078
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion
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