The Contribution of GWAS Loci in Familial Dyslipidemias

Show full item record

Permalink

http://hdl.handle.net/10138/164672

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

Title: The Contribution of GWAS Loci in Familial Dyslipidemias
Author: Ripatti, Pietari; Ramo, Joel T.; Soderlund, Sanni; Surakka, Ida; Matikainen, Niina; Pirinen, Matti; Pajukanta, Paivi; Sarin, Antti-Pekka; Service, Susan K.; Laurila, Pirkka-Pekka; Ehnholm, Christian; Salomaa, Veikko; Wilson, Richard K.; Palotie, Aarno; Freimer, Nelson B.; Taskinen, Marja-Riitta; Ripatti, Samuli
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Marja-Riitta Taskinen Research Group
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Medicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
Date: 2016-05
Number of pages: 14
Belongs to series: PLoS Genetics
ISSN: 1553-7404
URI: http://hdl.handle.net/10138/164672
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.
Subject: CORONARY-HEART-DISEASE
COMBINED HYPERLIPIDEMIA
ARTERY-DISEASE
HEPATIC LIPASE
LIPID-LEVELS
PHENOTYPE
RARE
HYPERCHOLESTEROLEMIA
HYPERTRIGLYCERIDEMIA
DEFICIENCY
3142 Public health care science, environmental and occupational health
3121 Internal medicine
3111 Biomedicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
asset.pdf 1.680Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record