The Contribution of GWAS Loci in Familial Dyslipidemias

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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 .

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 organization: Institute for Molecular Medicine Finland
Samuli Olli Ripatti / Principal Investigator
Marja-Riitta Taskinen Research Group
Diabetes and Obesity Research Program
Research Programs Unit
Department of Medicine
Kardiologian yksikkö
Endokrinologian yksikkö
Department of Medical and Clinical Genetics
Aarno Palotie / Principal Investigator
Department of Public Health
Biostatistics Helsinki
Complex Disease Genetics
Genomics of Neurological and Neuropsychiatric Disorders
Statistical and population genetics
Date: 2016-05
Language: eng
Number of pages: 14
Belongs to series: PLoS Genetics
ISSN: 1553-7404
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.
3142 Public health care science, environmental and occupational health
3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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