The Contribution of GWAS Loci in Familial Dyslipidemias

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 susce...

Full description

Bibliographic Details
Main Authors:	Ripatti, Pietari, Rämö, Joel T., Söderlund, Sanni, Surakka, Ida, Matikainen, Niina, Pirinen, Matti, Pajukanta, Päivi, 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
Format:	Online
Language:	English
Published:	Public Library of Science 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882070/

id	pubmed-4882070
recordtype	oai_dc
spelling	pubmed-48820702016-06-10 The Contribution of GWAS Loci in Familial Dyslipidemias Ripatti, Pietari Rämö, Joel T. Söderlund, Sanni Surakka, Ida Matikainen, Niina Pirinen, Matti Pajukanta, Päivi 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 Research Article 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. Public Library of Science 2016-05-26 /pmc/articles/PMC4882070/ /pubmed/27227539 http://dx.doi.org/10.1371/journal.pgen.1006078 Text en © 2016 Ripatti et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ripatti, Pietari Rämö, Joel T. Söderlund, Sanni Surakka, Ida Matikainen, Niina Pirinen, Matti Pajukanta, Päivi 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
spellingShingle	Ripatti, Pietari Rämö, Joel T. Söderlund, Sanni Surakka, Ida Matikainen, Niina Pirinen, Matti Pajukanta, Päivi 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 The Contribution of GWAS Loci in Familial Dyslipidemias
author_facet	Ripatti, Pietari Rämö, Joel T. Söderlund, Sanni Surakka, Ida Matikainen, Niina Pirinen, Matti Pajukanta, Päivi 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
author_sort	Ripatti, Pietari
title	The Contribution of GWAS Loci in Familial Dyslipidemias
title_short	The Contribution of GWAS Loci in Familial Dyslipidemias
title_full	The Contribution of GWAS Loci in Familial Dyslipidemias
title_fullStr	The Contribution of GWAS Loci in Familial Dyslipidemias
title_full_unstemmed	The Contribution of GWAS Loci in Familial Dyslipidemias
title_sort	contribution of gwas loci in familial dyslipidemias
description	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.
publisher	Public Library of Science
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882070/
_version_	1613584934639763456

The Contribution of GWAS Loci in Familial Dyslipidemias

Similar Items