title: The Contribution of GWAS Loci in Familial Dyslipidemias.
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.
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Pietari
authors.identifier: 0000-0002-6530-3243
authors.initials: P
authors.lastname: Ripatti
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.|Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Rämö
authors.affiliation: Research Programs Unit, Diabetes & Obesity, University of Helsinki, and Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sanni
authors.initials: S
authors.lastname: Söderlund
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.affiliation: Research Programs Unit, Diabetes & Obesity, University of Helsinki, and Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Matikainen
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles (UCLA), Los Angeles, California, United States of America.
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Antti-Pekka
authors.identifier: 0000-0002-5753-9782
authors.initials: AP
authors.lastname: Sarin
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California, United States of America.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Service
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.|Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.|Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Pirkka-Pekka
authors.initials: PP
authors.lastname: Laurila
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehnholm
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.|Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California, United States of America.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
authors.affiliation: Research Programs Unit, Diabetes & Obesity, University of Helsinki, and Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.|Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides