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Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
Pubmed ID: 24507775 RIS Download
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Database developed to archive and distribute clinical data and results from studies that have investigated interaction of genotype and phenotype in humans. Database to archive and distribute results of studies including genome-wide association studies, medical sequencing, molecular diagnostic assays, and association between genotype and non-clinical traits.
View all literature mentionsCollection of curated, non-redundant genomic DNA, transcript RNA, and protein sequences produced by NCBI. Provides a reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis, expression studies, and comparative analyses. Accessed through the Nucleotide and Protein databases.
View all literature mentionsOnline catalog of human genes and genetic disorders, for clinical features, phenotypes and genes. Collection of human genes and genetic phenotypes, focusing on relationship between phenotype and genotype. Referenced overviews in OMIM contain information on all known mendelian disorders and variety of related genes. It is updated daily, and entries contain copious links to other genetics resources.
View all literature mentionsSoftware program for checking relationships between pairs of individuals. There are many excellent programs that carry out similar tasks. Some of the unique features in relativeFinder are the batch mode options, that allow large jobs to be divided into many smaller jobs (suitable for deployment on a compute cluster environment), and the flexibility of the underlying Merlin engine, which allows relative finder to handle large pedigrees and consider a variety of alternate relationships -- including potential relationships specified by the user on the fly. (entry from Genetic Analysis Software)
View all literature mentionsThe JHS is the largest single-site longitudinal, population-based, cohort study of 5,302 persons initiated in the fall of 2000 to prospectively investigate the determinants of CVD among African Americans in the Jackson, MS metropolitan statistical area. The JHS investigates the various genotype and phenotype factors that affect high blood pressure, heart disease, strokes, diabetes and other important diseases in African Americans. The primary objective of the Jackson Heart Study is to investigate the causes of cardiovascular disease (CVD) in African Americans to learn how to best prevent this group of diseases in the future. More specific objectives include: 1. Identification of factors, which influence the development, and worsening of CVD in African Americans, with an emphasis on manifestations related to high blood pressure (such as remodeling of the left ventricle of the heart, coronary artery disease, heart failure, stroke and disorders affecting the blood vessels of the kidney). 2. Building research capabilities in minority institutions at the undergraduate and graduate level by developing partnerships between minority and majority institutions and enhancing participation of minority investigators in large-scale epidemiologic studies. 3. Attracting minority students to and preparing them for careers in health sciences.
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
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