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The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

Original publication

DOI

10.1038/nature14962

Type

Journal article

Journal

Nature

Publication Date

01/10/2015

Volume

526

Pages

82 - 90

Keywords

Adiponectin, Alleles, Cohort Studies, Disease, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genomics, Health, Humans, Lipid Metabolism, Male, Molecular Sequence Annotation, Receptors, LDL, Reference Standards, Sequence Analysis, DNA, Triglycerides, United Kingdom