Whole-genome sequence–based analysis of high-density lipoprotein cholesterol

Eric Boerwinkle and colleagues report whole-genome sequencing of a population-based sample of 962 individuals from three Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. They analyze the genetic architecture of high-density lipoprotein cholesterol (HDL-C) levels and estimate that common variation contributes more to HDL-C heritability than rare variation. We describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.