Not Just Genomewide Association Studies

Dyslipidemia (elevated low-density lipoprotein or elevated triglycerides and low high-density lipoprotein) is an established risk factor for the development of atherosclerosis.1 Heritability estimates for plasma lipids range from 25% to 80% and family studies suggest that within the family, genetic effects are more important than environmental.2 In a minority of cases, dyslipidemia is the result of mutation with high penetrance in a single gene, for example, familial hypercholesterolemia3; however, in the majority of cases, dyslipidemia is a complex trait with multiple genetic and environmental factors contributing to the condition.3Article see p 66Over the last few years, a number of genomewide association studies (GWAS) investigating the role of common genetic variants in determining plasma lipid levels have been performed. These studies culminated in the study of Teslovich et al4 who identified in a study including >100 000 individuals, 95 loci associated with plasma lipids with 59 showing a genomewide significant association with lipids for the first time. However, because these loci account for only 25% to 30% of the genetic variance in lipid levels, there has been a great deal of speculation as to what accounts for the missing heritability in GWAS.5–7One factor that has been extensively discussed is the role of multiple rare variants, that is, variants with a frequency ranging …