Abstract
Founder populations are ideally suited for studies on the clinical effects of alleles that are rare in general populations but occur at higher frequencies in these isolated populations. Whole genome sequencing in 98 Hutterites, a founder population of European descent, and subsequent imputation revealed 660,238 single nucleotide polymorphisms that are rare (<1%) or absent in European populations, but occur at frequencies >1% in the Hutterites. We examined the effects of these rare in European variants on plasma lipid levels in 828 Hutterites and applied a Bayesian hierarchical framework to prioritize potentially causal variants based on functional annotations. We identified two novel non-coding rare variants associated with LDL cholesterol (rs17242388 in LDLR) and HDL cholesterol (rs189679427 between GOT2 and APOOP5), and replicated previous associations of a splice variant in APOC3 (rs138326449) with triglycerides and HDL-C. All three variants are at well-replicated loci in GWAS but are independent from and have larger effect sizes than the known common variation in these regions. Candidate eQTL analyses in in LCLs in the Hutterites suggest that these rare non-coding variants are likely to mediate their effects on lipid traits by regulating gene expression.
Highlights
Blood lipid traits are under strong genetic control and are modifiable risk factors for cardiovascular disease, one of the leading causes of death[1]
Quantile-quantile plots showed no inflation of test statistics for any of the lipid traits (Supplementary Figure 1); the lead SNP for each locus is presented in Table 2 (Manhattan plots for all genome-wide association studies (GWAS) are shown in Supplementary Figure 2)
We detected two genome-wide significant loci (p < 5 × 10−8) associated with either increased low-density lipoprotein cholesterol (LDL-C) or with reduced TG levels and contained multiple rare variants of large effect in regions previously associated with lipid traits in GWAS5,6
Summary
Blood lipid traits are under strong genetic control and are modifiable risk factors for cardiovascular disease, one of the leading causes of death[1]. Sequencing studies in families or patients with rare monogenic lipid disorders have uncovered many novel genes harboring rare coding mutations of large effect and revealed critical pathways for lipid metabolism[8,9,10]. These studies have supported earlier observations suggesting that rare variants in the general population contribute significantly to lipid traits and possibly more generally to common, complex phenotypes. Their overall reduced genetic complexity and relatively homogenous environments and lifestyles can enhance the effects of rare genetic variants on phenotypic traits and thereby facilitate the detection of susceptibility loci that underlie complex disease, as elegantly illustrated in studies of the Amish and Icelandic populations[20,21,22]
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