Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations1, 2, 3, 4, 5. Common variants at these loci together explain <10% of variation in each lipid trait4, 5. Rare variants with large individual effects may also contribute to the heritability of lipid traits6, 7; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 × 10−8), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 × 10−5). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.
- Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008). et al.
- Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008). et al.
- Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat. Genet. 41, 35–46 (2009). et al.
- Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47–55 (2009). et al.
- Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009). et al.
- Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009). et al.
- Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007). , &
- Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872–878 (2009). , &
- Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). Arterioscler. Thromb. Vasc. Biol. 27, 2450–2455 (2007). et al.
- Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009). et al.
- Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004). et al.
- Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513–516 (2007). et al.
- Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 176, 1113–1120 (2007). , &
- A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum. Mol. Genet. 18, 4189–4194 (2009). et al.
- Polygenic determinants of severe hypertriglyceridemia. Hum. Mol. Genet. 17, 2894–2899 (2008). et al.
- APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia. Nat. Clin. Pract. Cardiovasc. Med. 5, 730–737 (2008). et al.
- Plasma lipoproteins: genetic influences and clinical implications. Nat. Rev. Genet. 10, 109–121 (2009).
- Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 15, 1025–1029 (1995). et al.
- Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler. Thromb. Vasc. Biol. 29, 956–962 (2009). et al.
- Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat. Genet. 39, 1483–1487 (2007). et al.
- Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet 356, 279–284 (2000). et al.
- Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009). et al.
- Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006). &
- PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). et al.
- Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006). , &
- Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006). et al.
- Computing measures of explained variation for logistic regression models. Comput. Methods Programs Biomed. 58, 17–24 (1999). &
- Supplementary Text and Figures (556K)
Supplementary Figures 1–3 and Supplementary Table 1