Analysis with the exome array identifies multiple new independent variants in lipid loci
Stavroula Kanoni1, Nicholas G D Masca2,3, Kathleen E Stirrups1,4
1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
Human Molecular Genetics
|July 29, 2016
Summary
Rare genetic variants, specifically low frequency (1-5% minor allele frequency) and rare (<1% MAF) types, significantly contribute to understanding the genetic basis of lipid traits. This study identified novel variants, increasing the explained heritability for cholesterol and triglyceride levels.
Area of Science:
- Genetics
- Human Genetics
- Complex Traits
Background:
- Low frequency (1-5% MAF) and rare (<1% MAF) variants with large effects are hypothesized to explain missing heritability in complex traits.
- Lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) are complex traits influenced by genetic factors.
Purpose of the Study:
- To investigate the contribution of low frequency and rare coding variants to lipid trait heritability.
- To identify novel genetic associations for lipid traits using a large-scale exome chip analysis.
Main Methods:
- Association analysis of lipid traits in up to 27,312 individuals using the ExomeChip.
- Conditional analysis of known lipid loci to identify independent signals and rare variants.
Main Results:
- No new genome-wide significant loci were identified.
- New lead variants were found in 26 known lipid association regions, with 16 being over 1000-fold more significant than previous variants.
- Conditional analysis revealed multiple independent signals, including rare variants, in a third of tested lipid loci.
- The inclusion of novel associations increased the proportion of heritability explained for lipid traits by 1.5- to 2.5-fold.
Conclusions:
- Rare coding variants play a significant role in the genetic architecture of lipid traits.
- The findings highlight the importance of exploring low frequency and rare variants to fully understand complex trait heritability.
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