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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
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Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol
Leslie A Lange1, Youna Hu2, He Zhang3
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
American Journal of Human Genetics
|February 11, 2014
Summary
Rare genetic variants in PNPLA5 and known lipid genes significantly impact low-density lipoprotein cholesterol (LDL-C) levels. This whole-exome sequencing study reveals novel insights into genetic contributions to high LDL-C, a key cardiovascular disease risk factor.
Area of Science:
- Genetics
- Cardiovascular Disease
- Lipid Metabolism
Background:
- Elevated low-density lipoprotein cholesterol (LDL-C) is a heritable risk factor for cardiovascular disease.
- Genome-wide association studies (GWASs) identify common variants but are limited in assessing rare variant impact on lipid levels.
Purpose of the Study:
- To investigate the association between rare and low-frequency coding variants and LDL-C levels.
- To identify novel genes and variants contributing to extreme LDL-C phenotypes.
Main Methods:
- Whole-exome sequencing of 2,005 individuals, including those with extreme LDL-C.
- Follow-up sequencing in 1,302 additional individuals and genotype analysis in 52,221 individuals.
- Analysis focused on the burden of rare or low-frequency variants in lipid-related genes.
Main Results:
- Significant association found between LDL-C and rare variants in PNPLA5, PCSK9, LDLR, and APOB.
- PNPLA5, a novel gene in this context, showed a significant association with LDL-C.
- Effect sizes for rare variant burdens were greater than those for individual single nucleotide polymorphisms (SNPs) from GWASs.
Conclusions:
- Whole-exome sequencing effectively identifies rare variants influencing LDL-C.
- This study implicates PNPLA5 in LDL-C regulation and provides a framework for future genetic studies of lipid disorders.
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