An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids

Abstract

Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7 ) was associated with fasting triglyceride levels ( P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 ( P = 1.77E-07) and SLCO2A1 ( P = 7.18E-07) and triglycerides, as well as between POT1 ( P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P -values of 0.04 ( ITGA7 ), 0.08 ( SLCO2A1 ), and 0.02 ( POT1 ). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides ( P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants

“…Exome sequencing was conducted separately in the ERF study, GOLDN, and RS, and exome sequencing, variant analysis, and quality control protocols are available elsewhere. 20 , 21 , 22 In ERF, sequencing was performed at a median depth of 57x and after preprocessing, variant calling was completed using the Unified Genotyper tool from the Genome Analysis Toolkit (GATK) v.2.314. 23 In GOLDN, variants were called with SAMtools version r963 and VarScan v.2.3.6.…”

Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma

“…Whole-exome sequencing (WES) is widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. 11,12 The present work was to identify disease-causing mutations in a Chinese JOAG family using WES.…”