Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies

Atherosclerosis. 2020 Mar:297:102-110. doi: 10.1016/j.atherosclerosis.2020.02.005. Epub 2020 Feb 14.


Backgrounds and aims: Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change.

Methods: We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies.

Results: We identified a novel association for HDL-C with GRID1 (p = 5.43 × 10-10), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10-6; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways.

Conclusions: Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation.

Keywords: GWAS; HDL-C metabolism; Healthy aging; Longevity; Longitudinal HDL-C change.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / genetics*
  • Cholesterol, HDL / blood*
  • Female
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Healthy Aging / blood
  • Healthy Aging / genetics*
  • Heart Disease Risk Factors
  • Humans
  • Longevity / genetics*
  • Male
  • Middle Aged
  • Prospective Studies
  • Risk Assessment
  • Sex Factors
  • Time Factors
  • Young Adult


  • Biomarkers
  • Cholesterol, HDL