Identification of six novel susceptibility loci for dyslipidemia using longitudinal exome-wide association studies in a Japanese population

Genomics. 2019 Jul;111(4):520-533. doi: 10.1016/j.ygeno.2018.05.015. Epub 2018 Jun 4.

Abstract

Recent genome-wide association studies have identified various dyslipidemia-related genetic variants. However, most studies were conducted in a cross-sectional manner. We thus performed longitudinal exome-wide association studies of dyslipidemia in a Japanese population. We used ~244,000 genetic variants and clinical data of 6022 Japanese individuals who had undergone annual health checkups for several years. After quality control, the association of dyslipidemia-related phenotypes with 24,691 single nucleotide polymorphisms (SNPs) was tested using the generalized estimating equation model. In total, 82 SNPs were significantly (P < 2.03 × 10-6) associated with dyslipidemia phenotypes. Of these SNPs, four (rs74416240 of TCHP, rs925368 of GIT2, rs7969300 of ATXN2, and rs12231744 of NAA25) and two (rs34902660 of SLC17A3 and rs1042127 of CDSN) were identified as novel genetic determinants of hypo-HDL- and hyper-LDL-cholesterolemia, respectively. A replication study using the cross-sectional data of 8310 Japanese individuals showed the association of the six identified SNPs with dyslipidemia-related traits.

Keywords: Dyslipidemia; Exome-wide association study; Generalized estimating equation; HDL-cholesterol; LDL-cholesterol; Triglyceride.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Ataxin-2 / genetics
  • Carrier Proteins / genetics
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Dyslipidemias / genetics*
  • Exome
  • Female
  • GTPase-Activating Proteins / genetics
  • Genetic Loci*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Japan
  • Male
  • Middle Aged
  • N-Terminal Acetyltransferase B / genetics
  • Polymorphism, Single Nucleotide*
  • Sodium-Phosphate Cotransporter Proteins, Type I / genetics

Substances

  • ATXN2 protein, human
  • Ataxin-2
  • CDSN protein, human
  • Carrier Proteins
  • Cholesterol, HDL
  • Cholesterol, LDL
  • GIT2 protein, human
  • GTPase-Activating Proteins
  • Intercellular Signaling Peptides and Proteins
  • NAA25 protein, human
  • SLC17A3 protein, human
  • Sodium-Phosphate Cotransporter Proteins, Type I
  • TCHP protein, human
  • N-Terminal Acetyltransferase B