Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Hannele Laivuori

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Original languageEnglish
Pages (from-to)2182
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 12 Apr 2021
Externally publishedYes
Publication typeA1 Journal article-refereed

Keywords

  • Cardiometabolic Risk Factors
  • Chromosomes, Human, X/genetics
  • Eye Proteins/metabolism
  • Female
  • Gene Expression Regulation
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Lipids/blood
  • Male
  • Middle Aged
  • Nerve Tissue Proteins/metabolism
  • Phenomics
  • Polymorphism, Single Nucleotide/genetics
  • Subcutaneous Tissue/metabolism
  • Whole Genome Sequencing

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