Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

Circulation. 2015 Jun 9;131(23):2061-2069. doi: 10.1161/CIRCULATIONAHA.115.015489. Epub 2015 Apr 10.

Abstract

Background: Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.

Methods and results: Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.

Conclusions: We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

Keywords: Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids.

Publication types

  • Comparative Study
  • Evaluation Study
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Biomarkers / metabolism
  • Brain / metabolism
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism*
  • Dyslipidemias / complications
  • Dyslipidemias / genetics*
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Inflammation / complications
  • Inflammation / genetics*
  • Lipids / blood*
  • Lipids / genetics
  • Male
  • Multifactorial Inheritance / genetics*
  • Peroxisomal Bifunctional Enzyme / genetics
  • Peroxisomal Bifunctional Enzyme / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism

Substances

  • Biomarkers
  • Lipids
  • C-Reactive Protein
  • Sulfotransferases
  • heparitin sulfotransferase
  • EHHADH protein, human
  • Peroxisomal Bifunctional Enzyme