Polygenic Overlap Between C-Reactive Protein, Plasma Lipids and Alzheimer's Disease
Background—Epidemiological findings suggest a relationship between Alzheimer's 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 over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 x 10-8) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 x 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, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
- Received January 14, 2015.
- Revision received April 1, 2015.
- Accepted April 6, 2015.