Analysis of pleiotropic genetic effects on cognitive impairment, systemic inflammation, and plasma lipids in the Health and Retirement Study.

Variants associated with modulation of c-reactive protein (CRP) and plasma lipids have been investigated for polygenic overlap with Alzheimer's disease risk variants. We examined pleiotropic genetic effects on cognitive impairment conditioned on genetic variants (SNPs) associated with systemic inflammation as measured by CRP and with plasma lipids using data from the Health and Retirement Study. SNP enrichment was observed for cognitive impairment conditioned on the secondary phenotypes of plasma CRP and lipids. Fold enrichment of 100%-800% was observed for increasingly stringent p-value thresholds for SNPs associated with cognitive impairment conditional on plasma CRP, 80%-800% for low-density lipoprotein, and 80%-600% for total cholesterol. Significant associations (false discovery rate Q ≤ 0.05) between cognitive impairment, conditional with either CRP, low-density lipoprotein, or total cholesterol, were found for the locus on chromosome 19 that contains the APOE, TOMM40, APOC1, and PVRL2 genes. Relative numbers of significant SNPs in each of the genes differed by the conditional associations with the secondary phenotypes. Biological interpretation of both the genetic pleiotropy results and the individual genome-wide association results showed that the variants and proximal genes identified are involved in multiple pathological processes including cholesterol metabolism, inflammation, and mitochondrial transport. These findings are potentially important for Alzheimer's disease risk prediction and development of novel therapeutic approaches.