[p4–082]: Analysis of Pleiotropic Genetic Effects on Cognitive Impairment and Systemic Inflammation in the Health and Retirement Study
Year: 2017
Type: article
Abstract: Genome-wide association studies(GWAS) for late-onset Alzheimer's disease (AD) have demonstrated associations between APOE genotype and gene variants involved in inflammatory and microglial activation pathways with AD risk, AD biomarkers (imaging, CSF) and cognitive impairment. Variants associated with modulation of c-reactive protein (CRP) and plasma lipids have been identified by GWAS and investigated for polygenic overlap with AD risk variants. Herein we investigate pleiotropic genetic effects on cognitive impairment conditioned on genetic variants associated with systemic inflammation using data from the Health and Retirement Study (HRS). A statistical framework designed to test for pleiotropic genetic effects based on conditional false discovery rates was used with data from a subsample of HRS participants (n=3856; for whom biomarker data was available), to investigate the overlap between variants associated with cognitive impairment and with systemic inflammation. Cognitive impairment was defined by using previously published thresholds for TICS-m: scores ≤ 10 considered cognitively impaired. Plasma CRP was used as a general marker for systemic inflammation. Fold enrichment and conditional q-q plots showed SNP enrichment for cognitive impairment conditioned on the secondary phenotype of plasma CRP. Three loci, stratified at a stringency level for association with CRP of -log10(pCRP) ≥ 1.5 compared with all SNPs showed the most significant fold enrichment for cognitive impairment with a median fold enrichment of 7 and a maximal 20-fold enrichment for one locus. Closest genes for the significant loci (conditional FDR ≤ 0.05) included CDC14C, HPR and RBMXP1. We identified polygenic overlap between cognitive impairment and a CRP phenotype in the HRS. Interpretation of the results is limited to cognitive impairment as non-AD causes of dementia are not differentiated. The variants and associated genes are involved in multiple pathological processes including metabolic, cardiovascular and immune response and are potentially important for AD risk prediction and development of novel therapeutic approaches based on anti-inflammatory mechanisms.
Source: Alzheimer s & Dementia
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2766130992