Evaluation of Genetic Architecture of Impaired Cognitive Disease With Coronary Artery Disease in AllofUS

Background: While genetic studies have focused on coronary artery disease (CAD) and impaired cognition (IC) separately, understanding the genetic architecture of IC with CAD (ICAD) can provide insight into shared gene-based clinical pathophysiology. &nbsp;&nbsp; <div> <br> </div> <div> Methods: We performed common variant exome wide association (ExWAS, MAF≥1%) on AllofUS (AoU) participants (Age ≥60), with ICAD and compared with CAD, IC. We defined CAD as a history of angina/ ischemic heart disease or having coronary revascularization and IC as mild cognitive impairment/all-cause dementia or impaired memory using ICD/SNOMED codes. We further curated a list of IC (n=230) and CAD (n=420) associated SNVs based on our ExWAS and previous genetic studies to compare traits between IC and CAD SNVs, through phenome-wide association analysis (PheWAS). We used a Bonferroni corrected significance threshold at p &lt; 2·7 x 10-7, and p&lt;1·5X10-5, and suggestive threshold at 10-4 and 2·9 X 10-5, for ExWAS and PheWAS respectively. &nbsp;&nbsp; </div> <div> <br> </div> <div> Findings: We identified rs429358 (APOE, OR:1·35 (1·27-1·45), p=7·1 x 10-21), rs11556505 (TOMM40, OR:1·24 (1·16-1·33), p=3·34 X 10-10), rs6857 (NECTIN2, OR:1·27 (1·19-1·35), p=1·3 x 10-12) and rs112502960 (ZNF652 (novel), OR:1·16 (1·10-1·22), p=9·5 X10-8) to be significantly associated with ICAD. Among shared traits between IC and CAD SNVs, we identified coronary atherosclerosis and hyperlipidemia associated with loci in APOE/APOC1/NECTIN2/ABCA1; hypertension with loci in LAMB2/TSPAN14/ZNF652; and conduction deficits with loci in TREML2/TMEM106B. &nbsp;&nbsp; </div> <div> <br> </div> <div> Interpretation: In the diverse AoU participants, we identified many loci significantly associated with ICAD. Through PheWAS, we identified many cardiometabolic traits (coronary atherosclerosis, hypertension, conduction deficits, and hyperlipidemia) shared by IC and CAD SNVs. </div>