Brief Communications: Phenome-wide Association Study of Cognitive Function in Multiethnic Asian population

Cognition is one of the most widely used measure of brain health. Poor cognitive function reflects both the progression of neurodegenerative disorders and the decline of cardiometabolic conditions. Moreover, the genetic determinants of cognitive function are pleiotropic with various aspects of physical health and mortality. To date, little research representing the diverse Asian populations has been done. To understand the epidemiological role of cognition and its biological underpinnings in this population, we performed PheWAS on 542 unique research variables collected in the HELIOS Study (Singapore), with a dataset comprising 8207 individuals (Chinese: Indian: Malay= 69:18:13) aged 30-84 years in whom ‘g’, general factor for cognition, was derived. We used ‘g’ as a predictor and adjusted for age, sex, ethnicity, the interaction of age and sex and genetically determined ancestries. We then performed 2-sample Mendelian Randomization and downstream sensitivity analyses using the GWAS summary statistics from the UK Biobank to ascertain causality. We found that ‘g’ was associated with a broad range of phenotypes (Bonferroni p<8.1x10 ^-5 , 148 [27.3%] phenotypes), ranging from greater familiarity with digital devices (β=0.21, p=5.5x10 ^-138 ), to smaller waist-hip-ratio (β =-0.06, p=2.5x10 ^-15 ) and lower carbohydrate intake (β=-0.07, p=3.5x10 ^-11 ). After further hierarchical clustering to reduce redundancies and ensure representativeness across domains, we shortlisted 23 (4.2%) representative phenotypes. The Inverse Variance Weighted 2-sample MR demonstrated causal linkage of genetically predicted ‘g’ with 14 demographic and physiological phenotypes, including less body fat percentage, lower alcohol consumptions, higher polyunsaturated/monounsaturated fatty acids (PUFA/MUFA) consumptions, household income and total year of education, with significant horizonal pleiotropy. From the initial 147 SNPs in the instrument-exposure ‘g’ , we selected 134 SNPs which uniquely predicts ‘ g ’ and performed further annotations. The SNPs are linked with genes involved in neural development, neurotransmission, neuroprotection, and chromatin modification and transcriptional regulation. Our study demonstrates broad implications of cognitive function in lifestyle choices and cardiometabolic health indices as potential targets for early health maintenance at population levels. Furthermore, the HELIOS Study addresses the diversity gap in the cognitive genetic research and presents an opportunity to improve the cardiometabolic and cognitive health in this multiethnic Asian populations.