Genome-wide study links cardiometabolic factors to cognition via APOA4-APOA5-ZPR1-BUD13 and other loci in rural Indians

INTRODUCTION

Cardiometabolic risks affect cognition during aging, yet genetic basis for both remain understudied in Indians.

METHODS

This study constructs an ancestry-matched Indian haplotype reference panel for genotype imputation of 5111 rural Indians. Single-locus, gene-based, conditional genome-wide association analyses are performed on 20 cognitive and 10 cardiometabolic traits, with subsequent follow-up of identified associations through multimodal functional annotation. Furthermore, causal interrelationships between cardiometabolic and cognitive phenotypes by Mendelian randomization are investigated.

RESULTS

One novel memory-associated and 17 novel cardiometabolic phenotypes-associated (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TG:HDL, and visceral adiposity index [VAI]) genome-wide significant loci, and multiple genes are identified. AMIGO1 (delayed-recall) and ZPR1-APOA5 (metabolic syndrome) exhibit distinct haplotype structure compared to other populations. Causal roles of cardiometabolic traits on various cognitive domains are identified via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13 among others.

DISCUSSION

These findings illustrate the impact of cardiometabolic factors on cognition in a rural socioeconomically disadvantaged population, advancing efforts to address health disparities.

Highlights

• Our newly constructed ancestry-matched haplotype reference panel gives better genotype imputation accuracy for the Indian population.
• One and 17 novel genome-wide significant single-loci were identified to be associated with cognitive and cardiometabolic traits, respectively. Several subgenome-wide hits for all phenotypes were identified.
• Collapsing protein truncating variants (PTVs), there were two genes identified to be associated with cardiometabolic traits at a genome-wide level of significance, correcting for multiple phenotypes tested.
• Haplotypic differences were identified compared to 1000 Genomes superpopulations for genes influencing delayed recall and metabolic syndrome.
• Adverse causal roles of cardiometabolic traits on cognition were uncovered via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13, among others, through Mendelian randomization.