Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition

Cognitive functioning is heritable, with metabolic risk factors known to accelerate age-associated cognitive decline. Identifying genetic underpinnings of cognition is thus crucial. Here, we undertake single-variant and gene-based association analyses upon 6 neurocogni-tive phenotypes across 6 cognition domains in whole-exome sequencing data from 157,160 individuals of the UK Biobank cohort to expound the genetic architecture of human cognition. We report 20 independent loci associated with 5 cognitive domains while con-trolling for APOE isoform-carrier status and metabolic risk factors; 18 of which were not previously reported, and implicated genes relating to oxidative stress, synaptic plasticity and connectivity, and neuroinflammation. A subset of significant hits for cognition indi-cates mediating effects via metabolic traits. Some of these variants also exhibit pleiotropic effects on metabolic traits. We further identify previously unknown interactions of APOE variants with LRP1 (rs34949484 and others, suggestively significant), AMIGO1 (rs146766120; pAla25Thr, significant), and ITPR3 (rs111522866, significant), controlling for lipid and glycemic risks. Our gene-based analysis also sug-gests that APOC1 and LRP1 have plausible roles along shared pathways of amyloid beta (AB) and lipid and/or glucose metabolism in affecting complex processing speed and visual attention. In addition, we report pairwise suggestive interactions of variants harbored in these genes with APOE affecting visual attention. Our report based on this large-scale exome-wide study highlights the effects of neuronal genes, such as LRP1, AMIGO1, and other genomic loci, thus providing further evidence of the genetic underpinnings for cogni-tion during aging.

Automated summary

Cognitive functioning is influenced by genetic factors, and metabolic risk factors can accelerate cognitive decline with age. This study aims to identify the genetic basis of cognition by analyzing data from whole-exome sequencing of 157,160 individuals. The findings reveal 20 loci associated with cognitive domains, implicating genes related to oxidative stress, synaptic plasticity, and neuroinflammation. The study also identifies interactions between APOE variants and LRP1, AMIGO1, and ITPR3, as well as their roles in amyloid beta and lipid/glucose metabolism pathways. The results highlight the importance of neuronal genes in cognition during aging.