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 neurocognitive 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 controlling 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 indicates 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 suggests that APOC1 and LRP1 have plausible roles along shared pathways of amyloid beta (Aβ) 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 cognition during aging. Exome-wide association study in >150,000 individuals identifies LRP1, AMIGO1, APOC1, and additional genetic loci acting in conjunction with APOE, revealing genetic underpinnings of 5 domains of cognition, in the presence of age-associated metabolic risks, for example, dyslipidemia and glycemic imbalance. These variants regulate expression of associated genes in cerebellum and cortex.