Exome-wide analysis reveals role of 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 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 variants with (rs34949484 and others, suggestively significant), (rs146766120; pAla25Thr, significant), and (rs111522866, significant), controlling for lipid and glycemic risks. Our gene-based analysis also suggests that and 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 affecting visual attention. Our report based on this large-scale exome-wide study highlights the effects of neuronal genes, such as , , and other genomic loci, thus providing further evidence of the genetic underpinnings for cognition during aging.