Exome-wide analysis reveals role ofLRP1and additional novel loci in cognition

Abstract

AbstractCognitive functioning is heritable, with metabolic risk factors known to accelerate ageassociated cognitive decline. Identifying genetic underpinnings of cognition is thus crucial.Here, we undertake single-variant and gene-based association analyses upon six neurocognitive phenotypes across six cognition domains in whole-exome sequencing data from 157,160 individuals in the UK Biobank to expound the genetic architecture of human cognition. We further identify genetic variants interacting withAPOE, a significant genetic risk factor for cognitive decline, while controlling for lipid and glycemic risks, towards influencing cognition. Additionally, considering lipid and glycemic traits, we conduct bivariate analysis to underscore pleiotropic effects and also highlight suggestive mediation effects of metabolic risks on cognition.We report 18 independent novel loci associated with five cognitive domains while controlling forAPOEisoform-carrier status and metabolic risk factors. Our novel variants are mostly in genes which could also impact cognition via their functions on synaptic plasticity and connectivity, oxidative stress, neuroinflammation. Variants in or near these identified loci show genetic links to cognitive functioning in association withAPOE, Alzheimer’s disease and related dementia phenotypes and brain morphology phenotypes, and are also eQTLs significantly controlling expression of their corresponding genes in various regions of the brain. We further report four novel pairwise interactions between exome-wide significant loci andAPOEvariants influencing episodic memory, and simple processing speed while accounting for serum lipid and serum glycemic traits. We obtain bothAPOC1andLRP1as significantly associated with complex processing speed and visual attention in our gene-based analysis. They also exhibit significant interaction effect withAPOEvariants in influencing visual attention. We find that variants inAPOC1andLRP1act as significant eQTLs for regulating their expression in basal ganglia and cerebellar hemispheres, crucial to visual attention. Taken together, our findings suggest thatAPOC1andLRP1have plausible roles along pathways of amyloid-β, lipid and/or glucose metabolism in affecting visual attention and complex processing speed. Interestingly, variants inMTFR1L, PPFIA1, PCDHB16, ATP2A1show evidence of pleiotropy and mediation effects through serum glucose/HDL levels affecting four different cognition domains.This is the first report from large-scale exome-wide study with evidence underscoring the effect ofLRP1on cognition. Our research highlights a novel set of loci that augments our understanding of the genetic underpinnings of cognition during ageing, considering cooccurring metabolic conditions that can confer genetic risk to cognitive decline in addition toAPOE, which can aid in finding causal determinants of cognitive decline.