Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s Disease

Abstract

AbstractWe generated a proxy Alzheimer’s disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease. We identified four genes significantly associated with the proxy phenotype, three of which have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40). We identified one gene (HEXA) which has not been previously associated with Alzheimer’s disease but is known to contribute to neurodegenerative disease. Here we show that proxy Alzheimer’s disease can capture some of the rare variant association signal for Alzheimer’s disease and can be used to highlight genes and variants of interest. The proxy phenotype allows for the utilisation of large genetic databases without clinically diagnosed Alzheimer’s disease patients to uncover variants and genes that contribute to Alzheimer’s disease.