Genetic associations with neuropathological outcomes revealed a novel role in neuritic plaque formation

Abstract

AbstractBackgroundNumerous genome‐wide association studies (GWASs) have been performed for the determination of genes and variants contributing to Alzheimer’s disease (AD). We hypothesized that it is important to explore whether the previously‐reported AD‐associated genes in GWASs can have neuropathological effects in the brain and can be employed as potential biomarkers for neuropathological outcomes such as neuritic plaque development. Neuritic plaques (also known as amyloid plaques) are extracellular deposits of the amyloid beta protein primarily found in the grey matter of the brain and are the most discernible neuropathological alterations observed in individuals with dementia.MethodHere, we report the genetic association study of neuropathology data such as neuritic plaque measurements in an AD cohort at the National Alzheimer’s Coordinating Center (NACC) using a sample of 1,283 individuals. We acquired the genetic data from the Alzheimer’s Disease Sequencing Project (ADSP) which generated whole genome sequencing data through the ADSP Quality Control pipeline. We employed 18 loci where the associations of these loci with AD risk were validated by the recent GWASs. Analysis was obtained using a linear mixed model after adjustment for covariates including age at death, gender, the number of the APOE e4 allele (i.e., 0, 1, and 2), ancestry representative principle components (i.e., population structure), and a genetic relatedness matrix (i.e., a polygenic effect due to genetic relatedness among individuals).ResultFrom our analysis, we generalized to the NACC cohort significant associations after Bonferroni correction with neuritic plaque measurements and one previously identified locus such as BIN1 on chromosome 2 (p = 4.65×10−5). Furthermore, we detected, at the significance level after Bonferroni correction, a novel locus for neuritic plaque formation that has not previously been reported: PICALM (or nearby LINC02695 or nearby RNU6‐560P) on chromosome 11 (p = 1.02×10−3). PICALM is a strong candidate for playing a role in neuritic plaque formation because deficiency in PICALM results in diminished amyloid‐β clearance.ConclusionThe results from our genetic association study of neuritic plaque formation in the AD cohort underline the potential of utilizing neuropathology data to discover additional support for relevant loci being associated with AD across diverse populations.