Genome-wide association study of multiple neuropathology endophenotypes identifies novel risk loci and provides insights into known Alzheimer's risk loci

Background Alzheimer's disease is highly heritable and exhibits neuropathological hallmarks of neurofibrillary tau tangles and neuritic amyloid plaques. Previous genome-wide association studies (GWAS) have identified over 70 genomic risk loci of clinically diagnosed Alzheimer's disease. However, upon autopsy, many Alzheimer's disease patients have multiple comorbid neuropathologies that may have independent or pleiotropic genomic risk factors. Autopsy data combined with GWAS provides the opportunity to study the genetic risk factors of individual neuropathologies. Methods We studied the genome-wide risk factors of eleven Alzheimer's disease-related neuropathology endophenotypes. We used four sources of neuropathological data: National Alzheimer's Coordinating Center, Religious Orders Study and Rush Memory and Aging Project, Adult Changes in Thought study, and Alzheimer's Disease Neuroimaging Initiative. We used generalized linear mixed models to identify risk loci, followed by Bayesian colocalization analyses to identify potential functional mechanisms by which genetic loci influence neuropathology risk. Results We identified two novel loci associated with neuropathology: one PIK3R5 locus (lead variant rs72807981) with neurofibrillary pathology, and one COL4A1 locus (lead variant rs2000660) with cerebral atherosclerosis. We also confirmed associations between known Alzheimer's genes and multiple neuropathology endophenotypes, including APOE (neurofibrillary tangles, neuritic plaques, diffuse plaques, cerebral amyloid angiopathy, and TDP-43 pathology); BIN1 (neurofibrillary tangles and neuritic plaques); and TMEM106B (TDP-43 pathology and hippocampal sclerosis). After adjusting for APOE genotype, we identified a locus near APOC2 (lead variant rs4803778) associated with cerebral amyloid angiopathy that influences DNA methylation at nearby CpG sites in the cerebral cortex. Conclusions rs2000660 is in strong linkage disequilibrium with a synonymous coding variant (rs650724) of COL4A1, providing a candidate functional variant. Two CpG sites affected by the cerebral amyloid angiopathy-associated APOC2 locus were previously associated with dementia in an independent cohort, suggesting that the effect of this locus on disease may be mediated by DNA methylation. BIN1 is associated with neurofibrillary tangles and neuritic plaques but not with amyloid pathology. TMEM106B is associated with hippocampal sclerosis and TDP-43 pathology but not the canonical Alzheimer's disease pathologies. These findings provide insights into known Alzheimer's disease risk loci by refining the pathways affected by these risk genes.