Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s disease related proteins
Stephanie R. Oatman, Joseph S. Reddy, Zachary Quicksall, Minerva M. Carrasquillo, Xue Wang, Chia‐Chen Liu, Yu Yamazaki, Thuy Nguyen, Kimberly G. Malphrus, Michael G. Heckman, Kristi Biswas, Kwangsik Nho, Matthew Baker, Yuka A. Martens, Na Zhao, Jun Pyo Kim, Shannon L. Risacher, Rosa Rademakers, Andrew J. Saykin, Michael DeTure, Melissa E. Murray, Takahisa Kanekiyo, for the Alzheimer’s Disease Neuroimaging Initiative, Dennis W. Dickson, Guojun Bu, Mariet Allen, Nilüfer Ertekin‐Taner
Abstract
BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. RESULTS: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. CONCLUSIONS: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.