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

Abstract

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.

Competing Interest Statement

J.A.S. reported personal fees from Observational Study Monitoring Board Framingham, Observational Study Monitoring Board Discovery (National Institute of Neurological Disorders and Stroke), and Takeda Pharma. A.J.S. reported support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); and Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior). All other authors declare that they have no competing interests.

Funding Statement

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: R56AG057191; F30NS124136; P30AG028383; the University of Kentucky Center for Clinical and Translational Science TL-1 Fellowship [grant number TL1TR001997]; the National Center for Advancing Translational Sciences [grant number UL1TR001998]; and the Dean of the College of Medicine, University of Kentucky. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the University of Kentucky. Genotyping was supported by the Alzheimer's Disease Genetics Consortium through the National Institute of Aging [grant numbers U01 AG032984, RC2AG036528]. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01). We thank the study participants and staff of the Rush Alzheimer's Disease Center. The Religious Orders Study and the Rush Memory and Aging Project are supported by grants from the National Institutes of Health: [grant number P30AG10161, P30AG72975, R01AG15819, R01AG17917, R01AG22018, R01AG33678, R01AG34374, R01AG36042, R01AG40039, R01AG042210, U01AG46152, U01AG61356, R01AG47976, R01AG43379, RF1AG54057, R01AG56352, R01NS78009, and UH2NS100599], and the Illinois Department of Public Health. The Adult Changes in Thought Study is funded through the National Institute on Aging [grant number U19AG066567]. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Institutional Review Board at University of Kentucky waived ethical approval for this work.

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Data Availability

All code used for data preparation and analysis is available at https://www.github.com/lincoln-shade/np_phewas. ROSMAP data can be requested at https://www.radc.rush.edu and https://www.synapse.org. ADGC data is can be requested from NIAGADS at https://www.niagads.org/resources/related-projects/alzheimers-disease-genetics-consortium-adgc-collection. NACC neuropathology data can be requested at https://naccdata.org/. ACT data can be requested at https://actagingresearch.org/. ADNI data can be downloaded at https://adni.loni.usc.edu/.

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