Genome-wide association study of brain arteriolosclerosis

Lincoln M.P. Shade, Yuriko Katsumata, Timothy J. Hohman, Kwangsik Nho, Andrew J. Saykin, Shubhabrata Mukherjee, Kevin L. Boehme, John S.K. Kauwe, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Richard P. Mayeux, Julie A. Schneider, Peter T. Nelson, David W. Fardo

Research output: Contribution to journalArticlepeer-review

Abstract

Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p = (Formula presented.) ; rs2603462, p = (Formula presented.)) were significant in the ADNI cohort (rs7902929, p = (Formula presented.) ; rs2603462, p = (Formula presented.)). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.

Original languageEnglish
Pages (from-to)1437-1450
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume42
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
The Religious Orders Study and the Memory and Aging Project are supported by grants from the National Institutes of Health: [grant number P30AG10161, RF1AG15819, R01AG17917, RF1AG22018, R01AG33678, R01AG34374, R01AG36042, R01AG40039, R01AG042210, U01AG46152, R01AG47976, R01AG43379, RF1AG54057, R01AG56352, R01NS78009, and UH2NS100599], and the Illinois Department of Public Health.

Funding Information:
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 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. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: R56AG057191; P30AG028383; the University of Kentucky Center for Clinical and Translational Science TL-1 Fellowship [grant number TLITR001997]; 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]. We thank Margaret A. Pericak-Vance, Ph.D., of the John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine for her work with the Alzheimer's Disease Genetics Consortium that provided data for this research. 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. The Religious Orders Study and the Memory and Aging Project are supported by grants from the National Institutes of Health: [grant number P30AG10161, RF1AG15819, R01AG17917, RF1AG22018, R01AG33678, R01AG34374, R01AG36042, R01AG40039, R01AG042210, U01AG46152, 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 NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADRCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD).

Funding Information:
Genotyping was supported by the Alzheimer’s Disease Genetics Consortium through the National Institute of Aging [grant numbers U01 AG032984, RC2AG036528]. We thank Margaret A. Pericak-Vance, Ph.D., of the John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine for her work with the Alzheimer's Disease Genetics Consortium that provided data for this research.

Funding Information:
The Adult Changes in Thought Study is funded through the National Institute on Aging [grant number U19AG066567].

Funding Information:
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.

Funding Information:
The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADRCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD). Acknowledgements

Funding Information:
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 ).

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: R56AG057191; P30AG028383; the University of Kentucky Center for Clinical and Translational Science TL-1 Fellowship [grant number TLITR001997]; 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.

Publisher Copyright:
© The Author(s) 2022.

Keywords

  • SVD
  • VCID
  • aging
  • arteriosclerosis
  • dementia
  • neuropathology

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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