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

doi:10.1177/0271678X211066299

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 journal › Article › peer-review

2 Scopus citations

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 language	English
Pages (from-to)	1437-1450
Number of pages	14
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	42
Issue number	8
DOIs	https://doi.org/10.1177/0271678X211066299
State	Published - Aug 2022

Bibliographical note

Publisher Copyright:
© The Author(s) 2022.

Funding

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). 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]. 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. 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 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. 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 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

Funders	Funder number
Northern California Institute for Research and Education
Alzheimer’s Disease Genetics Consortium
University of Kentucky
DOD ADNI
National Institute of Biomedical Imaging and Bioengineering	P30 AG028383, P30 AG013846, P30 AG008017, P30 AG053760, P30 AG010133, P50 AG005146, P50 AG033514, P50 AG005142, P50 AG005681, P30AG10161, P50 AG047366, P50 AG047266, P30 AG019610, P50 AG023501, P30 AG008051, P30 AG010129, P30 AG013854, P50 AG005138, P50 AG008702, P30 AG010124, P30 AG012300, P50 AG005134, P50 AG025688, P50 AG005136, P50 AG047270, U01 AG016976, P30 AG035982, P50 AG005131, P50 AG005133, P30 AG049638, P50 AG016574, P50 AG016573
National Institute of Biomedical Imaging and Bioengineering
National Institute on Aging	RC2AG036528, U19AG066567, U01 AG032984
National Institute on Aging
U.S. Department of Defense	W81XWH-12-2-0012
U.S. Department of Defense
The Pennsylvania State University	U24-AG041689-01
The Pennsylvania State University
University of Southern California	P30AG028383, R56AG057191
University of Southern California
National Institutes of Health (NIH)	R01AG56352, R01AG40039, RF1AG54057, UH2NS100599, R01AG33678, RF1AG15819, R01AG36042, R01AG34374, U01AG46152, R01AG47976, U01 AG024904, R01AG43379, R01AG17917, R01NS78009, R01AG042210, RF1AG22018
National Institutes of Health (NIH)
DoD Alzheimer's Disease Neuroimaging Initiative	U01 AG024904
DoD Alzheimer's Disease Neuroimaging Initiative
Illinois Department of Public Health	U19AG066567
Illinois Department of Public Health
Membership of the Alzheimer's Disease Genetics Consortium is provided in the Acknowledgments	U24 AG21886
National Center for Advancing Translational Sciences (NCATS)	UL1TR001998
National Center for Advancing Translational Sciences (NCATS)
University of Kentucky, Center for Clinical and Translational Science	TLITR001997
University of Kentucky, Center for Clinical and Translational Science

Keywords

SVD
VCID
aging
arteriosclerosis
dementia
neuropathology

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cardiology and Cardiovascular Medicine

Access to Document

10.1177/0271678X211066299

Cite this

Shade, L. M. P., Katsumata, Y., Hohman, T. J., Nho, K., Saykin, A. J., Mukherjee, S., Boehme, K. L., Kauwe, J. S. K., Farrer, L. A., Schellenberg, G. D., Haines, J. L., Mayeux, R. P., Schneider, J. A., Nelson, P. T., & Fardo, D. W. (2022). Genome-wide association study of brain arteriolosclerosis. Journal of Cerebral Blood Flow and Metabolism, 42(8), 1437-1450. https://doi.org/10.1177/0271678X211066299

@article{f275eeca760e411daa14b3f6d9c5c96d,

title = "Genome-wide association study of brain arteriolosclerosis",

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.",

keywords = "SVD, VCID, aging, arteriosclerosis, dementia, neuropathology",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2022.",

year = "2022",

month = aug,

doi = "10.1177/0271678X211066299",

language = "English",

volume = "42",

pages = "1437--1450",

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Shade, LMP, Katsumata, Y, Hohman, TJ, Nho, K, Saykin, AJ, Mukherjee, S, Boehme, KL, Kauwe, JSK, Farrer, LA, Schellenberg, GD, Haines, JL, Mayeux, RP, Schneider, JA, Nelson, PT & Fardo, DW 2022, 'Genome-wide association study of brain arteriolosclerosis', Journal of Cerebral Blood Flow and Metabolism, vol. 42, no. 8, pp. 1437-1450. https://doi.org/10.1177/0271678X211066299

TY - JOUR

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AU - Shade, Lincoln M.P.

AU - Katsumata, Yuriko

AU - Hohman, Timothy J.

AU - Nho, Kwangsik

AU - Saykin, Andrew J.

AU - Mukherjee, Shubhabrata

AU - Boehme, Kevin L.

AU - Kauwe, John S.K.

AU - Farrer, Lindsay A.

AU - Schellenberg, Gerard D.

AU - Haines, Jonathan L.

AU - Mayeux, Richard P.

AU - Schneider, Julie A.

AU - Nelson, Peter T.

AU - Fardo, David W.

N1 - Publisher Copyright: © The Author(s) 2022.

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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.

KW - SVD

KW - VCID

KW - aging

KW - arteriosclerosis

KW - dementia

KW - neuropathology

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JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 8

ER -

Genome-wide association study of brain arteriolosclerosis

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Genome-wide association study of brain arteriolosclerosis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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S'ORCe Collaborative Group (RENEWED)

Statistical ‘Omics Research Collaborative (S'ORCe)

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