Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis

Brian W. Kunkle, Michael Schmidt, Hans Ulrich Klein, Adam C. Naj, Kara L. Hamilton-Nelson, Eric B. Larson, Denis A. Evans, Phil L. De Jager, Paul K. Crane, Joe D. Buxbaum, Nilufer Ertekin-Taner, Lisa L. Barnes, M. Daniele Fallin, Jennifer J. Manly, Rodney C.P. Go, Thomas O. Obisesan, M. Ilyas Kamboh, David A. Bennett, Kathleen S. Hall, Alison M. GoateTatiana M. Foroud, Eden R. Martin, Li Sao Wang, Goldie S. Byrd, Lindsay A. Farrer, Jonathan L. Haines, Gerard D. Schellenberg, Richard Mayeux, Margaret A. Pericak-Vance, Christiane Reitz, Neill R. Graff-Radford, Izri Martinez, Temitope Ayodele, Mark W. Logue, Laura B. Cantwell, Melissa Jean-Francois, Amanda B. Kuzma, L. D. Adams, Jeffery M. Vance, Michael L. Cuccaro, Jaeyoon Chung, Jesse Mez, Kathryn L. Lunetta, Gyungah R. Jun, Oscar L. Lopez, Hugh C. Hendrie, Eric M. Reiman, Neil W. Kowall, James B. Leverenz, Scott A. Small, Allan I. Levey, Todd E. Golde, Andrew J. Saykin, Takiyah D. Starks, Marilyn S. Albert, Bradley T. Hyman, Ronald C. Petersen, Mary Sano, Thomas Wisniewski, Robert Vassar, Jeffrey A. Kaye, Victor W. Henderson, Charles Decarli, Frank M. Laferla, James B. Brewer, Bruce L. Miller, Russell H. Swerdlow, Linda J. Van Eldik, Henry L. Paulson, John Q. Trojanowski, Helena C. Chui, Roger N. Rosenberg, Suzanne Craft, Thomas J. Grabowski, Sanjay Asthana, John C. Morris, Stephen M. Strittmatter, Walter A. Kukull

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures: Diagnosis of Alzheimer disease. Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Original languageEnglish
Pages (from-to)102-113
Number of pages12
JournalJAMA Neurology
Volume78
Issue number1
DOIs
StatePublished - Jan 2021

Bibliographical note

Funding Information:
Funding/Support: This study was supported by the National Institutes of Health (NIH) (grants RF1 AG054023, U24 AG056270), Alzheimer’s Disease Genetics Consortium (grant U01 AG032984), National Institute on Aging (NIA) Genetics Initiative for Late-Onset Alzheimer’s Disease (grants U24 AG026395, U24 AG026390 [PI, Richard Mayeux, MD]), NIA Genetics of Alzheimer’s Disease Data Storage Site (grant U24 AG041689 [PI, Li-San Wang, PhD]), Washington Heights-Inwood Community Aging Project (grant R01 AG037212, R37 AG015473 [PI, Richard Mayeux, MD]), National Centralized Repository for Alzheimer’s Disease and Related Dementias (grant U24 AG021886 [PI, Tatiana Foroud, PhD]), Indianapolis AA (grants R01 AG009956, RC2 AG036650 [PI, Kathleen Hall, PhD]), ACT (grants U01 AG06781, U01 HG004610 [PI, Eric Larson, MD, MPH]), MIRAGE (grant R01 AG009029 [PI, Lindsay Farrer, PhD]), GenerAAtions (grant 5R01 AG20688 [PI, M. Daniele Fallin, PhD]), Pittsburg (grants P50 AG005133 [PI, O. Lopez], AG030653, AG041718, AG064877 [PI, M. Ilyas Kamboh, PhD]), Case Western Reserve University (grant R01 AG019085 [PI, Jonathan Haines, PhD]), CHAP (grants R01 AG11101, R01 AG030146, RC2 AG036650 [PI, Denis Evans, MD]), ROS/MAP (grants P30 AG10161, R01 AG15819, R01 AG30146, R01 AG17917, R01 AG15819 [PI, David Bennett, MD]), African-American AD Genetics Study (grant R01 AG028786 [PI, Jennifer Manly, PhD]), MARS/CORE (grants R01 AG22018, P30 AG10161 [PI, Lisa Barnes, PhD]), Mayo Clinic (grants P50 AG0016574, R01 032990, KL2 RR024151 [PIs, Ronald C. Petersen, MD, PhD, Nilufer Ertekin-Taner, MD, PhD, and Neill Graff-Radford, MD]), Miami (grants R01 AG027944, R01 AG028786 [PI, Margaret Pericak-Vance, PhD]), Wake Forest (PI, Goldie Byrd, PhD), MSSM (PI, Joseph Buxbaum, PhD), and MSSM (grants P50 AG05681, P01 AG03991, P01 AG026276 [PI, Alison Goate]). Dr Reitz was further supported by the NIH (grants RF1AG054080, U01AG052410, AG0087202). The NACC database is funded by NIA/NIH (grant U01 AG016976). National Alzheimer’s Coordinating Center data are contributed by the NIA-funded Alzheimer Disease Centers (grants P30 AG019610 [PI, Eric Reiman, MD], P30 AG013846 [PI, Neil Kowall, MD], P30 AG062428-01 [PI, James Leverenz, MD], P50 AG008702 [PI, Scott Small, MD], P50 AG025688 [PI, Allan Levey, MD, PhD], P50 AG047266 [PI, Todd Golde, MD, PhD], AG045058 [PI, Thomas Obisesan, MD, MPH], P30 AG010133 [PI, Andrew Saykin, PsyD], P50 AG005146 [PI, Marilyn Albert, PhD], P30 AG062421-01 [PI, Bradley Hyman, 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], P30 AG062429-01 [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], P30 AG062715-01 [PI, Sanjay Asthana, MD, FRCP], P50 AG005681 [PI, John C. Morris, MD], P50 AG047270 [PI, Stephen Strittmatter, MD, PhD]).

Funding Information:
reported grants from the National Institute of Aging (NIA) during the conduct of the study. Dr Schmidt reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Larson reported grants from NIA during the conduct of the study. Dr Graff-Radford reported grants from NIH during the conduct of the study; grants from AbbVie, Biogen, Eli Lilly and Company, and Novartis outside the submitted work. Dr Evans reported grants from NIH during the conduct of the study. Dr Vance reported grants from NIH/NIA during the conduct of the study. Dr Cuccaro reported grants from NIH during the conduct of the study and other support from John P. Hussman Foundation outside the submitted work. Dr Manly reported grants from NIA/NIH during the conduct of the study. Dr Mez reported grants from NIH during the conduct of the study. Dr Obisesan reported grants from NIH during the conduct of the study. Dr Bennett reported grants from NIH during the conduct of the study. Dr Hall reported grants from NIA during the conduct of the study. Dr Reiman reported grants from Banner Alzheimer’s Institute during the conduct of the study other support from Roche/Roche Diagnostics outside the submitted work. Dr Leverenz reported grants from NIA during the conduct of the study and grants from Alzheimer’s Drug Discovery Foundation, Avid Biopharmaceuticals, Biogen, GE Healthcare, Lewy Body Dementia Association, Michael J. Fox Foundation, National Institute of Neurologic Disorders, and Stroke, Sanofi; and consulting fees from Acadia, Aptinyx, Biogen, Eisai, Genzyme, Sanofi, and Takeda. Dr Levey reported personal fees from Karuna Pharmaceuticals and GENUV and grants from vTv Therapeutics, AbbVie, Biogen, Cognito, Esai, Genentech, and Novartis outside the submitted work. Dr Golde reported personal fees from Biogen, Eli Lilly and Company, and AbbVie; nonfinancial support from Lacerta Therapeutics outside the submitted work; and served on safety advisory boards for AbbVie, Promis Therapeutics, Biogen, and Eli Lilly and company. Dr Saykin reported grants from NIH grants during the conduct of the study and other support from Springer-Nature and grants from Eli Lilly and Company; multiprincipal investigator of NIA Small Business Innovation Research to Arkley BioTek, consultant to Bayer Oncology, and served on the advisory board of Neurovision outside the submitted work. Dr Albert reported grants from NIA during the conduct of the study and personal fees from Eli Lilly and Company outside the submitted work. Dr Hyman reported grants from NIH during the conduct of the study. Dr Petersen reported grants from NIH during the conduct of the study and personal fees from Hoffman-La Roche, Merck, Genentech, Biogen, GE Healthcare, and Eisai outside the submitted work. Dr Wisniewski reported grants from NIH during the conduct of the study and outside the submitted work. Dr Kaye reported grants from NIH during the conduct of the study. Dr Henderson reported grants from NIH during the conduct of the study. Dr DeCarli reported consulting for Novartis Pharmaceutical on a safety study in heart failure. Dr Brewer reported holds stock options in CorTechs Labs and Human Longevity and has served on advisory boards for Human Longevity and Eli Lilly and Company outside the submitted work. Dr Van Eldik reported grants from NIH during the conduct of the study. Dr Chui reported grants from NIA during the conduct of the study. Dr Rosenberg reported other support from Vitruvian during the conduct of the study; grants from NIH/ NIA, Zale Foundation, AWARE, Triumph over Alzheimer’s Disease, and Its Their Time outside the submitted work; has a patent to amyloid beta gene vaccines issued; and served as a former Editor of JAMA Neurology, editorial board of The Journal of the Neurological Sciences, and former editorial board member of JAMA. Dr Grabowski reported grants from NIH during the conduct of the study. Dr Asthana reported grants from NIA during the conduct of the study and grants from Genentech and Lundbeck outside the submitted work. Dr Morris reported grants from NIH during the conduct of the study. Dr Strittmatter reported being a founder and equity holder in ReNetX Bio and in Allyx Therapeutics, entities seeking to develop therapeutics for Neural Repair and Neurodegeneration, respectively. Dr Goate served on the scientific advisory board for Denali Therapeutics from 2015-2018 and has served as a consultant for Biogen, AbbVie, Pfizer, GlaxoSmithKline, Eisai, and Illumina. Dr Kukull reported grants from NIH/NIA during the conduct of the study. Dr Foroud reported grants from NIH during the conduct of the study. Dr Haines reported grants from NIH during the conduct of the study. Dr Schellenberg reported grants from University of Pennsylvania during the conduct of the study. Dr Pericak-Vance reported grants from NIH/NIA during the conduct of the study. Dr Reitz reported grants from NIH during the conduct of the study. No other disclosures were reported.

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ASJC Scopus subject areas

  • Clinical Neurology

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