Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

Brian W. Kunkle(University of Miami), Michael A. Schmidt(University of Miami), Hans‐Ulrich Klein(Columbia University), Adam C. Naj(University of Pennsylvania), Kara L. Hamilton‐Nelson(University of Miami), Eric B. Larson(Kaiser Permanente Washington Health Research Institute), Denis A. Evans(Rush University Medical Center), Phil L. De Jager(Columbia University), Paul K. Crane(University of Pennsylvania), Joseph D. Buxbaum(Allen Institute for Brain Science), Nilüfer Ertekin‐Taner(Jacksonville College), Lisa L. Barnes(Rush University Medical Center), M. Daniele Fallin(Johns Hopkins University), Jennifer J. Manly(Columbia University), Rodney C.P. Go(University of Alabama at Birmingham), Thomas O. Obisesan(Howard University Hospital), M. Ilyas Kamboh(University of Pittsburgh), David A. Bennett(Rush University Medical Center), Kathleen Hall(Indiana University School of Medicine), Alison Goate(Allen Institute for Brain Science), Tatiana M. Foroud(Indiana University – Purdue University Indianapolis), Eden R. Martin(University of Miami), Li‐San Wang(University of Pennsylvania), Goldie S. Byrd, Lindsay A. Farrer(Boston University), Jonathan L. Haines(Case Western Reserve University), Gerard D. Schellenberg(University of Pennsylvania), Richard Mayeux(Columbia University), Margaret A. Pericak‐Vance(University of Miami), Christiane Reitz(Columbia University), Erin L. Abner(Alzheimer’s Disease Neuroimaging Initiative), M. Adams Perrie(Alzheimer’s Disease Neuroimaging Initiative), L. Albin Roger(Alzheimer’s Disease Neuroimaging Initiative), G Apostolova Liana(Alzheimer’s Disease Neuroimaging Initiative), Eschrich Steven(Alzheimer’s Disease Neuroimaging Initiative), S Craig(Alzheimer’s Disease Neuroimaging Initiative), T. Baldwin Clinton(Alzheimer’s Disease Neuroimaging Initiative), C. Barber Robert(Alzheimer’s Disease Neuroimaging Initiative), Sandra Barral(Alzheimer’s Disease Neuroimaging Initiative), Gunther Thomas(Alzheimer’s Disease Neuroimaging Initiative), T. James(Alzheimer’s Disease Neuroimaging Initiative), W. Beecham Gary(Alzheimer’s Disease Neuroimaging Initiative), H. Bigio Eileen(Alzheimer’s Disease Neuroimaging Initiative), D. Thomas(Alzheimer’s Disease Neuroimaging Initiative), Deborah Blacker(Alzheimer’s Disease Neuroimaging Initiative), F. Boeve Bradley(Alzheimer’s Disease Neuroimaging Initiative), D. Bowen James(Alzheimer’s Disease Neuroimaging Initiative), Adam Boxer(Alzheimer’s Disease Neuroimaging Initiative), R. Burke James(Alzheimer’s Disease Neuroimaging Initiative), Morris Jeffrey(Alzheimer’s Disease Neuroimaging Initiative), J Cairns Nigel(Alzheimer’s Disease Neuroimaging Initiative), Chuanhai Cao(Alzheimer’s Disease Neuroimaging Initiative), M. Carlsson Cynthia(Alzheimer’s Disease Neuroimaging Initiative), M. Carney Regina(Alzheimer’s Disease Neuroimaging Initiative), M. Carrasquillo Minerva(Alzheimer’s Disease Neuroimaging Initiative), Hugh-Jones David(Alzheimer’s Disease Neuroimaging Initiative), Carlos Cruchaga(Alzheimer’s Disease Neuroimaging Initiative), Malcom Dick(Alzheimer’s Disease Neuroimaging Initiative), Dennis, W. Dickson(Alzheimer’s Disease Neuroimaging Initiative), Rachelle S. Doody(Alzheimer’s Disease Neuroimaging Initiative), Ranjan Duara(Alzheimer’s Disease Neuroimaging Initiative), M. Faber Kelley(Alzheimer’s Disease Neuroimaging Initiative), Jaya Thomas(Alzheimer’s Disease Neuroimaging Initiative), B. Kenneth(Alzheimer’s Disease Neuroimaging Initiative), W. Fardo David(Alzheimer’s Disease Neuroimaging Initiative), Roger Martin(Alzheimer’s Disease Neuroimaging Initiative), Steven H. Ferris(Alzheimer’s Disease Neuroimaging Initiative), P. Frosch Matthew(Alzheimer’s Disease Neuroimaging Initiative), R. Galasko Douglas(Alzheimer’s Disease Neuroimaging Initiative), Marla Gearing(Alzheimer’s Disease Neuroimaging Initiative), Hervé Daniel(Alzheimer’s Disease Neuroimaging Initiative), Bernardino Ghetti(Alzheimer’s Disease Neuroimaging Initiative), John, R. Gilbert(Alzheimer’s Disease Neuroimaging Initiative), C. Green Robert(Alzheimer’s Disease Neuroimaging Initiative), Harding John(Alzheimer’s Disease Neuroimaging Initiative), Håkon Håkonarson(Alzheimer’s Disease Neuroimaging Initiative), L. Hamilton Ronald(Alzheimer’s Disease Neuroimaging Initiative), John Hardy(Alzheimer’s Disease Neuroimaging Initiative), E. Harrell Lindy(Alzheimer’s Disease Neuroimaging Initiative), Steve Lawrence(Alzheimer’s Disease Neuroimaging Initiative), Mary Ryan(Alzheimer’s Disease Neuroimaging Initiative), J. Huentelman Matthew(Alzheimer’s Disease Neuroimaging Initiative), M Hulette Christine(Alzheimer’s Disease Neuroimaging Initiative), P. Jarvik Gail(Alzheimer’s Disease Neuroimaging Initiative), Lee‐Way Jin(Alzheimer’s Disease Neuroimaging Initiative), Anna Karydas(Alzheimer’s Disease Neuroimaging Initiative), J. Katz Mindy(Alzheimer’s Disease Neuroimaging Initiative), S. John(Alzheimer’s Disease Neuroimaging Initiative), C. Dirk Keene(Alzheimer’s Disease Neuroimaging Initiative), Ronald Kim(Alzheimer’s Disease Neuroimaging Initiative), H. Kramer Joel(Alzheimer’s Disease Neuroimaging Initiative), J. Lah James(Alzheimer’s Disease Neuroimaging Initiative), Yuk Yee Leung(Alzheimer’s Disease Neuroimaging Initiative), Ge Li(Alzheimer’s Disease Neuroimaging Initiative), Peter Andrew(Alzheimer’s Disease Neuroimaging Initiative), B. Richard(Alzheimer’s Disease Neuroimaging Initiative), G. Lyketsos Constantine(Alzheimer’s Disease Neuroimaging Initiative), John Malamon(Alzheimer’s Disease Neuroimaging Initiative), Chammiran Daniel(Alzheimer’s Disease Neuroimaging Initiative), Frank Martiniuk(Alzheimer’s Disease Neuroimaging Initiative), Eliezer Masliah(Alzheimer’s Disease Neuroimaging Initiative), C. McCormick Wayne(Alzheimer’s Disease Neuroimaging Initiative), M Susan(Alzheimer’s Disease Neuroimaging Initiative), Nesbit M Andrew(Alzheimer’s Disease Neuroimaging Initiative), Stefan McDonough(Alzheimer’s Disease Neuroimaging Initiative), Canfield Ann.(Alzheimer’s Disease Neuroimaging Initiative), Marsel Mesulam(Alzheimer’s Disease Neuroimaging Initiative), L. Miller Bruce(Alzheimer’s Disease Neuroimaging Initiative), A. Miller Carol(Alzheimer’s Disease Neuroimaging Initiative), J. Montine Thomas(Alzheimer’s Disease Neuroimaging Initiative), Shubhabrata Mukherjee(Alzheimer’s Disease Neuroimaging Initiative), J. Myers Amanda(Alzheimer’s Disease Neuroimaging Initiative), Eric Sid(Alzheimer’s Disease Neuroimaging Initiative), M. Olichney John(Alzheimer’s Disease Neuroimaging Initiative), E. Parisi Joseph(Alzheimer’s Disease Neuroimaging Initiative), Elaine R. Peskind(Alzheimer’s Disease Neuroimaging Initiative), Aimee Pierce(Alzheimer’s Disease Neuroimaging Initiative), W. Poon Wayne(Alzheimer’s Disease Neuroimaging Initiative), Huntington Potter(Alzheimer’s Disease Neuroimaging Initiative), Liming Qu(Alzheimer’s Disease Neuroimaging Initiative), F. Quinn Joseph(Alzheimer’s Disease Neuroimaging Initiative), Ashok Raj(Alzheimer’s Disease Neuroimaging Initiative), Murray A. Raskind(Alzheimer’s Disease Neuroimaging Initiative), ‌Barry Reisberg(Alzheimer’s Disease Neuroimaging Initiative), Joan, S. Reisch(Alzheimer’s Disease Neuroimaging Initiative), M. Ringman John(Alzheimer’s Disease Neuroimaging Initiative), D. Roberson Erik(Alzheimer’s Disease Neuroimaging Initiative), Ekaterina Rogaeva(Alzheimer’s Disease Neuroimaging Initiative), J. Rosen Howard(Alzheimer’s Disease Neuroimaging Initiative), R. Royall Donald(Alzheimer’s Disease Neuroimaging Initiative), A. Sager Mark(Alzheimer’s Disease Neuroimaging Initiative), A. Schneider Julie(Alzheimer’s Disease Neuroimaging Initiative), Su Lon(Alzheimer’s Disease Neuroimaging Initiative), W. Seeley William(Alzheimer’s Disease Neuroimaging Initiative), Scott A. Small(Alzheimer’s Disease Neuroimaging Initiative), Joshua, A. Sonnen(Alzheimer’s Disease Neuroimaging Initiative), Salvatore Spina(Alzheimer’s Disease Neuroimaging Initiative), Peter St George‐Hyslop(Alzheimer’s Disease Neuroimaging Initiative), Aiko Robert(Alzheimer’s Disease Neuroimaging Initiative), E. Tanzi Rudolph(Alzheimer’s Disease Neuroimaging Initiative), Caballero Juan(Alzheimer’s Disease Neuroimaging Initiative), W. Tsuang Debby(Alzheimer’s Disease Neuroimaging Initiative), Otto Valladares(Alzheimer’s Disease Neuroimaging Initiative), M. Van Deerlin Vivianna(Alzheimer’s Disease Neuroimaging Initiative), Nabeel Badri(Alzheimer’s Disease Neuroimaging Initiative), Vanessa Harry(Alzheimer’s Disease Neuroimaging Initiative), Jean Paul Vonsattel(Alzheimer’s Disease Neuroimaging Initiative), Sandra Weıntraub(Alzheimer’s Disease Neuroimaging Initiative), A Welsh-Bohmer Kathleen(Alzheimer’s Disease Neuroimaging Initiative), C W Kirk(Alzheimer’s Disease Neuroimaging Initiative), Jennifer Williamson(Alzheimer’s Disease Neuroimaging Initiative), SubinVarghese Thomas(Alzheimer’s Disease Neuroimaging Initiative), Linnell B. Randall(Alzheimer’s Disease Neuroimaging Initiative), Chuang‐Kuo Wu(Alzheimer’s Disease Neuroimaging Initiative), G. Younkin Steven(Alzheimer’s Disease Neuroimaging Initiative), Lei Yu(Alzheimer’s Disease Neuroimaging Initiative), Chang‐En Yu(Alzheimer’s Disease Neuroimaging Initiative), Yi Zhao(Alzheimer’s Disease Neuroimaging Initiative), Neill R. Graff‐Radford(Jacksonville College), Izri Martinez(Columbia University), Temitope Ayodele(Columbia University), Mark W. Logue(Boston University), Laura B. Cantwell(University of Pennsylvania), Melissa Jean‐Francois(University of Miami), Amanda Kuzma(University of Pennsylvania), Lonnie D. Adams(University of Miami), Jeffery M. Vance(University of Miami), Michael L. Cuccaro(University of Miami), Jaeyoon Chung(Boston University), Jesse Mez(Boston University), Kathryn L. Lunetta(Boston University), Gyungah Jun(Boston University), Oscar L. López(University of Pittsburgh), Hugh C. Hendrie(Indiana University School of Medicine), Eric M. Reiman(Alzheimer's Association), Neil W. Kowall(Boston University), James B. Leverenz(Cleveland Clinic), Scott A. Small(Alzheimer’s Disease Neuroimaging Initiative), Allan I. Levey(Emory University), Todd E. Golde(University of Florida), Andrew J. Saykin(Indiana University School of Medicine), Takiyah D. Starks, Marilyn S. Albert(Johns Hopkins University), Bradley T. Hyman(Massachusetts General Hospital), Ronald Petersen(Mayo Clinic), Mary Sano(Icahn School of Medicine at Mount Sinai), Thomas Wısnıewskı(Cognitive Research (United States)), Robert Vassar(Northwestern University), Jeffrey A. Kaye(Oregon Health & Science University), Victor W. Henderson(Stanford University), Charles DeCarli(University of California Davis Medical Center), Frank M. LaFerla(University of California, Irvine), James B. Brewer(University of California San Diego), Bruce L. Miller(University of California, San Francisco), Russell H. Swerdlow(University of Kansas), Linda J. Van Eldik(University of Kentucky), Henry L. Paulson(University of Michigan), John Q. Trojanowski(University of Pennsylvania), Helena C. Chui(University of Southern California), Roger N. Rosenberg(The University of Texas Southwestern Medical Center), Suzanne Craft(Wake Forest University), Thomas J. Grabowski(University of Washington), Sanjay Asthana(University of Wisconsin–Madison), John C. Morris(Washington University in St. Louis), Stephen M. Strittmatter(Yale University), Walter A. Kukull(University of Washington)
JAMA Neurology
October 19, 2020
10.1001/jamaneurol.2020.3536
Cited by 273Open Access
Full Text

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.

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