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

TitleNovel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.
Publication TypeJournal Article
Year of Publication2021
AuthorsKunkle BW, Schmidt M, Klein H-U, Naj AC, Hamilton-Nelson KL, Larson EB, Evans DA, De Jager PL, Crane PK, Buxbaum JD, Ertekin-Taner N, Barnes LL, M Fallin D, Manly JJ, Go RCP, Obisesan TO, M Kamboh I, Bennett DA, Hall KS, Goate AM, Foroud TM, Martin ER, Wang L-S, Byrd GS, Farrer LA, Haines JL, Schellenberg GD, Mayeux R, Pericak-Vance MA, Reitz C, Graff-Radford NR, Martinez I, Ayodele T, Logue MW, Cantwell LB, Jean-Francois M, Kuzma AB, Adams LD, Vance JM, Cuccaro ML, Chung J, Mez J, Lunetta KL, Jun GR, Lopez OL, Hendrie HC, Reiman EM, Kowall NW, Leverenz JB, Small SA, Levey AI, Golde TE, Saykin AJ, Starks TD, Albert MS, Hyman BT, Petersen RC, Sano M, Wisniewski T, Vassar R, Kaye JA, Henderson VW, DeCarli C, LaFerla FM, Brewer JB, Miller BL, Swerdlow RH, Van Eldik LJ, Paulson HL, Trojanowski JQ, Chui HC, Rosenberg RN, Craft S, Grabowski TJ, Asthana S, Morris JC, Strittmatter SM, Kukull WA
Corporate AuthorsWriting Group for the Alzheimer’s Disease Genetics Consortium(ADGC)
JournalJAMA Neurol
Volume78
Issue1
Pagination102-113
Date Published01/2021
ISSN2168-6157
KeywordsAfrican Americans, Aged, Alzheimer Disease, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged
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.

DOI10.1001/jamaneurol.2020.3536
Alternate JournalJAMA Neurol
PubMed ID33074286
PubMed Central IDPMC7573798
Grant ListP50 AG016573 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
R01 AG009029 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
P30 AG035982 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
U01 AG052410 / AG / NIA NIH HHS / United States
P30 AG066444 / AG / NIA NIH HHS / United States
P30 AG062428 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG053760 / AG / NIA NIH HHS / United States
R01 AG028786 / AG / NIA NIH HHS / United States
P30 AG049638 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P30 AG066512 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
P30 AG062421 / AG / NIA NIH HHS / United States
UL1 TR002369 / TR / NCATS NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
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P50 AG047266 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
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K25 AG055620 / AG / NIA NIH HHS / United States
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