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Meta-Analysis
. 2021 Jan 1;78(1):102-113.
doi: 10.1001/jamaneurol.2020.3536.

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

Brian W Kunkle  1   2 , Michael Schmidt  1   2 , Hans-Ulrich Klein  3   4   5 , Adam C Naj  6   7 , Kara L Hamilton-Nelson  1 , Eric B Larson  8   9 , Denis A Evans  10   11 , Phil L De Jager  3   4   5 , Paul K Crane  7 , Joe D Buxbaum  12   13   14   15 , Nilufer Ertekin-Taner  16   17 , Lisa L Barnes  18   19   20 , M Daniele Fallin  21 , Jennifer J Manly  3   4   5 , Rodney C P Go  22 , Thomas O Obisesan  23 , M Ilyas Kamboh  24   25 , David A Bennett  18   20 , Kathleen S Hall  26 , Alison M Goate  13   14   15   27 , Tatiana M Foroud  28 , Eden R Martin  1   2 , Li-Sao Wang  7 , Goldie S Byrd  29 , Lindsay A Farrer  30   31   32   33   34 , Jonathan L Haines  35 , Gerard D Schellenberg  7 , Richard Mayeux  3   4   5   36   37 , Margaret A Pericak-Vance  1   2 , Christiane Reitz  3   4   5   37 ; Writing Group for the Alzheimer’s Disease Genetics Consortium (ADGC); Neill R Graff-Radford  16   17 , Izri Martinez  4 , Temitope Ayodele  4 , Mark W Logue  30   38   39 , Laura B Cantwell  7 , Melissa Jean-Francois  1 , Amanda B Kuzma  7 , L D Adams  1 , Jeffery M Vance  1   2 , Michael L Cuccaro  1   2 , Jaeyoon Chung  30 , Jesse Mez  31 , Kathryn L Lunetta  32 , Gyungah R Jun  31   32   33 , Oscar L Lopez  25 , Hugh C Hendrie  26 , Eric M Reiman  40 , Neil W Kowall  41 , James B Leverenz  42 , Scott A Small  43 , Allan I Levey  44 , Todd E Golde  45 , Andrew J Saykin  28   46   47 , Takiyah D Starks  29 , Marilyn S Albert  48 , Bradley T Hyman  49 , Ronald C Petersen  50 , Mary Sano  12 , Thomas Wisniewski  51 , Robert Vassar  52 , Jeffrey A Kaye  53 , Victor W Henderson  54   55 , Charles DeCarli  56 , Frank M LaFerla  57 , James B Brewer  58 , Bruce L Miller  59 , Russell H Swerdlow  60 , Linda J Van Eldik  61 , Henry L Paulson  62 , John Q Trojanowski  63 , Helena C Chui  64 , Roger N Rosenberg  65 , Suzanne Craft  66 , Thomas J Grabowski  67   68 , Sanjay Asthana  69 , John C Morris  70 , Stephen M Strittmatter  71 , Walter A Kukull  72   73
Collaborators, Affiliations
Meta-Analysis

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

Brian W Kunkle et al. JAMA Neurol. .

Erratum in

  • Error in Author Name.
    [No authors listed] [No authors listed] JAMA Neurol. 2021 May 1;78(5):620. doi: 10.1001/jamaneurol.2021.0456. JAMA Neurol. 2021. PMID: 33749757 Free PMC article. No abstract available.

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kunkle 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.

Figures

Figure.
Figure.. Association Plots From Single-Variant Meta-analysis
Manhattan plots showing negative log10–transformed P values from the single-variant meta-analysis adjusted for age, sex, and population stratification (A, model 1) and age, sex, population stratification, and APOE (B, model 2). The horizontal lines represent the genome-wide significance threshold (P = 5 × 10−8; red) and suggestive threshold (P = 1 × 10−6; orange). Loci are labeled with the closest gene(s) to the sentinel variant. Known loci are in blue and novel loci are in red. The y-axis is truncated, and the lowest P value on chromosome 19 was 1.8 × 10−25.
See this image and copyright information in PMC

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