TY - JOUR
T1 - Novel Alzheimer Disease risk loci and pathways in african American individuals using the african genome resources panel a meta-analysis
AU - Writing Group for the Alzheimer's Disease Genetics Consortium (ADGC)
AU - Kunkle, Brian W.
AU - Schmidt, Michael
AU - Klein, Hans Ulrich
AU - Naj, Adam C.
AU - Hamilton-Nelson, Kara L.
AU - Larson, Eric B.
AU - Evans, Denis A.
AU - de Jager, Phil L.
AU - Crane, Paul K.
AU - Buxbaum, Joe D.
AU - Ertekin-Taner, Nilufer
AU - Barnes, Lisa L.
AU - Daniele Fallin, M.
AU - Manly, Jennifer J.
AU - Go, Rodney C.P.
AU - Obisesan, Thomas O.
AU - Ilyas Kamboh, M.
AU - Bennett, David A.
AU - Hall, Kathleen S.
AU - Goate, Alison M.
AU - Foroud, Tatiana M.
AU - Martin, Eden R.
AU - Wang, Li Sao
AU - Byrd, Goldie S.
AU - Farrer, Lindsay A.
AU - Haines, Jonathan L.
AU - Schellenberg, Gerard D.
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A.
AU - Reitz, Christiane
AU - Graff-Radford, Neill R.
AU - Martinez, Izri
AU - Ayodele, Temitope
AU - Logue, Mark W.
AU - Cantwell, Laura B.
AU - Jean-Francois, Melissa
AU - Kuzma, Amanda B.
AU - Adams, L. D.
AU - Vance, Jeffery M.
AU - Cuccaro, Michael L.
AU - Chung, Jaeyoon
AU - Mez, Jesse
AU - Lunetta, Kathryn L.
AU - Jun, Gyungah R.
AU - Lopez, Oscar L.
AU - Hendrie, Hugh C.
AU - Reiman, Eric M.
AU - Kowall, Neil W.
AU - Leverenz, James B.
AU - DeCarli, Charles
N1 - Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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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U2 - 10.1001/jamaneurol.2020.3536
DO - 10.1001/jamaneurol.2020.3536
M3 - Article
C2 - 33074286
AN - SCOPUS:85096553497
JO - JAMA Neurology
JF - JAMA Neurology
SN - 2168-6149
ER -