04444nas a2200505   4500000000100000008004100001260001500042100002000057700002000077700002200097700001600119700002800135700001900163700001900182700002100201700001800222700001900240700002600259700001900285700002200304700002200326700002000348700002300368700002000391700002100411700002100432700002000453700002200473700001900495700001600514700001900530700002200549700002300571700002700594700001900621700003000640700002100670700007500691245014100766856004900907300001200956490000700968520294900975022001403924       2021                            d  c2021-01-011 aBrian W. Kunkle1 aMichael Schmidt1 aHans-Ulrich Klein1 aAdam C. Naj1 aKara L. Hamilton-Nelson1 aEric B. Larson1 aDenis A. Evans1 aPhil L. De Jager1 aPaul K. Crane1 aJoe D. Buxbaum1 aNilufer Ertekin-Taner1 aLisa L. Barnes1 aM. Daniele Fallin1 aJennifer J. Manly1 aRodney C. P. Go1 aThomas O. Obisesan1 aM. Ilyas Kamboh1 aDavid A. Bennett1 aKathleen S. Hall1 aAlison M. Goate1 aTatiana M. Foroud1 aEden R. Martin1 aLi-San Wang1 aGoldie S. Byrd1 aLindsay A. Farrer1 aJonathan L. Haines1 aGerard D. Schellenberg1 aRichard Mayeux1 aMargaret A. Pericak-Vance1 aChristiane Reitz1 aWriting Group for the Alzheimer’s Disease Genetics Consortium (ADGC)00aNovel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis  uhttps://doi.org/10.1001/jamaneurol.2020.3536  a102-1130 v783 aCompared 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.To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.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.Diagnosis of Alzheimer disease.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.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.  a2168-6149