Journal
JAMA NEUROLOGY
Volume 78, Issue 1, Pages 102-113Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2020.3536
Keywords
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Categories
Funding
- National Institutes of Health (NIH) [RF1 AG054023, U24 AG056270]
- Alzheimer's Disease Genetics Consortium [U01 AG032984]
- National Institute on Aging (NIA) Genetics Initiative for Late-Onset Alzheimer's Disease [U24 AG026395, U24 AG026390]
- NIA Genetics of Alzheimer's Disease Data Storage Site [U24 AG041689]
- Washington Heights-Inwood Community Aging Project [R01 AG037212, R37 AG015473]
- National Centralized Repository for Alzheimer's Disease and Related Dementias [U24 AG021886]
- Indianapolis AA [R01 AG009956, RC2 AG036650]
- ACT [U01 AG06781, U01 HG004610]
- MIRAGE [R01 AG009029]
- GenerAAtions [5R01 AG20688]
- Pittsburg [P50 AG005133, AG030653, AG041718, AG064877]
- CaseWestern Reserve University [R01 AG019085]
- CHAP [RC2 AG036650, R01 AG11101, R01 AG030146]
- ROS/MAP [P30 AG10161, R01 AG30146, R01 AG17917, R01 AG15819]
- African-American AD Genetics Study [R01 AG028786]
- MARS/CORE [P30 AG10161, R01 AG22018]
- Mayo Clinic [P50 AG0016574, R01 032990, KL2 RR024151]
- Miami [R01 AG028786, R01 AG027944]
- Wake Forest
- MSSM [P50 AG05681, P01 AG03991, P01 AG026276]
- NIH [RF1AG054080, U01AG052410, AG0087202]
- NIA/NIH [U01 AG016976]
- NIA-funded Alzheimer Disease Centers [P50 AG005133, P30 AG010129, P50 AG016573, P30 AG062429-01, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG053760, P30 AG010124, P50 AG005142, P30 AG012300, P30 AG049638, P50 AG005136, P30 AG062715-01, P50 AG005681, P50 AG047270]
- The NIA-funded Alzheimer Disease Centers [P30 AG019610, P30 AG013846, P30 AG062428-01, P50 AG008702, P50 AG025688, P50 AG047266, AG045058, P30 AG010133, P50 AG005146, P30 AG062421-01, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366]
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This study identified additional Alzheimer disease risk loci in African American individuals, indicating that the disease risk in this population differs from other ethnic groups.
This genome-wide association study identifies additional Alzheimer disease risk loci in African American individuals using the African Genome Resource panel. 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 x 10(-7)), near the immune response gene ALCAM (3q13; P = 9.3 x 10(-7)), within GPC6 (13q31; P = 4.1 x 10(-7)), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 x 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 x 10(-9)) and 6 additional loci with suggestive significance (P <= 5 x 10(-7)) such as API5 at 11p12 (P = 8.8 x 10(-8)) and RBFOX1 at 16p13 (P = 5.4 x 10(-7)) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain beta-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. Question What genetic variants, genes, and pathways increase or decrease risk of Alzheimer disease in African American individuals? Findings In this genome-wide association meta-analysis of 2748 individuals with Alzheimer disease and 5222 controls, several novel genetic loci and pathways associated with Alzheimer disease in African American individuals were identified. Meaning While the major pathways involved in Alzheimer disease etiology in African American individuals are largely similar to those in non-Hispanic White individuals, many of the disease-associated loci within these pathways differ.
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