Mark W Logue1, Matthew Schu2, Badri N Vardarajan2, John Farrell2, David A Bennett3, Joseph D Buxbaum4, Goldie S Byrd5, Nilufer Ertekin-Taner6, Denis Evans7, Tatiana Foroud8, Alison Goate9, Neill R Graff-Radford6, M Ilyas Kamboh10, Walter A Kukull11, Jennifer J Manly12. 1. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 2. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA. 3. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. 4. Departments of Neuroscience and Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA. 5. Department of Biology, North Carolina A & T State University, Greensboro, NC, USA. 6. Departments of Neuroscience and Neurology, Mayo Clinic, Jacksonville, FL, USA. 7. Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA. 8. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA. 9. Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MI, USA. 10. Department of Human Genetics and Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA. 11. National Alzheimer's Coordinating Center and Department of Epidemiology, University of Washington, Seattle, WA, USA. 12. Department of Neurology and the Taub Institute, Columbia University, New York, NY, USA.
Abstract
BACKGROUND: Less is known about the genetic basis of Alzheimer's disease (AD) in African Americans (AAs) than in non-Hispanic whites. METHODS: Whole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD-related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1037 cases and 1869 controls from the Alzheimer Disease Genetics Consortium (ADGC). RESULTS: Forty-four single nucleotide polymorphisms (SNPs) from WES passed filtering criteria and were successfully genotyped. Nominally significant (P < .05) association to AD was observed with two African-descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (P = .014) and rs149979685 (P = .037). These associations were replicated in the ADGC sample (rs144662445: P = .0022, odds ratio [OR] = 2.75; rs149979685: P = .0022, OR = 3.61). CONCLUSIONS: Because AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism.
BACKGROUND: Less is known about the genetic basis of Alzheimer's disease (AD) in African Americans (AAs) than in non-Hispanic whites. METHODS: Whole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD-related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1037 cases and 1869 controls from the Alzheimer Disease Genetics Consortium (ADGC). RESULTS: Forty-four single nucleotide polymorphisms (SNPs) from WES passed filtering criteria and were successfully genotyped. Nominally significant (P < .05) association to AD was observed with two African-descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (P = .014) and rs149979685 (P = .037). These associations were replicated in the ADGC sample (rs144662445: P = .0022, odds ratio [OR] = 2.75; rs149979685: P = .0022, OR = 3.61). CONCLUSIONS: Because AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism.
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