Jesse Mez1, Jaeyoon Chung2, Gyungah Jun3, Joshua Kriegel4, Alexandra P Bourlas4, Richard Sherva2, Mark W Logue5, Lisa L Barnes6, David A Bennett7, Joseph D Buxbaum8, Goldie S Byrd9, Paul K Crane10, Nilüfer Ertekin-Taner11, Denis Evans6, M Daniele Fallin12, Tatiana Foroud13, Alison Goate8, Neill R Graff-Radford11, Kathleen S Hall14, M Ilyas Kamboh15, Walter A Kukull16, Eric B Larson17, Jennifer J Manly18, Jonathan L Haines19, Richard Mayeux18, Margaret A Pericak-Vance20, Gerard D Schellenberg21, Kathryn L Lunetta22, Lindsay A Farrer23. 1. Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA. Electronic address: jessemez@bu.edu. 2. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA. 3. 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; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA. 4. Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA. 5. 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. 6. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. 7. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. 8. Departments of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA. 9. Department of Biology, North Carolina A & T State University, Greensboro, NC, USA. 10. Department of Medicine, University of Washington, Seattle, WA, USA. 11. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. 12. Department of Mental Health, Johns Hopkins School of Public Health, Baltimore, MD, USA; Department of Biostatistics, Johns Hopkins School of Public Health, Baltimore, MD, USA; Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA. 13. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. 14. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA. 15. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. 16. Department of Epidemiology, University of Washington, Seattle, WA, USA. 17. Group Health, Group Health Research Institute, Seattle, WA, USA. 18. Department of Neurology and the Taub Institute, Columbia University, New York, NY, USA. 19. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. 20. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA. 21. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 22. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 23. Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA; 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; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
Abstract
INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.
INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.
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