Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

Jesse Mez; Jaeyoon Chung; Gyungah Jun; Joshua Kriegel; Alexandra P Bourlas; Richard Sherva; Mark W Logue; Lisa L Barnes; David A Bennett; Joseph D Buxbaum; Goldie S Byrd; Paul K Crane; Nilüfer Ertekin-Taner; Denis Evans; M Daniele Fallin; Tatiana Foroud; Alison Goate; Neill R Graff-Radford; Kathleen S Hall; M Ilyas Kamboh; Walter A Kukull; Eric B Larson; Jennifer J Manly; Alzheimer's Disease Genetics Consortium; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Gerard D Schellenberg; Kathryn L Lunetta; Lindsay A Farrer

doi:10.1016/j.jalz.2016.09.002

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

Alzheimers Dement. 2017 Feb;13(2):119-129. doi: 10.1016/j.jalz.2016.09.002. Epub 2016 Oct 20.

Authors

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; Alzheimer's Disease Genetics Consortium; Jonathan L Haines¹⁹, Richard Mayeux¹⁸, Margaret A Pericak-Vance²⁰, Gerard D Schellenberg²¹, Kathryn L Lunetta²², Lindsay A Farrer²³

Affiliations

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.

Keywords: ABCA7; APOE; African Americans; Age; Alzheimer's disease; COBL; Diabetes; Education; Genome-wide association study (GWAS); Informed conditioning on clinical covariates; Resveratrol; SLC10A2; Sex differences; Smoking.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

ATP-Binding Cassette Transporters / genetics
Aged
Aged, 80 and over
Alzheimer Disease / ethnology*
Alzheimer Disease / genetics*
Apolipoproteins E / genetics
Black or African American / genetics*
Diabetes Complications / ethnology
Diabetes Complications / genetics
Educational Status
Female
Genetic Loci*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Microfilament Proteins / genetics*
Organic Anion Transporters, Sodium-Dependent / genetics*
Polymorphism, Single Nucleotide*
Prevalence
Smoking / ethnology
Smoking / genetics
Symporters / genetics*

Substances

ABCA7 protein, human
ATP-Binding Cassette Transporters
Apolipoproteins E
Cobl protein, human
Microfilament Proteins
Organic Anion Transporters, Sodium-Dependent
Symporters
sodium-bile acid cotransporter

Abstract

Publication types

MeSH terms

Substances

Grants and funding