Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans

Mark W Logue; Matthew Schu; Badri N Vardarajan; John Farrell; David A Bennett; Joseph D Buxbaum; Goldie S Byrd; Nilufer Ertekin-Taner; Denis Evans; Tatiana Foroud; Alison Goate; Neill R Graff-Radford; M Ilyas Kamboh; Walter A Kukull; Jennifer J Manly; Alzheimer Disease Genetics Consortium; Alzheimer Disease Genetics Consortium

doi:10.1016/j.jalz.2014.06.010

Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans

Alzheimers Dement. 2014 Nov;10(6):609-618.e11. doi: 10.1016/j.jalz.2014.06.010. Epub 2014 Aug 27.

Authors

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; Alzheimer Disease Genetics Consortium; Alzheimer Disease Genetics Consortium

Collaborators

Jonathan L Haines¹³, Richard Mayeux¹², Margaret A Pericak-Vance¹⁴, Gerard D Schellenberg¹⁵, Kathryn L Lunetta¹⁶, Clinton T Baldwin¹⁷, M Daniele Fallin¹⁸, Lindsay A Farrer¹⁹

Affiliations

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.
¹³ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
¹⁴ The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
¹⁵ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
¹⁷ Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, MA, USA.
¹⁸ Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, MD, USA.
¹⁹ Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, 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. Electronic address: farre

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.

Keywords: AKAP9; African American; Genetic association; Late-onset Alzheimer's disease; Rare variant; Whole-exome sequencing.

MeSH terms

A Kinase Anchor Proteins / genetics*
Aged
Aged, 80 and over
Alzheimer Disease / ethnology*
Alzheimer Disease / genetics*
Black or African American / genetics*
Cluster Analysis
Cytoskeletal Proteins / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Genotype
Humans
Linkage Disequilibrium
Male
Polymorphism, Single Nucleotide / genetics*

Substances

A Kinase Anchor Proteins
AKAP9 protein, human
Cytoskeletal Proteins

Abstract

MeSH terms

Substances

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