. 2014 Nov;10(6):609-618.e11.

doi: 10.1016/j.jalz.2014.06.010. Epub 2014 Aug 27.

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

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, Affiliations

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

PMID: 25172201
PMCID: PMC4253055
DOI: 10.1016/j.jalz.2014.06.010

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

Mark W Logue et al. Alzheimers Dement. 2014 Nov.

. 2014 Nov;10(6):609-618.e11.

doi: 10.1016/j.jalz.2014.06.010. Epub 2014 Aug 27.

Authors

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

PMID: 25172201
PMCID: PMC4253055
DOI: 10.1016/j.jalz.2014.06.010

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.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest:

The authors of this paper have no conflicts of interest to report.

Figures

**Figure 1**
The overall study design including a whole-exome sequencing (WES) of 7 AA late-onset AD cases, followed by variant prioritization and filtering, genotyping in a larger AA discovery sample, and replication in a large AA ADGC cohort.

**Figure 2**
Examination of the 1000 Genomes subjects with the haplotype containing the two identified *AKAP9* variants including (A) a phylogenetic dendogram of haplotypes and (B) positions of infrequent SNPs (<5% MAF) shared by haplotypes with 0, 1, and 2 variants. Key: HAP0: The background haplotype which contains the two identified *AKAP9* variants. HAP0+ the background variant with one or more of the two putatively AD-associated variants; HAP0− the background haplotype without either AD-associated variants; HAP0+1 the background haplotype with one of the AD-associated *AKAP9* variants; HAP0+2 the background haplotype with both AD-associated *AKAP9* variants.

**Figure 3**
Annotated protein domain of *AKAP9* canonical transcript Q99996-1 including Yotiao; AKAP450; the PKA binding sites; the PACT domain; Long QT syndrome amino-acid change; and the conservation of the two AD-associated variants rs144662445 (I2558M) and rs149979685 (S3771L).

See this image and copyright information in PMC

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical