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Neurobiol Aging. 2018 Dec;72:188.e3-188.e12. doi: 10.1016/j.neurobiolaging.2018.08.001. Epub 2018 Aug 9.

Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease.

Author information

1
Medical Genomics Research Unit, GIGA-R, University of Liège, Belgium. Electronic address: gusareva.elena@gmail.com.
2
Molecular Biology of Diseases Research Unit, GIGA-R, University of Liège, Belgium.
3
Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
4
U1167-RID-AGE, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissementa, Universite de Lille Nord de France, Lille, France; NSERM U1167, Institut Pasteur de Lille, Universite de Lille Nord de France, Lille, France.
5
Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA; Department of Physiology, University of Kentucky, College of Medicine, Lexington, KY, USA; Epilepsy Center, University of Kentucky, College of Medicine, Lexington, KY, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, College of Medicine, Lexington, KY, USA.
6
Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA; Department of Physiology, University of Kentucky, College of Medicine, Lexington, KY, USA.
7
Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA.
8
Medical Genomics Research Unit, GIGA-R, University of Liège, Belgium.
9
Department of Epidemiology, Erasmus University Medical center, Rotterdam, the Netherlands.
10
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
11
Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
12
Department of Neurology, Erasmus University Medical center, Rotterdam, the Netherlands; Department of Radiology, Erasmus University Medical center, Rotterdam, the Netherlands.
13
Department of Neurology, Gertrude H. Sergievsky Center, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
14
Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Neurology, and Epidemiology, Boston University, Boston, MA, USA.
15
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
16
Department of Human Genetics, The John P. Hussman Institute for Human Genomics, Dr John T. Macdonald Foundation, University of Miami, Coral Gables, FL, USA.
17
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
18
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
19
NSERM U1167, Institut Pasteur de Lille, Universite de Lille Nord de France, Lille, France.
20
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
21
Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
22
Medical Genomics Research Unit, GIGA-R, University of Liège, Belgium; Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Belgium; Department of Human Genetics, KU Leuven, Leuven, Belgium.

Abstract

Systematic epistasis analyses in multifactorial disorders are an important step to better characterize complex genetic risk structures. We conducted a hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimer's disease (AD) susceptibility. We identified a statistical epistasis signal between the single nucleotide polymorphisms rs3733980 and rs7175766 that was associated with AD in males (genome-wide significant pBonferroni-corrected=0.0165). This signal pointed toward the genes WW and C2 domain containing 1, aka KIBRA; 5q34 and TLN2 (talin 2; 15q22.2). Gene-based meta-analysis in 3 independent consortium data sets confirmed the identified interaction: the most significant (pmeta-Bonferroni-corrected=9.02*10-3) was for the single nucleotide polymorphism pair rs1477307 and rs4077746. In functional studies, WW and C2 domain containing 1, aka KIBRA and TLN2 coexpressed in the temporal cortex brain tissue of AD subjects (β=0.17, 95% CI 0.04 to 0.30, p=0.01); modulated Tau toxicity in Drosophila eye experiments; colocalized in brain tissue cells, N2a neuroblastoma, and HeLa cell lines; and coimmunoprecipitated both in brain tissue and HEK293 cells. Our finding points toward new AD-related pathways and provides clues toward novel medical targets for the cure of AD.

KEYWORDS:

Alzheimer's disease; Epistasis; Gene-gene interaction; Protein-protein interaction; TLN2; WWC1

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