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

Elena S Gusareva; Jean-Claude Twizere; Kristel Sleegers; Pierre Dourlen; Jose F Abisambra; Shelby Meier; Ryan Cloyd; Blaine Weiss; Bart Dermaut; Kyrylo Bessonov; Sven J van der Lee; Minerva M Carrasquillo; Yuriko Katsumata; Majid Cherkaoui; Bob Asselbergh; M. Arfan Ikram; Richard Mayeux; Lindsay A Farrer; Jonathan L Haines; Margaret A Pericak-Vance; Gerard D Schellenberg; Rebecca Sims; Julie Williams; Philippe Amouyel; Cornelia M van Duijn; Nilüfer Ertekin-Taner; Christine Van Broeckhoven; Franck Dequiedt; David W Fardo; Jean-Charles Lambert; Kristel Van Steen

doi:10.1016/j.neurobiolaging.2018.08.001

Back

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

Journal article

Open access

Peer reviewed

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

Elena S Gusareva, Jean-Claude Twizere, Kristel Sleegers, Pierre Dourlen, Jose F Abisambra, Shelby Meier, Ryan Cloyd, Blaine Weiss, Bart Dermaut, Kyrylo Bessonov, …

Neurobiology of aging, Vol.72, pp.188.e3-188.e12

2018-12

DOI: https://doi.org/10.1016/j.neurobiolaging.2018.08.001

PMCID: PMC6769421

PMID: 30201328

Abstract

Epistasis

Gene-gene interaction

TLN2

Protein-protein interaction

Alzheimer's disease

WWC1

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.

Files and links (1)

url

https://doi.org/10.1016/j.neurobiolaging.2018.08.001View

Published (Version of record) Open

Metrics

8 Record Views

19 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.108 Molecular & Cell Biology - Cancer & Development; 1.108.2215 Hippo Pathway
Web Of Science research areas: Geriatrics & Gerontology; Neurosciences
ESI research areas: Neuroscience & Behavior

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease
Creators: Elena S Gusareva - Medical Genomics Research Unit, GIGA-R, University of Liège, Belgium
Jean-Claude Twizere - Molecular Biology of Diseases Research Unit, GIGA-R, University of Liège, Belgium
Kristel Sleegers - Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium
Pierre Dourlen - U1167-RID-AGE, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissementa, Universite de Lille Nord de France, Lille, France
Jose F Abisambra - Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA
Shelby Meier - Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA
Ryan Cloyd - Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA
Blaine Weiss - Sanders-Brown Center on Aging, University of Kentucky, College of Medicine, Lexington, KY, USA
Bart Dermaut - U1167-RID-AGE, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissementa, Universite de Lille Nord de France, Lille, France
Kyrylo Bessonov - Medical Genomics Research Unit, GIGA-R, University of Liège, Belgium
Sven J van der Lee - Department of Epidemiology, Erasmus University Medical center, Rotterdam, the Netherlands
Minerva M Carrasquillo - Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA
Yuriko Katsumata - Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA
Majid Cherkaoui - Molecular Biology of Diseases Research Unit, GIGA-R, University of Liège, Belgium
Bob Asselbergh - Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium
M. Arfan Ikram - Department of Neurology, Erasmus University Medical center, Rotterdam, the Netherlands
Richard Mayeux - Department of Neurology, Gertrude H. Sergievsky Center, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA
Lindsay A Farrer - Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Neurology, and Epidemiology, Boston University, Boston, MA, USA
Jonathan L Haines - Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
Margaret A Pericak-Vance - Department of Human Genetics, The John P. Hussman Institute for Human Genomics, Dr John T. Macdonald Foundation, University of Miami, Coral Gables, FL, USA
Gerard D Schellenberg - Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Rebecca Sims - Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK
Julie Williams - Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK
Philippe Amouyel - NSERM U1167, Institut Pasteur de Lille, Universite de Lille Nord de France, Lille, France
Cornelia M van Duijn - Department of Epidemiology, Erasmus University Medical center, Rotterdam, the Netherlands
Nilüfer Ertekin-Taner - Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA
Christine Van Broeckhoven - Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium
Franck Dequiedt - Molecular Biology of Diseases Research Unit, GIGA-R, University of Liège, Belgium
David W Fardo - Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA
Jean-Charles Lambert - NSERM U1167, Institut Pasteur de Lille, Universite de Lille Nord de France, Lille, France
Kristel Van Steen - Medical Genomics Research Unit, GIGA-R, University of Liège, Belgium
Publication Details: Neurobiology of aging, Vol.72, pp.188.e3-188.e12
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 30201328
PMCID: PMC6769421
Record Identifier: 991031576137302976