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

Gusareva, Elena S., Twizere, Jean-Claude, Sleegers, Kristel, Dourlen, Pierre, Abisambra, Jose F., Meier, Shelby, Cloyd, Ryan, Weiss, Blaine, Dermaut, Bart, Bessonov, Kyrylo, van der Lee, Sven J., Carrasquillo, Minerva M., Katsumata, Yuriko, Cherkaoui, Majid, Asselbergh, Bob, Ikram, M. Arfan, Mayeux, Richard, Farrer, Lindsay A., Haines, Jonathan L., Pericak-Vance, Margaret A., Schellenberg, Gerard D., Sims, Rebecca ORCID:, Williams, Julie ORCID:, Amouyel, Philippe, van Duijn, Cornelia M., Ertekin-Taner, Nilüfer, Van Broeckhoven, Christine, Dequiedt, Franck, Fardo, David W., Lambert, Jean-Charles and Van Steen, Kristel 2018. Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiology of Aging 72 , e3-e12. 10.1016/j.neurobiolaging.2018.08.001

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0197-4580
Date of First Compliant Deposit: 28 September 2018
Date of Acceptance: 1 August 2018
Last Modified: 06 Nov 2023 16:28

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