Article (Scientific journals)
Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease.
Gusareva, Elena S.; Twizere, Jean-Claude; Sleegers, Kristel et al.
2018In Neurobiology of Aging, 72, p. 188.e3-188.e12
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Keywords :
Alzheimer's disease; Epistasis; Gene-gene interaction; Protein-protein interaction; TLN2; WWC1
Abstract :
[en] 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 (beta=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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Gusareva, Elena S.
Twizere, Jean-Claude  ;  Université de Liège - ULiège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Microbial, food and biobased technologies
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
Williams, Julie
Amouyel, Philippe
van Duijn, Cornelia M.
Ertekin-Taner, Nilufer
Van Broeckhoven, Christine
Dequiedt, Franck  ;  Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Fardo, David W.
Lambert, Jean-Charles
Van Steen, Kristel  ;  Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
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Title :
Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease.
Publication date :
Journal title :
Neurobiology of Aging
Publisher :
Elsevier, Netherlands
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Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2018 Elsevier Inc. All rights reserved.
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since 28 February 2019


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