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

[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

More authors (21 more)

Language :

English

Title :

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

Publication date :

2018

Journal title :

Neurobiology of Aging

ISSN :

0197-4580

eISSN :

1558-1497

Publisher :

Elsevier, Netherlands

Volume :

Pages :

188.e3-188.e12

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 28 February 2019

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