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

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15 Scopus citations


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.

Original languageEnglish
Pages (from-to)188.e3-188.e12
JournalNeurobiology of Aging
StatePublished - Dec 2018

Bibliographical note

Funding Information:
We thank all participating subjects of this study. We thank Dr Jixin Dong (University of Nebraska Medical Center, Omaha, Nebraska, USA) and Dr Richard O. McCann (Mercer University School of Medicine, Macon, GA, USA) for providing plasmid DNA constructs, as well as the GIGA-Research technology platforms (Interactome and Imaging) for technical assistance. We thank Dr Pedro Vera and the Lexington VA Medical Center for microscopy support, as well as Ela Patel and Sonya Anderson with their assistance accessing the human brain tissue. We thank Ivy Cuijt for technical support and Bavo Heeman for helpful discussions (both at VIB Department of Molecular Genetics, University of Antwerp, Belgium). Funding sources are listed in the Note S12.

Publisher Copyright:
© 2018 Elsevier Inc.


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

ASJC Scopus subject areas

  • Neuroscience (all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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