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

Genetic and Environmental Risk in Alzheimer's Disease 1 consortium (GERAD1), Alzheimer's Disease Genetics Consortium (ADGC), The European Alzheimer Disease Initiative Investigators (EADI1 Consortium)

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)188.e3-188.e12
JournalNeurobiology of Aging
Volume72
DOIs
StatePublished - Dec 1 2018

Fingerprint

Alzheimer Disease
Genes
Single Nucleotide Polymorphism
Brain
Talin
Genome
Genetic Structures
HEK293 Cells
Disease Susceptibility
Temporal Lobe
Neuroblastoma
HeLa Cells
Drosophila
Meta-Analysis
Cell Line
C2 Domains

Keywords

  • 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

Cite this

Genetic and Environmental Risk in Alzheimer's Disease 1 consortium (GERAD1), Alzheimer's Disease Genetics Consortium (ADGC), & The European Alzheimer Disease Initiative Investigators (EADI1 Consortium) (2018). Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiology of Aging, 72, 188.e3-188.e12. https://doi.org/10.1016/j.neurobiolaging.2018.08.001

Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. / Genetic and Environmental Risk in Alzheimer's Disease 1 consortium (GERAD1); Alzheimer's Disease Genetics Consortium (ADGC); The European Alzheimer Disease Initiative Investigators (EADI1 Consortium).

In: Neurobiology of Aging, Vol. 72, 01.12.2018, p. 188.e3-188.e12.

Research output: Contribution to journalArticle

Genetic and Environmental Risk in Alzheimer's Disease 1 consortium (GERAD1), Alzheimer's Disease Genetics Consortium (ADGC) & The European Alzheimer Disease Initiative Investigators (EADI1 Consortium) 2018, 'Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease', Neurobiology of Aging, vol. 72, pp. 188.e3-188.e12. https://doi.org/10.1016/j.neurobiolaging.2018.08.001
Genetic and Environmental Risk in Alzheimer's Disease 1 consortium (GERAD1), Alzheimer's Disease Genetics Consortium (ADGC), The European Alzheimer Disease Initiative Investigators (EADI1 Consortium). Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiology of Aging. 2018 Dec 1;72:188.e3-188.e12. https://doi.org/10.1016/j.neurobiolaging.2018.08.001
Genetic and Environmental Risk in Alzheimer's Disease 1 consortium (GERAD1) ; Alzheimer's Disease Genetics Consortium (ADGC) ; The European Alzheimer Disease Initiative Investigators (EADI1 Consortium). / Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. In: Neurobiology of Aging. 2018 ; Vol. 72. pp. 188.e3-188.e12.
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abstract = "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.",
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AU - The European Alzheimer Disease Initiative Investigators (EADI1 Consortium)

AU - Gusareva, Elena S.

AU - Twizere, Jean Claude

AU - Sleegers, Kristel

AU - Dourlen, Pierre

AU - Abisambra, Jose F.

AU - Meier, Shelby

AU - Cloyd, Ryan

AU - Weiss, Blaine

AU - Dermaut, Bart

AU - Bessonov, Kyrylo

AU - van der Lee, Sven J.

AU - Carrasquillo, Minerva M

AU - Katsumata, Yuriko

AU - Cherkaoui, Majid

AU - Asselbergh, Bob

AU - Ikram, M. Arfan

AU - Mayeux, Richard

AU - Farrer, Lindsay A.

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A.

AU - Schellenberg, Gerard D.

AU - Sims, Rebecca

AU - Williams, Julie

AU - Amouyel, Philippe

AU - van Duijn, Cornelia M.

AU - Taner, Nilufer

AU - Van Broeckhoven, Christine

AU - Dequiedt, Franck

AU - Fardo, David W.

AU - Lambert, Jean Charles

AU - Van Steen, Kristel

PY - 2018/12/1

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N2 - 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.

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KW - Gene-gene interaction

KW - Protein-protein interaction

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KW - WWC1

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