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

doi:10.1016/j.neurobiolaging.2018.08.001

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

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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 p_{Bonferroni-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 (p_{meta-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 language	English
Pages (from-to)	188.e3-188.e12
Journal	Neurobiology of Aging
Volume	72
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.08.001
State	Published - 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.

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

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10.1016/j.neurobiolaging.2018.08.001

Cite this

@article{875ae92d140249b897d6c382bfd1f3b8,

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

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.",

keywords = "Alzheimer's disease, Epistasis, Gene-gene interaction, Protein-protein interaction, TLN2, WWC1",

author = "Gusareva, {Elena S.} and Twizere, {Jean Claude} and Kristel Sleegers and Pierre Dourlen and Abisambra, {Jose F.} and Shelby Meier and Ryan Cloyd and Blaine Weiss and Bart Dermaut and Kyrylo Bessonov and {van der Lee}, {Sven J.} and Carrasquillo, {Minerva M.} and Yuriko Katsumata and Majid Cherkaoui and Bob Asselbergh and Ikram, {M. Arfan} and Richard Mayeux and Farrer, {Lindsay A.} and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Schellenberg, {Gerard D.} and Rebecca Sims and Julie Williams and Philippe Amouyel and {van Duijn}, {Cornelia M.} and Nil{\"u}fer Ertekin-Taner and {Van Broeckhoven}, Christine and Franck Dequiedt and Fardo, {David W.} and Lambert, {Jean Charles} and {Van Steen}, Kristel",

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: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = dec,

doi = "10.1016/j.neurobiolaging.2018.08.001",

language = "English",

volume = "72",

pages = "188.e3--188.e12",

}

TY - JOUR

T1 - Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease

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 - Ertekin-Taner, Nilüfer

AU - Van Broeckhoven, Christine

AU - Dequiedt, Franck

AU - Fardo, David W.

AU - Lambert, Jean Charles

AU - Van Steen, Kristel

N1 - 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.

PY - 2018/12

Y1 - 2018/12

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.

AB - 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.

KW - Alzheimer's disease

KW - Epistasis

KW - Gene-gene interaction

KW - Protein-protein interaction

KW - TLN2

KW - WWC1

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UR - http://www.scopus.com/inward/citedby.url?scp=85053019724&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.08.001

DO - 10.1016/j.neurobiolaging.2018.08.001

M3 - Article

C2 - 30201328

AN - SCOPUS:85053019724

VL - 72

SP - 188.e3-188.e12

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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