Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease
Open accessAbstract
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.
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Genetic screens identified p130CAS, Fak, Eph, Rab3-GEF, cindr, Fit1, Aret and Rhea, orthologs of CASS4, PTK2B, EPHA1, MADD, CD2AP, FERMT2, CELF1 and TLN2, as modulators of Tau toxicity.
“Beyond BIN1, this approach identified p130CAS, Fak, Eph, Rab3-GEF, cindr, Fit1, Aret and Rhea respective orthologs of CASS4, PTK2B, EPHA1, MADD, CD2AP, FERMT2, CELF1 and TLN2 [26, 42, 119].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [42]
The Results (Functional analysis and biological validation; page unavailable) identify rhea as the Drosophila ortholog of TLN2 and report evidence that it modifies Tau toxicity. The Discussion mentions other modifiers identified by earlier studies, but our copy does not identify the other seven fly genes, establish their stated ortholog pairs, or report that this paper's screen identified them. (LLM, conf=0.86)
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- Authors
- Gusareva, E. S., Twizere, J.-C., Sleegers, K., Dourlen, P., Abisambra, J. F., Meier, S., Cloyd, R., Weiss, B., Dermaut, B., Bessonov, K., van der Lee, S. J., Carrasquillo, M. M., Katsumata, Y., Cherkaoui, M., Asselbergh, B., Ikram, M. A., Mayeux, R., Farrer, L. A., Haines, J. L., Pericak-Vance, M. A., Schellenberg, G. D., Sims, R., Williams, J., Amouyel, P., van Duijn, C. M., Ertekin-Taner, N., Van Broeckhoven, C., Dequiedt, F., Fardo, D. W., Lambert, J.-C., & Van Steen, K.
- Affiliations
- University of Liège (BE)
- University of Antwerp (BE)
- Université de Lille (FR)
- University of Kentucky (US)
- Mayo Clinic in Florida (US)
- Erasmus MC (NL)
- Columbia University Irving Medical Center (US)
- Boston University (US)
- Case Western Reserve University (US)
- University of Pennsylvania (US)
- Cardiff University (GB)
- Corresponding author
- Gusareva, Elena S.
- ORCID
- Gusareva, Elena S.
- Twizere, Jean-Claude
- Sleegers, Kristel
- Dourlen, Pierre
- Abisambra, Jose F.
- Meier, Shelby
- Cloyd, Ryan
- Weiss, Blaine
- Dermaut, Bart
- Bessonov, Kyrylo
- Carrasquillo, Minerva M.
- Katsumata, Yuriko
- Asselbergh, Bob
- Ikram, M. Arfan
- Mayeux, Richard
- Farrer, Lindsay A.
- Haines, Jonathan L.
- Schellenberg, Gerard D.
- Sims, Rebecca
- Williams, Julie
- Amouyel, Philippe
- Fardo, David W.
- Lambert, Jean-Charles
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 72
- Pages
- 188.e3-188.e12
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC6769421
- OpenAlex
- W2887484282
- Cited by
- 32
- References
- 8
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 7 · 2018: 1
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HAL (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by-nc-nd)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- Lirias (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- University of Nebraska Medical Center
- Universiteit Antwerpen
- Medical Research Council (MR/L023784/1, MR/L023784/2, MR/K013041/1, MR/M009076/1, MR/L501517/1)
- National Institute on Aging (R01AG017917, R01AG015819, P30AG010161, U01AG032984, R01AG032990, U01AG046139, U24AG021886)
- National Institute of Neurological Disorders and Stroke (R01NS080820, R01NS091329)
- National Institute on Minority Health and Health Disparities (L32 MD009205)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, epistasis, WWC1, KIBRA, gene-gene interaction, single nucleotide polymorphisms, tau toxicity, Drosophila eye, genetic risk
- MeSH terms
- Alzheimer Disease, Epistasis, Genetic, Female, Humans, Male, Phosphoproteins, Sex Characteristics, Sex Factors, Meta-Analysis as Topic, Cohort Studies, Talin, Intracellular Signaling Peptides and Proteins
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