Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease
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 stat...
| Հիմնական հեղինակներ: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Ձևաչափ: | Journal article |
| Լեզու: | English |
| Հրապարակվել է: |
Elsevier
2018
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| _version_ | 1826273631939854336 |
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| author | Gusareva, E Twizere, J Sleegers, K Dourlen, P Abisambra, J Meier, S Cloyd, R Weiss, B Dermaut, B Bessonov, K Van Der Lee, S Carrasquillo, M Katsumata, Y Cherkaoui, M Asselbergh, B Ikram, M Mayeux, R Farrer, L Haines, J Pericak-Vance, M Schellenberg, G Genetic And Environmental Risk In Alzheimer'S Disease 1 Consortium (GERAD1), Alzheimer'S Disease Genetics Consortium (ADGC) European Alzheimer Disease Initiative Investigators (EADI1 Consortium) Sims, R Williams, J Amouyel, P Van Duijn, C Ertekin-Taner, N Van Broeckhoven, C Dequiedt, F Fardo, D Lambert, J Van Steen, K |
| author_facet | Gusareva, E Twizere, J Sleegers, K Dourlen, P Abisambra, J Meier, S Cloyd, R Weiss, B Dermaut, B Bessonov, K Van Der Lee, S Carrasquillo, M Katsumata, Y Cherkaoui, M Asselbergh, B Ikram, M Mayeux, R Farrer, L Haines, J Pericak-Vance, M Schellenberg, G Genetic And Environmental Risk In Alzheimer'S Disease 1 Consortium (GERAD1), Alzheimer'S Disease Genetics Consortium (ADGC) European Alzheimer Disease Initiative Investigators (EADI1 Consortium) Sims, R Williams, J Amouyel, P Van Duijn, C Ertekin-Taner, N Van Broeckhoven, C Dequiedt, F Fardo, D Lambert, J Van Steen, K |
| author_sort | Gusareva, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:31:09Z |
| format | Journal article |
| id | oxford-uuid:58512c51-0f2d-4b74-a94a-8f2b4a243902 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:31:09Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:58512c51-0f2d-4b74-a94a-8f2b4a2439022022-03-26T17:02:38ZMale-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's diseaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:58512c51-0f2d-4b74-a94a-8f2b4a243902EnglishSymplectic Elements at OxfordElsevier2018Gusareva, ETwizere, JSleegers, KDourlen, PAbisambra, JMeier, SCloyd, RWeiss, BDermaut, BBessonov, KVan Der Lee, SCarrasquillo, MKatsumata, YCherkaoui, MAsselbergh, BIkram, MMayeux, RFarrer, LHaines, JPericak-Vance, MSchellenberg, GGenetic And Environmental Risk In Alzheimer'S Disease 1 Consortium (GERAD1),Alzheimer'S Disease Genetics Consortium (ADGC)European Alzheimer Disease Initiative Investigators (EADI1 Consortium)Sims, RWilliams, JAmouyel, PVan Duijn, CErtekin-Taner, NVan Broeckhoven, CDequiedt, FFardo, DLambert, JVan Steen, KSystematic 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. |
| spellingShingle | Gusareva, E Twizere, J Sleegers, K Dourlen, P Abisambra, J Meier, S Cloyd, R Weiss, B Dermaut, B Bessonov, K Van Der Lee, S Carrasquillo, M Katsumata, Y Cherkaoui, M Asselbergh, B Ikram, M Mayeux, R Farrer, L Haines, J Pericak-Vance, M Schellenberg, G Genetic And Environmental Risk In Alzheimer'S Disease 1 Consortium (GERAD1), Alzheimer'S Disease Genetics Consortium (ADGC) European Alzheimer Disease Initiative Investigators (EADI1 Consortium) Sims, R Williams, J Amouyel, P Van Duijn, C Ertekin-Taner, N Van Broeckhoven, C Dequiedt, F Fardo, D Lambert, J Van Steen, K Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease |
| title | Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease |
| title_full | Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease |
| title_fullStr | Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease |
| title_full_unstemmed | Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease |
| title_short | Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease |
| title_sort | male specific epistasis between wwc1 and tln2 genes is associated with alzheimer s disease |
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