Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes
<p dir="ltr">Genome-wide association studies suggest significant overlaps in Parkinson’s disease (PD) and schizophrenia (SZ) risks, but the underlying mechanisms remain elusive. The protein-protein interaction network (‘interactome’) plays a crucial role in PD and SZ and can incorpor...
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| مؤلفون آخرون: | , , , |
| منشور في: |
2024
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| _version_ | 1864513543220494336 |
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| author | Kalyani B. Karunakaran (12478431) |
| author2 | Sanjeev Jain (598431) Samir K. Brahmachari (7586024) N. Balakrishnan (2445499) Madhavi K. Ganapathiraju (12478434) |
| author2_role | author author author author |
| author_facet | Kalyani B. Karunakaran (12478431) Sanjeev Jain (598431) Samir K. Brahmachari (7586024) N. Balakrishnan (2445499) Madhavi K. Ganapathiraju (12478434) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kalyani B. Karunakaran (12478431) Sanjeev Jain (598431) Samir K. Brahmachari (7586024) N. Balakrishnan (2445499) Madhavi K. Ganapathiraju (12478434) |
| dc.date.none.fl_str_mv | 2024-02-27T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41537-024-00439-3 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Parkinson_s_disease_and_schizophrenia_interactomes_contain_temporally_distinct_gene_clusters_underlying_comorbid_mechanisms_and_unique_disease_processes/29651138 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Neurosciences Parkinson’s disease (PD) Schizophrenia (SZ) Transcriptomics Brain development Neurodevelopmental disorders |
| dc.title.none.fl_str_mv | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Genome-wide association studies suggest significant overlaps in Parkinson’s disease (PD) and schizophrenia (SZ) risks, but the underlying mechanisms remain elusive. The protein-protein interaction network (‘interactome’) plays a crucial role in PD and SZ and can incorporate their spatiotemporal specificities. Therefore, to study the linked biology of PD and SZ, we compiled PD- and SZ-associated genes from the DisGeNET database, and constructed their interactomes using BioGRID and HPRD. We examined the interactomes using clustering and enrichment analyses, in conjunction with the transcriptomic data of 26 brain regions spanning foetal stages to adulthood available in the BrainSpan Atlas. PD and SZ interactomes formed four gene clusters with distinct temporal identities (Disease Gene Networks or ‘DGNs’1-4). DGN1 had unique SZ interactome genes highly expressed across developmental stages, corresponding to a neurodevelopmental SZ subtype. DGN2, containing unique SZ interactome genes expressed from early infancy to adulthood, correlated with an inflammation-driven SZ subtype and adult SZ risk. DGN3 contained unique PD interactome genes expressed in late infancy, early and late childhood, and adulthood, and involved in mitochondrial pathways. DGN4, containing prenatally-expressed genes common to both the interactomes, involved in stem cell pluripotency and overlapping with the interactome of 22q11 deletion syndrome (comorbid psychosis and Parkinsonism), potentially regulates neurodevelopmental mechanisms in PD-SZ comorbidity. Our findings suggest that disrupted neurodevelopment (regulated by DGN4) could expose risk windows in PD and SZ, later elevating disease risk through inflammation (DGN2). Alternatively, variant clustering in DGNs may produce disease subtypes, e.g., PD-SZ comorbidity with DGN4, and early/late-onset SZ with DGN1/DGN2.</p><p dir="ltr">Correction to: Author Correction: Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes: <a href="https://doi.org/10.1038/s41537-024-00455-3" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41537-024-00455-3</a>, published online 21 February 2024.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Published in: Schizophrenia<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41537-024-00439-3" target="_blank">https://dx.doi.org/10.1038/s41537-024-00439-3</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_7942f96fc94c0692ef47e2f53643b9df |
| identifier_str_mv | 10.1038/s41537-024-00439-3 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/29651138 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processesKalyani B. Karunakaran (12478431)Sanjeev Jain (598431)Samir K. Brahmachari (7586024)N. Balakrishnan (2445499)Madhavi K. Ganapathiraju (12478434)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesNeurosciencesParkinson’s disease (PD)Schizophrenia (SZ)TranscriptomicsBrain developmentNeurodevelopmental disorders<p dir="ltr">Genome-wide association studies suggest significant overlaps in Parkinson’s disease (PD) and schizophrenia (SZ) risks, but the underlying mechanisms remain elusive. The protein-protein interaction network (‘interactome’) plays a crucial role in PD and SZ and can incorporate their spatiotemporal specificities. Therefore, to study the linked biology of PD and SZ, we compiled PD- and SZ-associated genes from the DisGeNET database, and constructed their interactomes using BioGRID and HPRD. We examined the interactomes using clustering and enrichment analyses, in conjunction with the transcriptomic data of 26 brain regions spanning foetal stages to adulthood available in the BrainSpan Atlas. PD and SZ interactomes formed four gene clusters with distinct temporal identities (Disease Gene Networks or ‘DGNs’1-4). DGN1 had unique SZ interactome genes highly expressed across developmental stages, corresponding to a neurodevelopmental SZ subtype. DGN2, containing unique SZ interactome genes expressed from early infancy to adulthood, correlated with an inflammation-driven SZ subtype and adult SZ risk. DGN3 contained unique PD interactome genes expressed in late infancy, early and late childhood, and adulthood, and involved in mitochondrial pathways. DGN4, containing prenatally-expressed genes common to both the interactomes, involved in stem cell pluripotency and overlapping with the interactome of 22q11 deletion syndrome (comorbid psychosis and Parkinsonism), potentially regulates neurodevelopmental mechanisms in PD-SZ comorbidity. Our findings suggest that disrupted neurodevelopment (regulated by DGN4) could expose risk windows in PD and SZ, later elevating disease risk through inflammation (DGN2). Alternatively, variant clustering in DGNs may produce disease subtypes, e.g., PD-SZ comorbidity with DGN4, and early/late-onset SZ with DGN1/DGN2.</p><p dir="ltr">Correction to: Author Correction: Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes: <a href="https://doi.org/10.1038/s41537-024-00455-3" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41537-024-00455-3</a>, published online 21 February 2024.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Published in: Schizophrenia<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41537-024-00439-3" target="_blank">https://dx.doi.org/10.1038/s41537-024-00439-3</a></p>2024-02-27T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41537-024-00439-3https://figshare.com/articles/journal_contribution/Parkinson_s_disease_and_schizophrenia_interactomes_contain_temporally_distinct_gene_clusters_underlying_comorbid_mechanisms_and_unique_disease_processes/29651138CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/296511382024-02-27T09:00:00Z |
| spellingShingle | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes Kalyani B. Karunakaran (12478431) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Neurosciences Parkinson’s disease (PD) Schizophrenia (SZ) Transcriptomics Brain development Neurodevelopmental disorders |
| status_str | publishedVersion |
| title | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| title_full | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| title_fullStr | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| title_full_unstemmed | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| title_short | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| title_sort | Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes |
| topic | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Neurosciences Parkinson’s disease (PD) Schizophrenia (SZ) Transcriptomics Brain development Neurodevelopmental disorders |