Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO
Alzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/174175 |
| Acceso en línea: | https://hdl.handle.net/11441/174175 https://doi.org/10.1007/s10142-025-01581-6 |
| Access Level: | acceso abierto |
| Palabra clave: | Keywords Aβ42 CSF biomarkers PET tomography GWAS Proteome |
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Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCOPuerta, Raquelde Rojas, ItziarGarcía-González, PabloOlivé, ClàudiaSotolongo-Grau, OscarGarcía-Sánchez, AinhoaReal Navarrete, Luis MiguelMir Rivera, PabloRuiz, AgustínAlzheimer’s Disease Neuroimaging InitiativeKeywords Aβ42CSF biomarkersPET tomographyGWASProteomeAlzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may provide insights into the underlying biology of the disease. We performed a meta-GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of Aβ phenotypes in CSF and PET measures, only genetic signals showing opposite directions were considered for analysis (n = 376,599). We explored the amyloidosis signature in the CSF proteome using SOMAscan proteomics (ACE cohort, n = 1,008), connected it with GWAS loci modulating amyloidosis and performed an enrichment analysis of overlapping hits. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n = 13,409) and PET (n = 13,116). After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and annotated nine suggestive hits. We replicated the APOE loci using the large CSF-PET meta-GWAS, identifying multiple AD-associated genes including the novel GADL1 locus. Additionally, we found 1,387 FDR-significant SOMAscan proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was minimal (n = 35). The enrichment analysis revealed mechanisms connecting amyloidosis with the plasma membrane's anchored component, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Combining CSF and PET amyloid GWAS with CSF proteome analyses may effectively elucidate causative molecular mechanisms behind amyloid mobilization and AD physiopathology.SpringerBioquímica Médica y Biología Molecular e InmunologíaMedicinaGobierno de EspañaInstituto de Salud Carlos IIIEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/174175https://doi.org/10.1007/s10142-025-01581-6reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésFunctional & integrative genomics, 25 (1), 73.PI13/02434PI16/01861PI17/01474PI19/00335PI19/01240PI19/01301PI22/01403PI22/00258PI13/02434PI16/01861PI17/01474PI19/00335PI19/01240PI19/01301PI22/01403PI22/00258https://link.springer.com/article/10.1007/s10142-025-01581-6info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1741752026-06-17T12:51:07Z |
| dc.title.none.fl_str_mv |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| title |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| spellingShingle |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO Puerta, Raquel Keywords Aβ42 CSF biomarkers PET tomography GWAS Proteome |
| title_short |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| title_full |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| title_fullStr |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| title_full_unstemmed |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| title_sort |
Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO |
| dc.creator.none.fl_str_mv |
Puerta, Raquel de Rojas, Itziar García-González, Pablo Olivé, Clàudia Sotolongo-Grau, Oscar García-Sánchez, Ainhoa Real Navarrete, Luis Miguel Mir Rivera, Pablo Ruiz, Agustín Alzheimer’s Disease Neuroimaging Initiative |
| author |
Puerta, Raquel |
| author_facet |
Puerta, Raquel de Rojas, Itziar García-González, Pablo Olivé, Clàudia Sotolongo-Grau, Oscar García-Sánchez, Ainhoa Real Navarrete, Luis Miguel Mir Rivera, Pablo Ruiz, Agustín Alzheimer’s Disease Neuroimaging Initiative |
| author_role |
author |
| author2 |
de Rojas, Itziar García-González, Pablo Olivé, Clàudia Sotolongo-Grau, Oscar García-Sánchez, Ainhoa Real Navarrete, Luis Miguel Mir Rivera, Pablo Ruiz, Agustín Alzheimer’s Disease Neuroimaging Initiative |
| author2_role |
author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Bioquímica Médica y Biología Molecular e Inmunología Medicina Gobierno de España Instituto de Salud Carlos III European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) |
| dc.subject.none.fl_str_mv |
Keywords Aβ42 CSF biomarkers PET tomography GWAS Proteome |
| topic |
Keywords Aβ42 CSF biomarkers PET tomography GWAS Proteome |
| description |
Alzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may provide insights into the underlying biology of the disease. We performed a meta-GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of Aβ phenotypes in CSF and PET measures, only genetic signals showing opposite directions were considered for analysis (n = 376,599). We explored the amyloidosis signature in the CSF proteome using SOMAscan proteomics (ACE cohort, n = 1,008), connected it with GWAS loci modulating amyloidosis and performed an enrichment analysis of overlapping hits. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n = 13,409) and PET (n = 13,116). After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and annotated nine suggestive hits. We replicated the APOE loci using the large CSF-PET meta-GWAS, identifying multiple AD-associated genes including the novel GADL1 locus. Additionally, we found 1,387 FDR-significant SOMAscan proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was minimal (n = 35). The enrichment analysis revealed mechanisms connecting amyloidosis with the plasma membrane's anchored component, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Combining CSF and PET amyloid GWAS with CSF proteome analyses may effectively elucidate causative molecular mechanisms behind amyloid mobilization and AD physiopathology. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/11441/174175 https://doi.org/10.1007/s10142-025-01581-6 |
| url |
https://hdl.handle.net/11441/174175 https://doi.org/10.1007/s10142-025-01581-6 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Functional & integrative genomics, 25 (1), 73. PI13/02434 PI16/01861 PI17/01474 PI19/00335 PI19/01240 PI19/01301 PI22/01403 PI22/00258 PI13/02434 PI16/01861 PI17/01474 PI19/00335 PI19/01240 PI19/01301 PI22/01403 PI22/00258 https://link.springer.com/article/10.1007/s10142-025-01581-6 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
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Springer |
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Springer |
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reponame:idUS. Depósito de Investigación de la Universidad de Sevilla instname:Universidad de Sevilla (US) |
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Universidad de Sevilla (US) |
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