Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO
Por:
Puerta, R, de Rojas, I, García-González, P, Olivé, C, Sotolongo-Grau, O, García-Sánchez, A, García-Gutiérrez, F, Montrreal, L, Tartari, JP, Sanabria, A, Pytel, V, Lage, C, Quintela, I, Aguilera, N, Rodriguez-Rodriguez, E, Alarcón-Martín, E, Orellana, A, Pastor, P, Pérez-Tur, J, Piñol-Ripoll, G, de Munain, AL, García-Alberca, JM, Royo, JL, Bullido, MJ, Alvarez, V, Real, LM, Anchuelo, AC, Gómez-Garre, D, Larrad, MTM, Franco-Macías, E, Mir, P, Medina, M, Sánchez-Valle, R, Dols-Icardo, O, Sáez, ME, Carracedo, A, Tárraga, L, Alegret, M, Valero, S, Marquié, M, Boada, M, Juan, PS, Cavazos, JE, Cabrera-Socorro, A, Cano, A, Ruiz, A, Alzheimers Dis Neuroimaging Initiative
Publicada:
1 dic 2025
Resumen:
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 A beta 42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of A beta 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 A beta 42 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.
Filiaciones:
Puerta, R:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Univ Barcelona, Doctorate Biotechnol, Fac Farm & Ciencies Alimentacio, Avda Diagonal 643, Barcelona 08028, Spain
de Rojas, I:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
García-González, P:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Olivé, C:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Sotolongo-Grau, O:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
García-Sánchez, A:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
García-Gutiérrez, F:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Montrreal, L:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Tartari, JP:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Sanabria, A:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Pytel, V:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Lage, C:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Cantabria, Marques Valdecilla Univ Hosp, IDIVAL, Santander, Spain
Quintela, I:
Univ Santiago de Compostela, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Grp Med Xen, Santiago De Compostela, Spain
Aguilera, N:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Rodriguez-Rodriguez, E:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Cantabria, Marques Valdecilla Univ Hosp, IDIVAL, Santander, Spain
Alarcón-Martín, E:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Orellana, A:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Pastor, P:
Univ Hosp Germans Trias i Pujol, Dept Neurol, Unit Neurodegenerat Dis, Badalona, Barcelona, Spain
Germans Trias i Pujol Res Inst IGTP, Badalona, Barcelona, Spain
Pérez-Tur, J:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
CSIC, Inst Biomed Valencia, Unitat Genet Mol, Valencia, Spain
Inst Invest Sanitaria La Fe, Unidad Mixta Neurol Genet, Valencia, Spain
Piñol-Ripoll, G:
Hosp Univ Santa Maria de Lleida, Unitat Trastorns Cognitius, Lleida, Spain
Inst Recerca Biomed Lleida IRBLLeida, Lleida, Spain
de Munain, AL:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Hosp Univ Donostia, Dept Neurol, San Sebastian, Spain
Univ Basque Country, Fac Med & Nursery, Dept Neurosci, San Sebastian, Spain
Inst Biodonostia, Neurosci Area, San Sebastian, Spain
García-Alberca, JM:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Andalusian Inst Neurosci, Alzheimer Res Ctr, Malaga, Spain
Andalusian Inst Neurosci, Memory Clin, Malaga, Spain
Royo, JL:
Univ Malaga, Bioquim Inmunol Sch Med, Dept Especial Quirurg, Malaga, Spain
Bullido, MJ:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
UAM, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain
Inst Invest Sanitaria Hosp La Paz IdiPaz, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Alvarez, V:
Hosp Univ Cent Asturias, Lab Genet, Oviedo, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Real, LM:
Univ Seville, Hosp Univ Virgen de Valme, Dept Bioquim Med Biol Mol Inmunol, Inst Biomed Sevilla,CSIC, Seville, Spain
Inst Salud Carlos III, CIBERINFEC, Madrid, Spain
Anchuelo, AC:
Hosp Clin San Carlos, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Madrid, Spain
Gómez-Garre, D:
Hosp Clin San Carlos, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Madrid, Spain
Univ Complutense Madrid UCM, Hosp Clin San Carlos, Lab Riesgo Cardiovasc & Microbiota, Madrid, Spain
Univ Complutense Madrid UCM, Fac Med, Dept Fisiol, Madrid, Spain
Biomed Res Networking Ctr Cardiovasc Dis CIBERCV, Madrid, Spain
Larrad, MTM:
Hosp Clin San Carlos, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Madrid, Spain
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
Franco-Macías, E:
Hosp Univ Virgen del Rocio, Dept Neurol, Dementia Unit, Inst Biomed Sevilla IBiS, Seville, Spain
Mir, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Hosp Univ Virgen del Rocio, Serv Neurol & Neurofisiol, Unidad Trastornos Movimiento,CSIC,Inst Biomed Sevi, Seville, Spain
Medina, M:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Queen Sofia Fdn Alzheimer Ctr, CIEN Fdn, Madrid, Spain
Sánchez-Valle, R:
Univ Barcelona, Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer, Serv Neurol,AlzheimerS Dis & Other Cognit Disorder, Barcelona, Spain
Dols-Icardo, O:
Univ Autonoma Barcelona, Hosp St Creu i St Pau, St Pau Biomed Res Inst, Dept Neurol,St Pau Memory Unit, Barcelona, Spain
Sáez, ME:
Ctr Andaluz Estudios Bioinformat, Seville, Spain
Carracedo, A:
Univ Santiago de Compostela, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Grp Med Xen, Santiago De Compostela, Spain
Fdn Publ Galega Med Xen, Santiago De Compostela, Spain
Tárraga, L:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Alegret, M:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Valero, S:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Marquié, M:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Boada, M:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Juan, PS:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
ISCIII, CIEN Fdn, Reina Sofia Alzheimer Ctr, Madrid, Spain
Cavazos, JE:
South Texas Alzheimers Dis Res Ctr, San Antonio Harlingen, TX, Mexico
Univ Texas Hlth Sci Ctr San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA
Cabrera-Socorro, A:
Janssen Res & Dev, Neurosci Therapeut Area, Turnhoutseweg 30, B-2340 Beerse, Belgium
Cano, A:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Ruiz, A:
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, C Marques de Sentmenat 57, Barcelona 08029, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Texas Hlth Sci Ctr San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA
Univ Texas Hlth Sci Ctr San Antonio, Long Sch Med, Dept Microbiol Immunol & Mol Genet, San Antonio, TX 78229 USA
Green Submitted, hybrid
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