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dc.contributor.authorMoreno-Grau, Sonia
dc.contributor.authorFernández, Maria Victoria
dc.contributor.authorde Rojas, Itziar
dc.contributor.authorGarcia-González, Pablo
dc.contributor.authorHernández, Isabel
dc.contributor.authorFarias, Fabiana
dc.contributor.authorBudde, John P
dc.contributor.authorQuintela, Inés
dc.contributor.authorMadrid, Laura
dc.contributor.authorGonzález-Pérez, Antonio
dc.contributor.authorMontrreal, Laura
dc.contributor.authorAlarcón-Martín, Emilio
dc.contributor.authorAlegret, Montserrat
dc.contributor.authorMaroñas, Olalla
dc.contributor.authorPineda, Juan Antonio
dc.contributor.authorMacías, Juan
dc.contributor.authorMarquié, Marta
dc.contributor.authorValero, Sergi
dc.contributor.authorBenaque, Alba
dc.contributor.authorClarimón, Jordi
dc.contributor.authorBullido, Maria Jesus
dc.contributor.authorGarcía-Ribas, Guillermo
dc.contributor.authorPástor, Pau
dc.contributor.authorSánchez-Juan, Pascual
dc.contributor.authorÁlvarez, Victoria
dc.contributor.authorPiñol-Ripoll, Gerard
dc.contributor.authorGarcía-Alberca, Jose María
dc.contributor.authorRoyo, José Luis
dc.contributor.authorFranco-Macías, Emilio
dc.contributor.authorMir, Pablo
dc.contributor.authorCalero, Miguel 
dc.contributor.authorMedina, Miguel
dc.contributor.authorRábano, Alberto
dc.contributor.authorÁvila, Jesús
dc.contributor.authorAntúnez, Carmen
dc.contributor.authorReal, Luis Miguel
dc.contributor.authorOrellana, Adelina
dc.contributor.authorCarracedo, Ángel
dc.contributor.authorSáez, María Eugenia
dc.contributor.authorTárraga, Lluís
dc.contributor.authorBoada, Mercè
dc.contributor.authorCruchaga, Carlos
dc.contributor.authorRuiz, Agustín
dc.identifier.citationTransl Psychiatry . 2021 Feb 24;11(1):142es_ES
dc.description.abstractLong runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10-5; βFROH (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10-16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10-4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.es_ES
dc.description.sponsorshipThe Genome Research at Fundació ACE project (GR@ACE) is supported by Fundación bancaria “La Caixa,” Grifols SA, Fundació ACE, and ISCIII (Ministry of Health, Spain). We also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundació ACE). We are indebted to the Trinitat Port-Carbó legacy and her family for their support of Fundació ACE research programs. Fundació ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED and MOPEAD projects (Grants No. 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (Grant PI-0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the ethical and scientific committees of these institutions. The present work was performed as part of the Biochemistry, Molecular Biology and Biomedicine doctoral program of S. Moreno-Grau at Universitat Autònoma de Barcelona (Barcelona, Spain). This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, and R01AG057777) and the Alzheimer’s Association (NIRG-11-200110, BAND-14-338165, AARG-16-441560, and BFG-15-362540). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. For additional information about GR@ACE & DEGESCO consortia, please contact with The GR@ACE study group is composed by: Abdelnour C, Aguilera N, Alarcon E, Alegret M, Benaque A, Boada M, Buendia M, Cañabate P, Carracedo A, Corbatón A, de Rojas I, Diego S, Espinosa A, Gailhajenet A, García González P, Gil S, Guitart M, González Pérez A, Hernández I, Ibarria, M, Lafuente A, Macias J, Maroñas O, Martín E, Martínez MT, Marquié M, Mauleón A1, Monté-Rubio G, Montrreal L, Moreno-Grau S, Moreno M, Orellana A, Ortega G, Pancho A, Pelejà E, Pérez-Cordon A, Pineda JA, Preckler S, Quintela I, Real LM3,8, Rodríguez-Gómez O, Rosende-Roca M, Ruiz A, Ruiz S, Sáez ME, Sanabria A, Santos-Santos MA, Serrano-Rios M, Sotolongo-Grau O, Tárraga L, Valero S, Vargas L. The DEGESCO consortium is composed by: Adarmes-Gómez A.D, Alarcón-Martín E, Álvarez I, Álvarez V, Amer-Ferrer G, Antequera M, Antúnez C, Baquero M, Bernal M, Blesa R, Boada M, Buiza-Rueda D, Bullido M.J, Burguera J.A, Calero M, Carrillo F, Carrión-Claro M, Casajeros MJ, Clarimón J, Cruz-Gamero J.M, de Pancorbo MM, de Rojas I, del Ser T Diez-Fairen M, Fortea J, Franco E, Frank-García A, García-Alberca JM, Garcia Madrona S, Garcia-Ribas G, Gómez-Garre P, Hernández I, Hevilla S, Jesús S, Labrador Espinosa MA, Lage C, Legaz A, Lleó A, López de Munáin A, López-García S, Macias D, Manzanares S, Marín M, Marín-Muñoz J, Marín T, Marquié M, Martín Montes A, Martínez B, Martínez C, Martínez V, Martínez-Lage Álvarez P, Medina M, Mendioroz Iriarte M, Menéndez-González M, Mir P, Molinuevo J.L, Monté-Rubio G, Montrreal L, Moreno-Grau S, Orellana A, Pastor A.B, Pastor P, Pérez Tur J, Periñán-Tocino T Piñol Ripoll G, Rábano A, Real de Asúa D, Rodrigo S, Rodríguez-Rodríguez E, Royo J.L, Ruiz A, Sanchez del Valle Díaz R, Sánchez-Juan P, Sastre I, Sotolongo-Grau O, Tárraga L, Valero S, Vicente M.P, Vivancos L. Data collection and sharing for this project was partially funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer’s Association; the Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticalses_ES
dc.publisherSpringer Naturees_ES
dc.relation.isversionofPublisher's versiones_ES
dc.titleLong runs of homozygosity are associated with Alzheimer's disease.es_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderNational Institutes of Health (United States)es_ES
dc.contributor.funderAlzheimer's Associationes_ES
dc.contributor.funderFundación La Caixaes_ES
dc.contributor.funderInstituto de Salud Carlos IIIes_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderMinisterio de Sanidad (España)es_ES
dc.contributor.funderAlzheimer’s Disease Neuroimaging Initiativees_ES
dc.contributor.funderU.S. National Institute on Aginges_ES
dc.contributor.funderNational Institute of Biomedical Imaging and Bioengineeringes_ES
dc.identifier.journalTranslational psychiatryes_ES
dc.repisalud.centroISCIII::Servicios Centraleses_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI13 / 02434es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI16 / 01861es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI17 / 01474es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI19 / 01301es_ES

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