Long runs of homozygosity are associated with Alzheimer’s disease

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作者
Sonia Moreno-Grau
Maria Victoria Fernández
Itziar de Rojas
Pablo Garcia-González
Isabel Hernández
Fabiana Farias
John P. Budde
Inés Quintela
Laura Madrid
Antonio González-Pérez
Laura Montrreal
Emilio Alarcón-Martín
Montserrat Alegret
Olalla Maroñas
Juan Antonio Pineda
Juan Macías
Marta Marquié
Sergi Valero
Alba Benaque
Jordi Clarimón
Maria Jesus Bullido
Guillermo García-Ribas
Pau Pástor
Pascual Sánchez-Juan
Victoria Álvarez
Gerard Piñol-Ripoll
Jose María García-Alberca
José Luis Royo
Emilio Franco-Macías
Pablo Mir
Miguel Calero
Miguel Medina
Alberto Rábano
Jesús Ávila
Carmen Antúnez
Luis Miguel Real
Adelina Orellana
Ángel Carracedo
María Eugenia Sáez
Lluís Tárraga
Mercè Boada
Carlos Cruchaga
Agustín Ruiz
机构
[1] Universitat Internacional de Catalunya,Research Center and Memory clinic Fundació ACE. Institut Català de Neurociències Aplicades
[2] Carlos III Institute of Health,CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases
[3] Washington University School of Medicine,Department of Psychiatry
[4] Washington University School of Medicine,Hope Center for Neurological Disorders
[5] Universidade de Santiago de Compostela,Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN
[6] CAEBI. Centro Andaluz de Estudios Bioinformáticos,PRB3
[7] Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme,ISCIII)
[8] Universitat Autònoma de Barcelona,Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau
[9] Universidad Autónoma de Madrid,Centro de Biología Molecular Severo Ochoa (C.S.I.C.
[10] Instituto de Investigación Sanitaria “Hospital la Paz” (IdIPaz),U.A.M.)
[11] Hospital Universitario Ramón y Cajal,Fundació per la Recerca Biomèdica i Social Mútua Terrassa, and Memory Disorders Unit, Department of Neurology, Hospital Universitari Mútua de Terrassa
[12] University of Barcelona School of Medicine,Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida
[13] Terrassa,Alzheimer Research Center & Memory Clinic
[14] Neurology Service “Marqués de Valdecilla” University Hospital (University of Cantabria and IDIVAL),Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine
[15] Laboratorio de Genética Hospital Universitario Central de Asturias,Unidad de Demencias, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS)
[16] Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA),Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS)
[17] Institut de Recerca Biomédica de Lleida (IRBLLeida),Department of Molecular Neuropathology, Centro de Biología Molecular “Severo Ochoa” (CBMSO)
[18] Andalusian Institute for Neuroscience,Department of Neurology
[19] University of Málaga,Neurology Service
[20] Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla,undefined
[21] Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla,undefined
[22] CIEN Foundation,undefined
[23] Queen Sofia Foundation Alzheimer Center,undefined
[24] Instituto de Salud Carlos III (ISCIII),undefined
[25] BT-CIEN,undefined
[26] Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM),undefined
[27] Unidad de Demencias,undefined
[28] Hospital Clínico Universitario Virgen de la Arrixaca,undefined
[29] Fundación Pública Galega de Medicina Xenómica- CIBERER-IDIS,undefined
[30] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas,undefined
[31] CIBERDEM,undefined
[32] Hospital Clínico San Carlos,undefined
[33] Hospital Universitario Son Espases,undefined
[34] Servei de Neurologia,undefined
[35] Hospital Universitari i Politècnic La Fe,undefined
[36] BIOMICs,undefined
[37] País Vasco; Centro de Investigación Lascaray. Universidad del País Vasco UPV/EHU,undefined
[38] Hospital Universitario La Paz (UAM),undefined
[39] Hospital Donostia de San Sebastián,undefined
[40] Fundación para la Formación e Investigación Sanitarias de la Región de Murcia,undefined
[41] Servicio de Neurología-Hospital de Cabueñes-Gijón,undefined
[42] Centro de Investigación y Terapias Avanzadas. Fundación CITA-alzheimer,undefined
[43] Navarrabiomed,undefined
[44] Servicio de Neurología -Hospital Universitario Central de Asturias,undefined
[45] Barcelona βeta Brain Research Center – Fundació Pasqual Maragall,undefined
[46] Unitat de Genètica Molecular. Institut de Biomedicina de València-CSIC,undefined
[47] Unidad Mixta de Neurologia Genètica. Instituto de Investigación Sanitaria La Fe,undefined
[48] Hospital Universitario La Princesa,undefined
[49] Hospital Clínic Barcelona,undefined
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摘要
Long 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.
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