期刊
TRANSLATIONAL PSYCHIATRY
卷 11, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41398-020-01145-1
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类别
资金
- Fundacion bancaria La Caixa
- Fundacio ACE
- ISCIII (Ministry of Health, Spain)
- Grifols SA
- Piramal AG
- Laboratorios Echevarne
- Araclon Biotech S.A.
- European Union/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED project [115975]
- European Union/EFPIA Innovative Medicines Initiative Joint Undertaking MOPEAD project [115985]
- ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion
- Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa)
- Consejeria de Salud de la Junta de Andalucia [PI-0001/2017]
- National Institutes of Health [R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG057777]
- Alzheimer's Association [NIRG-11-200110, BAND-14-338165, AARG-16-441560, BFG-15-362540, ADGC-10-196728]
- NIH [P50 AG05681, P01 AG03991, P01 AG026276]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd and its Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institute of Health Research
- EFPIA companies
- SMEs as part of InnoMed (Innovative Medicines in Europe)
- European Union under the Sixth Framework program priority FP6-2004LIFESCIHEALTH-5
- NIA Division of Neuroscience [U01-AG032984]
- NIA [P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, AG081220]
- NINDS [R01 NS080820]
- CurePSP Foundation
- Mayo Foundation
- Fundacion Alzheimur (Murcia)
- Ministerio de Educacion y Ciencia (Gobierno de Espana)
- Corporacion Tecnologica de Andalucia
- Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia)
- Diabetes Research Laboratory
- Biomedical Research Foundation
- CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM)
- Illinois Department of Public Health
- Translational Genomics Research Institute
- Kronos Life Sciences Laboratories
- National Institute on Aging (Arizona Alzheimer's Disease Center) [P30 AG19610, RO1 AG023193]
- National Institute on Aging (Mayo Clinic Alzheimer's Disease Center) [P50 AG16574]
- National Institute on Aging (Intramural Research Program)
- National Alzheimer's Coordinating Center [U01 AG016976]
- state of Arizona
- French National Foundation on Alzheimer's Disease and Related Disorders
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant
- Inserm
- Institut Pasteur de Lille
- Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [U01 AG016976, R01 AG033193, U01 AG032984, U24 AG021886]
- AGES contract [N01-AG-12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center
- Erasmus University
- [PI13/02434]
- [PI16/01861]
- [PI17/01474]
- [PI19/01301]
Research suggests that Alzheimer's disease cases have increased homozygosity compared to controls, indicating that recessive effects may contribute to a portion of AD heritability.
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 [beta(AVROH) (CI 95%) = 0.070 (0.037-0.104); P = 3.91 x 10(-5); beta(FROH) (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 x 10(-16)). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482-11,305,456), (beta (CI 95%) = 1.09 (0.48 - 1.48), p value = 9.03 x 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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