دورية أكاديمية
Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data.
| العنوان: | Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data. |
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| المؤلفون: | Kibinge NK; Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom., Relton CL; Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom., Gaunt TR; Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom., Richardson TG; Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom. Electronic address: Tom.G.Richardson@bristol.ac.uk. |
| المصدر: | American journal of human genetics [Am J Hum Genet] 2020 Jun 04; Vol. 106 (6), pp. 885-892. Date of Electronic Publication: 2020 May 14. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2008- : [Cambridge, MA] : Cell Press Original Publication: Baltimore, American Society of Human Genetics. |
| مواضيع طبية MeSH: | Phenomics* , Proteomics*, Brain/*metabolism , Genetic Variation/*genetics , Nervous System Diseases/*genetics , Proteome/*genetics, Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Armadillo Domain Proteins/genetics ; Carrier Proteins/genetics ; Cathepsin H/genetics ; Cytoskeletal Proteins/genetics ; Depression/genetics ; Genome-Wide Association Study ; Humans ; Intelligence/genetics ; Nervous System Diseases/metabolism ; Neuroticism ; Nuclear Proteins/genetics ; Phenotype ; Proteome/metabolism ; Schizophrenia/genetics ; Sleep Initiation and Maintenance Disorders/genetics ; Sorting Nexins/genetics |
| مستخلص: | Leveraging high-dimensional molecular datasets can help us develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Furthermore, genetic colocalization provided evidence that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotype. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system (p = 4.29 × 10 -11 with neuroticism), as well as SARM1, which has been previously implicated in axonal degeneration (p = 1.76 × 10 -08 with amyotrophic lateral sclerosis). We additionally conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases. Our findings suggest that genes such as SNX32, which was initially associated with increased risk of Alzheimer disease, may potentially influence other complex traits in the opposite direction. In contrast, genes such as CTSH (which was also associated with Alzheimer disease) and SARM1 may make worthwhile therapeutic targets because they did not have genetically predicted effects on any of the other phenotypes after correcting for multiple testing. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | MC_UU_12013/2 United Kingdom MRC_ Medical Research Council; MC_UU_00011/5 United Kingdom MRC_ Medical Research Council; MC_UU_00011/4 United Kingdom MRC_ Medical Research Council; MR/S003886/1 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: Mendelian randomization; brain-derived proteins; cognitive; genetic colocalization; neurological; phenome-wide association study; protein quantitative trait loci; psychaitric |
| المشرفين على المادة: | 0 (Armadillo Domain Proteins) 0 (Carrier Proteins) 0 (Cytoskeletal Proteins) 0 (DSCC1 protein, human) 0 (Nuclear Proteins) 0 (Proteome) 0 (SARM1 protein, human) 0 (SNX33 protein, human) 0 (Sorting Nexins) EC 3.4.22.16 (CTSH protein, human) EC 3.4.22.16 (Cathepsin H) |
| تواريخ الأحداث: | Date Created: 20200516 Date Completed: 20201008 Latest Revision: 20240328 |
| رمز التحديث: | 20240329 |
| مُعرف محوري في PubMed: | PMC7273531 |
| DOI: | 10.1016/j.ajhg.2020.04.007 |
| PMID: | 32413284 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1537-6605 |
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| DOI: | 10.1016/j.ajhg.2020.04.007 |