title: Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.
abstract: Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.|Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keogh
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.|Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Wilson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Coxhead
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ryan
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Marzena
authors.initials: M
authors.lastname: Kurzawa-Akanbi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Turner
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Chris-Anne
authors.initials: CA
authors.lastname: McKenzie
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, United Kingdom.
authors.forename: Safa
authors.initials: S
authors.lastname: Al Sarraj
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Morris
authors.affiliation: Department of Neuropathology, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: James W
authors.initials: JW
authors.lastname: Ironside
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, United Kingdom.|MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D035843:Biomedical Research; D001921:Brain / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000473:pathology; D004247:DNA / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D000073359:Exome Sequencing / Q000379:methods*
chemical_list: D004247:DNA