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.

Germline burden of rare damaging variants negatively affects human healthspan and lifespan

“…For the UK Brain Bank Network (UKBBN), we ran a survival analysis against the age at death (Keogh et al, 2017). For UKB subjects, we tested the effects of mutations on lifespan and healthspan.…”

Systematic review of genetic association studies in people with Lewy body dementia

“…The APOE variants, especially its ε4 allele, are the most studied among all genetic variants in people with LBD . Apolipoprotein E (APOE) is involved in cholesterol mobilisation and redistribution during neuronal growth and injury, and it may promote β‐amyloid aggregation .…”

“…GBA variants are likely to increase the risk of earlier onset cognitive impairment in PD. Six studies including four good quality studies have reported statistically significant associations between DLB and GBA variants including rs2230288, rs76763715, rs368060, rs35749011, and rs421016 (Table ). Moreover, two studies have reported statistically significant associations between GBA variants and PDD (Table ).…”

“…The GWAS has replicated the association between DLB and rs7314908 of CNTN1. 11 The reported genetic associations between DLB and rs897984 (BCL7C), 11 2 bp in exon 6 of CHRFAM7A, 17 rs1426210 (GABRB3), 11 11,28,65 Studies that investigated the genetic associations of DLB with variants in A2M, 66 AACT, 29 ADORA1, 67 74 and TF 75 did not find statistically significant associations. Moreover, two studies have reported conflicting evidence regarding the genetic associations between PDD and variants in ESR1.…”

Germline burden of rare damaging variants negatively affects human healthspan and lifespan

“…We characterized the effect of ultra-rare damaging mutation burden on human traits associated with longevity. For the UK Brain Bank Network (UKBBN) postmortem samples, we run a survival analysis against the age at death 15 . For UKB subjects, we tested the effect of mutations on the remaining lifespan (or simply lifespan), that is survival within the available follow-up of eleven years.…”