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The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
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Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.
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DNA Mitocondrial/genética , Genoma Mitocondrial , Herança Materna , Óvulo/crescimento & desenvolvimento , Seleção Genética , Feminino , Variação Genética , HumanosRESUMO
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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Demência/genética , Longevidade/genética , Mutação , Fosfolipase C gama/genética , Alelos , Doença de Alzheimer/genética , Esclerose Lateral Amiotrófica/genética , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Demência Frontotemporal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Doença por Corpos de Lewy/genética , Microglia/metabolismo , Esclerose Múltipla/genética , Neuroimagem , Doença de Parkinson/genética , RiscoRESUMO
PURPOSE: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. METHODS: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. RESULTS: We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10-10 per base pair per individual. CONCLUSION: These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.
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Encéfalo/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Exoma/genética , Doenças Genéticas Inatas/genética , Encéfalo/patologia , Doenças Genéticas Inatas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Análise de Sequência de DNA , Sequenciamento do ExomaRESUMO
Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.
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Encéfalo/metabolismo , Variação Genética , Células Clonais , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Mutação/genética , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes. METHODS: We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years). RESULTS: We identified and confirmed nine somatic variants (allele fractions: 0.2%-10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon-based deep sequencing. DISCUSSION: Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases.
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Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Feminino , Genes Dominantes/genética , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: Several studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series. METHODS: We analysed 980 neuropathologically characterised human brains with Alzheimer's disease (AD), Parkinson's disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as 'oligogenic'. RESULTS: The majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls. CONCLUSIONS: A priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
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Doença de Alzheimer/genética , Esclerose Lateral Amiotrófica/genética , Encéfalo/patologia , Demência Frontotemporal/genética , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/patologia , Feminino , Demência Frontotemporal/patologia , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Doença por Corpos de Lewy/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologiaRESUMO
Human-to-human transmission of Creutzfeldt-Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aß) protein associated with Alzheimer's disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aß accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aß, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aß seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aß and give insights into the possibility of iatrogenic transmission of AD and CAA.
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Peptídeos beta-Amiloides/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Síndrome de Creutzfeldt-Jakob/terapia , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Adulto , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Sistema Nervoso Central/metabolismo , Estudos de Coortes , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Priônicas , Índice de Gravidade de Doença , Resultado do Tratamento , Reino Unido/epidemiologia , Sequenciamento do Exoma , Adulto Jovem , Proteínas tau/metabolismoRESUMO
Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), Frontotemporal dementia - Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation.
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Encefalopatias/genética , Encefalopatias/metabolismo , Encéfalo/metabolismo , Variações do Número de Cópias de DNA , DNA Mitocondrial , Mutação Puntual , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Encéfalo/patologia , Encefalopatias/patologia , Estudos de Coortes , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
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.
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Encéfalo/patologia , Variações do Número de Cópias de DNA/genética , Sequenciamento do Exoma/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Pesquisa Biomédica , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , DNA/genética , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Genótipo , Humanos , Doença de Parkinson/genética , Doença de Parkinson/patologiaRESUMO
Mitochondrial dysfunction is observed in both the aging brain, and as a core feature of several neurodegenerative diseases. A central mechanism mediating this dysfunction is acquired molecular damage to mitochondrial DNA (mtDNA). In addition, inherited stable mtDNA variation (mitochondrial haplogroups), and inherited low level variants (heteroplasmy) have also been associated with the development of neurodegenerative disease and premature neural aging respectively. Herein we review the evidence for both inherited and acquired mtDNA mutations contributing to neural aging and neurodegenerative disease. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
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DNA Mitocondrial/genética , Mutação , Doenças Neurodegenerativas/genética , Trifosfato de Adenosina/biossíntese , Doença de Alzheimer/genética , Animais , Humanos , Doença por Corpos de Lewy/genética , Acidente Vascular Cerebral/genéticaAssuntos
Doenças dos Gânglios da Base/fisiopatologia , Calcinose/fisiopatologia , Genes sis/genética , Adulto , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/patologia , Calcinose/genética , Calcinose/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Mutations in STXBP1 have recently been identified as a cause of infantile epileptic encephalopathy. The underlying mechanism of the disorder remains unclear and, recently, several case reports have described broad and progressive neurological phenotypes in addition to early-onset epilepsy. Herein, we describe a patient with early-onset epilepsy who subsequently developed a progressive neurological phenotype including parkinsonism in her early teens. A de novo mutation in STXBP1 (c.416C>T, p.(Pro139Leu)) was detected with exome sequencing together with profound impairment of complex I of the mitochondrial respiratory chain on muscle biopsy. These findings implicate a secondary impairment of mitochondrial function in the progressive nature of the disease phenotype.
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Complexo I de Transporte de Elétrons/deficiência , Epilepsia/genética , Doenças Mitocondriais/genética , Proteínas Munc18/genética , Mutação de Sentido Incorreto , Transtornos Parkinsonianos/genética , Encéfalo/fisiopatologia , Criança , Progressão da Doença , Eletroencefalografia , Complexo I de Transporte de Elétrons/genética , Epilepsia/complicações , Exoma , Feminino , Humanos , Doenças Mitocondriais/complicações , Transtornos Parkinsonianos/complicações , FenótipoRESUMO
OBJECTIVE: The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA). METHODS: One series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association with MSA. RESULTS: In the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio [OR] = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest single-variant association was again observed for p.M2397T (OR = 0.59, p = 0.0005). CONCLUSIONS: These findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important.
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Predisposição Genética para Doença , Variação Genética , Atrofia de Múltiplos Sistemas/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Éxons , Feminino , Técnicas de Genotipagem , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Risco , Reino Unido , Estados UnidosRESUMO
Neuroferritinopathy remains the only autosomal dominant syndrome of neurodegeneration with brain iron accumulation (NBIA). While the majority of identified cases appear to be part of an extended pedigree in the northeast of England, patients are increasingly being identified across the globe. Since its discovery in 2001, there have been significant developments in our understanding of the pathological, radiological, and clinical aspects of the condition, though several key pathomechanistic questions, and crucially treatment paradigms, remain unaddressed. This chapter summarizes the genetic etiology, pathological, radiological, and clinical data from all published data to date and suggested potential new avenues for therapy.