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1.
Aging (Albany NY) ; 11(10): 2912-2913, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31102504
3.
Neurobiol Aging ; 66: 179.e17-179.e29, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29544907

RESUMO

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aß dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Leucodistrofia Metacromática/genética , Mutação , Receptor Notch3/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Córtex Cerebral/metabolismo , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Risco
4.
PLoS One ; 13(3): e0193961, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29547662

RESUMO

Animal models of disease are an indispensable element in our quest to understand pathophysiology and develop novel therapies. Ex vivo studies have severe limitations, in particular their inability to study individual disease progression over time. In this respect, non-invasive in vivo technologies offer multiple advantages. We here used bilateral common carotid artery occlusion (BCCAO) in mice, an established model for ischemic retinopathy, and performed a multimodal in vivo and ex vivo follow-up. We used scanning laser ophthalmoscopy (SLO), ocular coherence tomography (OCT) and electroretinography (ERG) over 6 weeks followed by ex vivo analyses. BCCAO leads to vascular remodeling with thickening of veins starting at 4 weeks, loss of photoreceptor synapses with concomitant reduced b-waves in the ERG and thinning of the retina. Mononuclear phagocytes showed fluctuation of activity over time. There was large inter-individual variation in the severity of neuronal degeneration and cellular inflammatory responses. Ex vivo analysis confirmed these variable features of vascular remodeling, neurodegeneration and inflammation. In summary, we conclude that multimodal follow-up and subgroup analysis of retinal changes in BCCAO further calls into question the use of ex vivo studies with distinct single end-points. We propose that our approach can foster the understanding of retinal disease as well as the clinical translation of emerging therapeutic strategies.


Assuntos
Arteriopatias Oclusivas/patologia , Doenças das Artérias Carótidas/patologia , Retina/patologia , Vasos Retinianos/patologia , Animais , Artéria Carótida Primitiva/patologia , Modelos Animais de Doenças , Progressão da Doença , Isquemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oftalmoscopia/métodos , Degeneração Retiniana/patologia , Tomografia de Coerência Óptica/métodos
6.
Genome Med ; 9(1): 100, 2017 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-29183403

RESUMO

BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. RESULTS: Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aß42 (p value = 0.0003) and in the Aß42/Aß40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). CONCLUSIONS: Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.


Assuntos
Doença de Alzheimer/genética , Proteínas rab de Ligação ao GTP/genética , Idoso de 80 Anos ou mais , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Polimorfismo de Nucleotídeo Único
7.
Alzheimers Dement ; 13(8): 858-869, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28264768

RESUMO

INTRODUCTION: We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes. METHODS: We diagnosed 22 affected individuals belonging to eight families and 43 sporadic cases with FTD in Apulia, Southern Italy, in 2 years. Mutations in common causative FTD genes (GRN, MAPT, VCP, and TARDBP) and C9ORF72 expansions were screened. RESULTS: Behavioral variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively). Social conduct impairment/disinhibition, loss of insight, and inflexibility were the most frequent clinical features observed at onset. One new mutation was identified in GRN in family A. DISCUSSION: Disease onset in sporadic FTD was more frequently characterized by a clustering of behavioral symptoms with apathy and loss of personal hygiene. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the Southern Italian population.


Assuntos
Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Idade de Início , Idoso , Proteína C9orf72/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Família , Feminino , Demência Frontotemporal/fisiopatologia , Demência Frontotemporal/psicologia , Predisposição Genética para Doença , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Progranulinas , Sistema de Registros , Proteína com Valosina/genética , Proteínas tau/genética
8.
J Alzheimers Dis ; 53(2): 475-85, 2016 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-27258413

RESUMO

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.


Assuntos
Saúde da Família , Demência Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Sítios de Splice de RNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Estudos de Coortes , Biologia Computacional , Feminino , Demência Frontotemporal/sangue , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Itália , Masculino , Pessoa de Meia-Idade , Progranulinas
9.
PLoS One ; 11(6): e0150079, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27249223

RESUMO

The cerebral deposition of Aß42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aß metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aß degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4

Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Biologia Computacional , Exoma , Humanos
10.
Neurobiol Aging ; 46: 235.e1-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27289440

RESUMO

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco
11.
Neurobiol Aging ; 35(12): 2881.e1-2881.e6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25104557

RESUMO

The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Presenilina-1/genética , Presenilina-2/genética , Príons/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Estudos de Coortes , Demência/diagnóstico , Demência/genética , Diagnóstico Diferencial , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Priônicas , Progranulinas
12.
Neurobiol Aging ; 35(10): 2422.e13-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24880964

RESUMO

Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).


Assuntos
Doença de Alzheimer/genética , Exoma/genética , Estudos de Associação Genética , Mutação/genética , Presenilina-1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Precursor de Proteína beta-Amiloide/genética , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Genes Dominantes/genética , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-2/genética , Análise de Sequência de DNA , Reino Unido
13.
Neurobiol Aging ; 35(6): 1510.e19-26, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24439484

RESUMO

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.


Assuntos
Doença de Alzheimer/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Mutação de Sentido Incorreto/genética , Receptores Imunológicos/genética , Doença de Alzheimer/prevenção & controle , Biomarcadores/líquido cefalorraquidiano , Cromossomos Humanos Par 6 , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Receptores Imunológicos/fisiologia , Risco
14.
Nature ; 505(7484): 550-554, 2014 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-24336208

RESUMO

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-ß precursor protein (APP) and extracellular Aß42 and Aß40 (the 42- and 40-residue isoforms of the amyloid-ß peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aß42 and Aß40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Fosfolipase D/genética , Afro-Americanos/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Europa (Continente)/etnologia , Exoma/genética , Feminino , Humanos , Masculino , Fragmentos de Peptídeos/metabolismo , Fosfolipase D/deficiência , Fosfolipase D/metabolismo , Processamento de Proteína Pós-Traducional/genética , Proteólise
15.
Am J Hum Genet ; 92(2): 245-51, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23332917

RESUMO

Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid ß-glucosidase 1. ß-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding ß-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121(∗)] and c.1018C>T [p.Arg340(∗)]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans.


Assuntos
Ataxia Cerebelar/complicações , Ataxia Cerebelar/genética , Genes Recessivos/genética , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Mutação/genética , beta-Glucosidase/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Tunísia , beta-Glucosidase/química
16.
N Engl J Med ; 368(2): 117-27, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23150934

RESUMO

BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).


Assuntos
Doença de Alzheimer/genética , Glicoproteínas de Membrana/genética , Mutação , Receptores Imunológicos/genética , Idoso , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Exoma/genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Técnicas de Genotipagem , Heterozigoto , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos A , RNA Mensageiro/metabolismo , Receptores Imunológicos/metabolismo , Fatores de Risco , Análise de Sequência de DNA/métodos
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