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1.
J Alzheimers Dis ; 79(3): 1195-1201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427744

RESUMO

BACKGROUND: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia. OBJECTIVE: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD. METHODS: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics. RESULTS: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia. CONCLUSION: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33216869

RESUMO

Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic-risk-scores (PRS) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N=343), a population-matched cohort of older-adults from five cohorts (N=2905), and summary statistics data from a GWAS on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older-adults. This PRS was also associated with longer survival in an independent sample of younger individuals, (p=0.02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human lifespan is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

5.
Lancet Neurol ; 19(10): 840-848, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32949544

RESUMO

BACKGROUND: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. METHODS: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. FINDINGS: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. INTERPRETATION: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. FUNDING: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.


Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/epidemiologia , Predisposição Genética para Doença/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
6.
Transl Psychiatry ; 10(1): 332, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994401

RESUMO

Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was ß-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to ß-amyloid metabolism.

7.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
8.
Acta Neuropathol ; 140(6): 811-830, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32926214

RESUMO

Alzheimer's disease (AD) is characterized by amyloid-beta (Aß) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aß deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aß-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aß-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrPC), Aß isoform composition (Aß40, Aß42, AßN3pE, pSer8Aß), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aß40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aß40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aß plaque-type associated with EOAD. Differences in Aß processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aß deposits. Disentangling specific Aß deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

9.
Neurology ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913026

RESUMO

OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMB). METHODS: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMB were rated on susceptibility-weighted or T2*-weighted gradient echo magnetic resonance imaging sequences, and further classified as lobar, or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMB. RESULTS: BMB were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead SNP rs769449; ORany BMB (95% CI)=1.33 (1.21-1.45); p=2.5x10-10). APOE ε4 alleles were associated with strictly lobar (OR (95% CI)=1.34 (1.19-1.50); p=1.0x10-6) but not with mixed BMB counts (OR (95% CI)=1.04 (0.86-1.25); p=0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral haemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB. CONCLUSIONS: Genetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMB. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

10.
Acta Neuropathol ; 139(6): 1025-1044, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32166339

RESUMO

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

11.
JAMA Netw Open ; 3(2): e200094, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32101309

RESUMO

Importance: Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging. Objective: To identify individuals who escape cognitive decline until extreme ages and to investigate the prevalence of associated risk factors. Design, Setting, and Participants: The 100-plus Study is a prospective observational cohort study of community-based Dutch centenarians enrolled between 2013 and 2019 who were visited annually until death or until participation was no longer possible. The centenarians self-reported their cognitive health, as confirmed by a proxy. Of the 1023 centenarians approached for study inclusion, 340 fulfilled the study criteria and were included in analyses. Data analysis was performed from April 2019 to December 2019. Main Outcomes and Measures: Cognition was assessed using the Mini-Mental State Examination (MMSE). To identify centenarians who escape cognitive decline, this study investigated the association of baseline cognition with survivorship and cognitive trajectories for at least 2 years of follow-up using linear mixed models, adjusted for sex, age, and education. This study investigated the prevalence of apolipoprotein E (APOE) genotypes and cardiovascular disease as risk factors associated with cognitive decline. Results: At baseline, the median age of 340 centenarians was 100.5 years (range, 100.0-108.2 years); 245 participants (72.1%) were female. The maximum survival estimate plateaued at 82% per year (95% CI, 77% to 87%) across centenarians who scored 26 to 30 points on the baseline MMSE (hazard ratio, 0.56; 95% CI, 0.42 to 0.75; P < .001), suggesting that an MMSE score of 26 or higher is representative of both cognitive and physical health. Among the 79 centenarians who were followed up for 2 years or longer, those with baseline MMSE score less than 26 experienced a decline in MMSE score of 1.68 points per year (95% CI, -2.45 to -0.92 points per year; P = .02), whereas centenarians with MMSE scores of 26 or higher at baseline experienced a decline of 0.71 point per year (95% CI, -1.08 to -0.35 points per year). For 73% of the centenarians with baseline MMSE scores of 26 or higher, no cognitive changes were observed, which often extended to ensuing years or until death. It is estimated that this group is representative of less than 10% of Dutch centenarians. In this group, 18.6% carried at least 1 APOE-ε4 allele, compared with 5.6% of the centenarians with lower and/or declining cognitive performance. Conclusions and Relevance: Most centenarians who scored 26 or higher on the MMSE at baseline maintained high levels of cognitive performance for at least 2 years, in some cases despite the presence of risk factors associated with cognitive decline. Investigation of this group might reveal the processes underlying resilience against risk factors associated with cognitive decline.


Assuntos
Envelhecimento/fisiologia , Cognição/fisiologia , Testes de Estado Mental e Demência/estatística & dados numéricos , Idoso de 80 Anos ou mais , Envelhecimento/genética , Apolipoproteína E4/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos
13.
Nat Genet ; 51(11): 1624-1636, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636452

RESUMO

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Drosophila melanogaster/metabolismo , Variação Genética , Estudo de Associação Genômica Ampla , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Adulto , Idoso , Animais , Estudos de Coortes , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tamanho do Órgão
14.
Commun Biol ; 2: 285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396565

RESUMO

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.


Assuntos
Lobo Frontal/crescimento & desenvolvimento , Loci Gênicos , Variação Genética , Lobo Occipital/crescimento & desenvolvimento , Lobo Parietal/crescimento & desenvolvimento , Lobo Temporal/crescimento & desenvolvimento , Lobo Frontal/diagnóstico por imagem , Regulação da Expressão Gênica no Desenvolvimento , Estudo de Associação Genômica Ampla , Genótipo , Hereditariedade , Humanos , Imagem por Ressonância Magnética , Lobo Occipital/diagnóstico por imagem , Tamanho do Órgão/genética , Lobo Parietal/diagnóstico por imagem , Fenótipo , Lobo Temporal/efeitos dos fármacos , Reino Unido
17.
Acta Neuropathol ; 138(2): 237-250, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31131421

RESUMO

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.


Assuntos
Demência/genética , Longevidade/genética , Mutação , Fosfolipase C gama/genética , Alelos , Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/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 , Risco
18.
Alzheimers Res Ther ; 11(1): 47, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31097030

RESUMO

BACKGROUND: There is increasing evidence that dementia risk associated with vascular disorders is age dependent. Large population-based studies of incident dementia are necessary to further elucidate this effect. Therefore, the aim of the present study was to determine the association of vascular disorders with incident dementia in different age groups in a large primary care database. METHODS: We included 442,428 individuals without dementia aged ≥ 65 years from the longitudinal primary care Integrated Primary Care Information (IPCI) database. We determined in 6 age groups (from 65-70 to ≥ 90 years) the risk of hypertension, diabetes mellitus, dyslipidemia, stroke, myocardial infarction, heart failure, and atrial fibrillation for all-cause dementia using incidence rate ratios, Cox regression, and Fine and Gray regression models. RESULTS: The mean age at inclusion of the total study sample was 72.4 years, 45.7% of the participants were male, and median follow-up was 3.6 years. During 1.4 million person-years of follow-up, 13,511 individuals were diagnosed with dementia. The risk for dementia decreased with increasing age for all risk factors and was no longer significant in individuals aged ≥ 90 years. Adjusting for mortality as a competing risk did not change the results. CONCLUSIONS: We conclude that vascular disorders are no longer a risk factor for dementia at high age. Possible explanations include selective survival of individuals who are less susceptible to the negative consequences of vascular disorders and differences in follow-up time between individuals with and without a vascular disorder. Future research should focus on the identification of other risk factors than vascular disorders, for example, genetic or inflammatory processes, that can potentially explain the strong age-related increase in dementia risk.


Assuntos
Demência/epidemiologia , Doenças Vasculares/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Demência/complicações , Feminino , Humanos , Incidência , Masculino , Fatores de Risco , Doenças Vasculares/complicações
19.
Nat Genet ; 51(3): 414-430, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30820047

RESUMO

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aß processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Imunidade/genética , Lipídeos/genética , Proteínas tau/genética , Idoso , Estudos de Casos e Controles , Feminino , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Metabolismo dos Lipídeos/genética , Masculino
20.
Neurology ; 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651383

RESUMO

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

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