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Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
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Doença de Parkinson , alfa-Sinucleína , Humanos , Doença de Parkinson/metabolismo , Corpos de Processamento , Estabilidade de RNA , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.
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Doença de Alzheimer , Predisposição Genética para Doença , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Herança Multifatorial/genética , Feminino , Masculino , Idoso , Fatores de Risco , Estudo de Associação Genômica Ampla , Fenótipo , Apolipoproteínas E/genética , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Disfunção Cognitiva/genética , Estratificação de Risco GenéticoRESUMO
The extent of shared and distinct neural mechanisms underlying major depressive disorder (MDD), anxiety, and stress-related disorders is still unclear. We compared the neural signatures of these disorders in 5,405 UK Biobank patients and 21,727 healthy controls. We found the greatest casecontrol differences in resting-state functional connectivity and cortical thickness in MDD, followed by anxiety and stress-related disorders. Neural signatures for MDD and anxiety disorders were highly concordant, whereas stress-related disorders showed a distinct pattern. Controlling for cross-disorder genetic risk somewhat decreased the similarity between functional neural signatures of stress-related disorders and both MDD and anxiety disorders. Among cases and healthy controls, reduced within-network and increased between-network frontoparietal and default mode connectivity were associated with poorer cognitive performance (processing speed, attention, associative learning, and fluid intelligence). These results provide evidence for distinct neural circuit function impairments in MDD and anxiety disorders compared to stress disorders, yet cognitive impairment appears unrelated to diagnosis and varies with circuit function.
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Transtornos de Ansiedade , Encéfalo , Transtorno Depressivo Maior , Vias Neurais , Estresse Psicológico , Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/fisiopatologia , Humanos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/fisiopatologiaRESUMO
INTRODUCTION: Understanding the factors influencing vaping cessation among young people is crucial for targeted interventions. This review aimed to summarize the individual and environmental factors that predict vaping cessation related behaviours in the young population. METHODS: We systematically searched five databases for studies investigating predictors of vaping cessation behaviours among young people aged 10-35 years. Studies that examined predictors of cessation of cigarettes, other tobacco products, cannabis vaping, and studies evaluating efficacy of cessation interventions were excluded. Quality in Prognosis Studies tool was used to assess risk of bias. RESULTS: We found 24 studies analyzing predictors of intention to quit vaping (n=15), quit attempts (n=11), and vaping abstinence (n=7). Most studies had low risk of bias, except for study attrition. We identified 107 predictors and grouped them into 'probable', 'possible', 'insufficient evidence', 'probably unrelated', and 'inconsistent direction' categories. For 'probable' predictors, we found 11 for intention to quit, 8 for quit attempts and 5 for vaping abstinence. Overall, harm perception of vaping, current other tobacco products use, frequency of use, and level of nicotine dependence were common 'probable' predictors across three outcomes, with low harm perception of vaping, dual use, and poly tobacco use associated with decreased intention to quit and quit attempts in younger population (~10-19 years). CONCLUSIONS: Predictive modelling studies investigating vaping cessation related behaviours among young people is still limited. Future research should specifically study the natural history of vaping in youth in different jurisdictions, populations, and age groups to expand our knowledge on this area. IMPLICATIONS: We identified and categorized predictors of intention to quit vaping, quit attempts, and vaping abstinence among young people. While the 'probable' predictors can inform public health and policymakers to plan targeted vaping cessation programs for high-risk populations, raising public harm perception of vaping and encouraging to quit other tobacco products might increase intention to quit and quit attempts among younger population. However, the 'possible', 'insufficient evidence' and 'inconsistent direction' predictors needs further testing by future prospective longitudinal research. Additionally, we emphasized the significance of appropriate study designs, conducting research across various jurisdictions, and different population groups to obtain comprehensive insights.
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BACKGROUND: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.
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Complexo de Endopeptidases do Proteassoma , Ubiquitina , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Proteostase , Proteômica , Neurônios/metabolismoRESUMO
Many neuropsychiatric disorders are characterised by altered cortical thickness, but the cell types underlying these changes remain largely unknown. Virtual histology (VH) approaches map regional patterns of gene expression with regional patterns of MRI-derived phenotypes, such as cortical thickness, to identify cell types associated with case-control differences in those MRI measures. However, this method does not incorporate valuable information of case-control differences in cell type abundance. We developed a novel method, termed case-control virtual histology (CCVH), and applied it to Alzheimer's disease (AD) and dementia cohorts. Leveraging a multi-region gene expression dataset of AD cases (n = 40) and controls (n = 20), we quantified AD case-control differential expression of cell type-specific markers across 13 brain regions. We then correlated these expression effects with MRI-derived AD case-control cortical thickness differences across the same regions. Cell types with spatially concordant AD-related effects were identified through resampling marker correlation coefficients. Among regions thinner in AD, gene expression patterns identified by CCVH suggested fewer excitatory and inhibitory neurons, and greater proportions of astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and endothelial cells in AD cases vs. controls. In contrast, original VH identified expression patterns suggesting that excitatory but not inhibitory neuron abundance was associated with thinner cortex in AD, despite the fact that both types of neurons are known to be lost in the disorder. Compared to original VH, cell types identified through CCVH are more likely to directly underlie cortical thickness differences in AD. Sensitivity analyses suggest our results are largely robust to specific analysis choices, like numbers of cell type-specific marker genes used and background gene sets used to construct null models. As more multi-region brain expression datasets become available, CCVH will be useful for identifying the cellular correlates of cortical thickness across neuropsychiatric illnesses.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Células Endoteliais/patologia , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Estudos de Casos e ControlesRESUMO
Identifying ancestry-specific molecular profiles of late-onset Alzheimer's Disease (LOAD) in brain tissue is crucial to understand novel mechanisms and develop effective interventions in non-European, high-risk populations. We performed gene differential expression (DE) and consensus network-based analyses in RNA-sequencing data of postmortem brain tissue from 39 Caribbean Hispanics (CH). To identify ancestry-concordant and -discordant expression profiles, we compared our results to those from two independent non-Hispanic White (NHW) samples (n = 731). In CH, we identified 2802 significant DE genes, including several LOAD known-loci. DE effects were highly concordant across ethnicities, with 373 genes transcriptome-wide significant in all three cohorts. Cross-ancestry meta-analysis found NPNT to be the top DE gene. We replicated over 82% of meta-analyses genome-wide signals in single-nucleus RNA-seq data (including NPNT and LOAD known-genes SORL1, FBXL7, CLU, ABCA7). Increasing representation in genetic studies will allow for deeper understanding of ancestry-specific mechanisms and improving precision treatment options in understudied groups.
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Doença de Alzheimer , Transcriptoma , Humanos , Doença de Alzheimer/genética , População do Caribe , Etnicidade , Encéfalo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genéticaRESUMO
Cognitive impairment in the elderly features complex molecular pathophysiology extending beyond the hallmark pathologies of traditional disease classification. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured â¼8000 proteins across >600 dorsolateral prefrontal cortex tissues with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia. Unbiased classification of MCI and AD cases based on individual proteomic profiles resolved three classes with expression differences across numerous cell types and biological ontologies. Two classes displayed molecular signatures atypical of AD neurodegeneration, such as elevated synaptic and decreased inflammatory markers. In one class, these atypical proteomic features were associated with clinical and pathological hallmarks of cognitive resilience. We were able to replicate these classes and their clinicopathological phenotypes across two additional tissue cohorts. These results promise to better define the molecular heterogeneity of cognitive impairment and meaningfully impact its diagnostic and therapeutic precision.
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Doença de Alzheimer , Disfunção Cognitiva , Idoso , Humanos , Proteoma , Proteômica , EncéfaloRESUMO
BACKGROUND: Our understanding of major depression is complicated by substantial heterogeneity in disease presentation, which can be disentangled by data-driven analyses of depressive symptom dimensions. We aimed to determine the clinical portrait of such symptom dimensions among individuals in the community. METHODS: This cross-sectional study consisted of 25 261 self-reported White UK Biobank participants with major depression. Nine questions from the UK Biobank Mental Health Questionnaire encompassing depressive symptoms were decomposed into underlying factors or 'symptom dimensions' via factor analysis, which were then tested for association with psychiatric diagnoses and polygenic risk scores for major depressive disorder (MDD), bipolar disorder and schizophrenia. Replication was performed among 655 self-reported non-White participants, across sexes, and among 7190 individuals with an ICD-10 code for MDD from linked inpatient or primary care records. RESULTS: Four broad symptom dimensions were identified, encompassing negative cognition, functional impairment, insomnia and atypical symptoms. These dimensions replicated across ancestries, sexes and individuals with inpatient or primary care MDD diagnoses, and were also consistent among 43 090 self-reported White participants with undiagnosed self-reported depression. Every dimension was associated with increased risk of nearly every psychiatric diagnosis and polygenic risk score. However, while certain psychiatric diagnoses were disproportionately associated with specific symptom dimensions, the three polygenic risk scores did not show the same specificity of associations. CONCLUSIONS: An analysis of questionnaire data from a large community-based cohort reveals four replicable symptom dimensions of depression with distinct clinical, but not genetic, correlates.
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Transtorno Bipolar , Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/complicações , Depressão/genética , Estudos Transversais , Predisposição Genética para Doença , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/complicações , Herança MultifatorialRESUMO
Deciphering the environmental contexts at which genetic effects are most prominent is central for making full use of GWAS results in follow-up experiment design and treatment development. However, measuring a large number of environmental factors at high granularity might not always be feasible. Instead, here we propose extracting cellular embedding of environmental factors from gene expression data by using latent variable (LV) analysis and taking these LVs as environmental proxies in detecting gene-by-environment (GxE) interaction effects on gene expression, i.e., GxE expression quantitative trait loci (eQTLs). Applying this approach to two largest brain eQTL datasets (n = 1,100), we show that LVs and GxE eQTLs in one dataset replicate well in the other dataset. Combining the two samples via meta-analysis, 895 GxE eQTLs are identified. On average, GxE effect explains an additional â¼4% variation in expression of each gene that displays a GxE effect. Ten of these 52 genes are associated with cell-type-specific eQTLs, and the remaining genes are multi-functional. Furthermore, after substituting LVs with expression of transcription factors (TF), we found 91 TF-specific eQTLs, which demonstrates an important use of our brain GxE eQTLs.
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Encéfalo/metabolismo , Genótipo , Transcriptoma , Humanos , Locos de Características QuantitativasRESUMO
OBJECTIVE: Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH). METHODS: We used a CH discovery (n = 4,312) and independent validation sample (n = 1,850) to construct an ancestry-specific PRS ("CH-PRS") and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH-PRS predicted conversion to LOAD in a subsample with longitudinal data (n = 1,239). We also tested the CH-PRS in an independent replication CH cohort (n = 200) and brain autopsy cohort (n = 33). Finally, we tested the effect of ancestry on PRS by using European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS"). RESULTS: The full model (LOAD ~ CH-PRS + sex + age + APOE-É4), achieved an AUC = 74% (ORCH-PRS = 1.51 95%CI = 1.36-1.68), raising to >75% in APOE-É4 non-carriers. CH-PRS alone achieved an AUC = 72% in the autopsy cohort, raising to AUC = 83% in full model. Higher CH-PRS was significantly associated with clinical LOAD in the replication CH cohort (OR = 1.61, 95%CI = 1.19-2.17) and significantly predicted conversion to LOAD (HR = 1.93, CI = 1.70-2.20) in the longitudinal subsample. EUR-PRS and AA-PRS reached lower prediction accuracy (AUC = 58% and 53%, respectively). INTERPRETATION: Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. ANN NEUROL 2021;90:366-376.
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Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Hispânico ou Latino/genética , Herança Multifatorial/genética , Idoso , Idoso de 80 Anos ou mais , Região do Caribe/etnologia , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Mental health problems and substance use co-morbidities during and after the COVID-19 pandemic are a public health priority. Identifying individuals at high-risk of developing mental health problems and potential sequela can inform mitigating strategies. We aimed to identify distinct groups of individuals (i.e., latent classes) based on patterns of self-reported mental health symptoms and investigate their associations with alcohol and cannabis use. METHODS: We used data from six successive waves of a web-based cross-sectional survey of adults aged 18 years and older living in Canada (6,021 participants). We applied latent class analysis to three domains of self-reported mental health most likely linked to effects of the pandemic: anxiety, depression, and loneliness. Logistic regression was used to characterize latent class membership, estimate the association of class membership with alcohol and cannabis use, and perform sex-based analyses. RESULTS: We identified two distinct classes: (1) individuals with low scores on all three mental health indicators (no/low-symptoms) and (2) those reporting high scores across the three measures (high-symptoms). Between 73.9 and 77.1% of participants were in the no/low-symptoms class and 22.9-26.1% of participants were in the high-symptom class. We consistently found across all six waves that individuals at greater risk of being in the high-symptom class were more likely to report worrying about getting COVID-19 with adjusted odds ratios (aORs) between 1.72 (95%CI:1.17-2.51) and 3.51 (95%CI:2.20-5.60). Those aged 60 + were less likely to be in this group with aORs (95%CI) between 0.26 (0.15-0.44) and 0.48 (0.29-0.77) across waves. We also found some factors associated with class membership varied at different time points. Individuals in the high-symptom class were more likely to use cannabis at least once a week (aOR = 2.28, 95%CI:1.92-2.70), drink alcohol heavily (aOR = 1.71, 95%CI:1.49-1.96); and increase the use of cannabis (aOR = 3.50, 95%CI:2.80-4.37) and alcohol (aOR = 2.37, 95%CI:2.06-2.74) during the pandemic. Women in the high-symptom class had lower odds of drinking more alcohol during the pandemic than men. CONCLUSIONS: We identified the determinants of experiencing high anxiety, depression, and loneliness symptoms and found a significant association with alcohol and cannabis consumption. This suggests that initiatives and supports are needed to address mental health and substance use multi-morbidities.
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COVID-19 , Cannabis , Transtornos Relacionados ao Uso de Substâncias , Adulto , COVID-19/epidemiologia , Estudos Transversais , Feminino , Humanos , Análise de Classes Latentes , Masculino , Saúde Mental , Pandemias , Autorrelato , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
Identifying genes underlying memory function will help characterize cognitively resilient and high-risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)-stratified genome-wide association study (GWAS) analyses and combined individual cohorts' results via meta-analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10-8 ) among non-carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10-4 ) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P = .007) and inferior frontal gyrus (P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance.
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Doença de Alzheimer , Memória Episódica , Humanos , Idoso , Apolipoproteína E4/genética , Estudo de Associação Genômica Ampla , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Transcriptoma , Encéfalo/metabolismo , Apolipoproteínas E/genética , Proteínas Associadas aos MicrotúbulosRESUMO
BACKGROUND: Sleep problems are both symptoms of and modifiable risk factors for many psychiatric disorders. Wrist-worn accelerometers enable objective measurement of sleep at scale. Here, we aimed to examine the association of accelerometer-derived sleep measures with psychiatric diagnoses and polygenic risk scores in a large community-based cohort. METHODS AND FINDINGS: In this post hoc cross-sectional analysis of the UK Biobank cohort, 10 interpretable sleep measures-bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration-were derived from 7-day accelerometry recordings across 89,205 participants (aged 43 to 79, 56% female, 97% self-reported white) taken between 2013 and 2015. These measures were examined for association with lifetime inpatient diagnoses of major depressive disorder, anxiety disorders, bipolar disorder/mania, and schizophrenia spectrum disorders from any time before the date of accelerometry, as well as polygenic risk scores for major depression, bipolar disorder, and schizophrenia. Covariates consisted of age and season at the time of the accelerometry recording, sex, Townsend deprivation index (an indicator of socioeconomic status), and the top 10 genotype principal components. We found that sleep pattern differences were ubiquitous across diagnoses: each diagnosis was associated with a median of 8.5 of the 10 accelerometer-derived sleep measures, with measures of sleep quality (for instance, sleep efficiency) generally more affected than mere sleep duration. Effect sizes were generally small: for instance, the largest magnitude effect size across the 4 diagnoses was ß = -0.11 (95% confidence interval -0.13 to -0.10, p = 3 × 10-56, FDR = 6 × 10-55) for the association between lifetime inpatient major depressive disorder diagnosis and sleep efficiency. Associations largely replicated across ancestries and sexes, and accelerometry-derived measures were concordant with self-reported sleep properties. Limitations include the use of accelerometer-based sleep measurement and the time lag between psychiatric diagnoses and accelerometry. CONCLUSIONS: In this study, we observed that sleep pattern differences are a transdiagnostic feature of individuals with lifetime mental illness, suggesting that they should be considered regardless of diagnosis. Accelerometry provides a scalable way to objectively measure sleep properties in psychiatric clinical research and practice, even across tens of thousands of individuals.
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Acelerometria/instrumentação , Bancos de Espécimes Biológicos , Transtornos Mentais/fisiopatologia , Sono/fisiologia , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Reprodutibilidade dos Testes , Fatores de Risco , Autorrelato , Reino UnidoRESUMO
The brain-derived neurotrophic factor (BDNF) is critical for brain development, and the functional BDNF Val66Met polymorphism is implicated in risk for mood disorders. The objective of this study was to determine how the Val66Met polymorphism influences amygdala-cortical connectivity during neurodevelopment and assess the relevance for mood disorders. Age- and sex-specific effects of the BDNF Val66Met polymorphism on amygdala-cortical connectivity were assessed by examining covariance of amygdala volumes with thickness throughout the cortex in a sample of Caucasian youths ages 8-22 that were part of the Philadelphia Neurodevelopmental Cohort (n = 339). Follow-up analyses assessed corresponding BDNF genotype effects on resting-state functional connectivity (n = 186) and the association between BDNF genotype and major depressive disorder (MDD) (n = 2749). In adolescents, amygdala-cortical covariance was significantly stronger in Met allele carriers compared with Val/Val homozygotes in amygdala-cortical networks implicated in depression; these differences were driven by females. In follow-up analyses, the Met allele was also associated with stronger resting-state functional connectivity in adolescents and increased likelihood of MDD in adolescent females. The BDNF Val66Met polymorphism may confer risk for mood disorders in females through effects on amygdala-cortical connectivity during adolescence, coinciding with a period in the lifespan when onset of depression often occurs, more commonly in females.
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Tonsila do Cerebelo/diagnóstico por imagem , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/diagnóstico por imagem , Depressão/diagnóstico por imagem , Depressão/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Fatores Etários , Criança , Estudos de Coortes , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Metionina/genética , Vias Neurais/diagnóstico por imagem , Oxigênio/sangue , Escalas de Graduação Psiquiátrica , Fatores Sexuais , Valina/genética , Adulto JovemRESUMO
INTRODUCTION: The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. METHODS AND FINDINGS: "Residual cognition" was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10-5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = -0.40, 95% CI -0.69 to -0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10-5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. CONCLUSIONS: Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.
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Envelhecimento/fisiologia , Encéfalo/patologia , Transtornos Cognitivos/genética , Cognição/fisiologia , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Proteínas Nucleares/genética , Receptores de Superfície Celular/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cognitivos/metabolismo , Metilação de DNA , Depressão/metabolismo , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/metabolismo , Memória , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Netrina , Neuropeptídeos/metabolismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , RNA/metabolismo , Receptores de Superfície Celular/metabolismo , Proteinopatias TDP-43/genéticaRESUMO
INTRODUCTION: The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid ß (Aß) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans. METHODS: We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aß plaques. The same SORL1-BDNF interactions also significantly influenced Aß load as measured with [18F]Florbetapir positron emission tomography. DISCUSSION: Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.
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Envelhecimento , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Epistasia Genética/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Compostos de Anilina/farmacocinética , Anisotropia , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Coortes , Etilenoglicóis/farmacocinética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Polimorfismo de Nucleotídeo Único , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. METHODS: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study's original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. RESULTS: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). CONCLUSIONS: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.
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Antipsicóticos/uso terapêutico , Catecol O-Metiltransferase/genética , Variantes Farmacogenômicos , Polimorfismo Genético , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/efeitos adversos , Humanos , Razão de Chances , Farmacogenética , Testes Farmacogenômicos , Transtornos Psicóticos/enzimologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/psicologia , Indução de Remissão , Fatores de Risco , Esquizofrenia/enzimologia , Esquizofrenia/genética , Psicologia do Esquizofrênico , Resultado do TratamentoRESUMO
BACKGROUND: Pittsburgh compound B ([11C]-PIB) identifies amyloid-ß (Aß) deposition in vivo. Asymptomatic Aß deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aß deposition. OBJECTIVE: Comparison of Aß deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia. METHODS: Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff. RESULTS: The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD. CONCLUSIONS: Aß deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aß deposition. Copyright © 2016 John Wiley & Sons, Ltd.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Demência Frontotemporal/metabolismo , Idoso , Compostos de Anilina , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , TiazóisRESUMO
The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.