RESUMO
Uncovering the genetic architectures of brain morphology offers valuable insights into brain development and disease. Genetic association studies of brain morphological phenotypes have discovered thousands of loci. However, interpretation of these loci presents a significant challenge. One potential solution is exploring the genetic overlap between brain morphology and disorders, which can improve our understanding of their complex relationships, ultimately aiding in clinical applications. In this review, we examine current evidence on the genetic associations between brain morphology and neuropsychiatric traits. We discuss the impact of these associations on the diagnosis, prediction, and treatment of neuropsychiatric diseases, along with suggestions for future research directions.
Assuntos
Encéfalo , Transtornos Mentais , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/anatomia & histologia , Transtornos Mentais/genética , Transtornos Mentais/patologia , Fenótipo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Associação GenéticaRESUMO
Accumulating evidence confirms that sleep insufficiency is a high risk factor for cognitive impairment, which involves inflammation and synaptic dysfunction. Resveratrol, an agonist of the Sirt1, has demonstrated anti-inflammation and neuroprotective effects in models of Alzheimer's disease, Parkinson's disease, and schizophrenia. However, the beneficial effects of resveratrol on sleep deprivation-induced cognitive deficits and its underlying molecular mechanisms are unclear. In the present study, thirty-two male C57BL/6 J mice were randomly divided into a Control+DMSO group, Control+Resveratrol group, SD+DMSO group, and SD+Resveratrol group. The mice in the SD+Resveratrol group underwent 5 days of sleep deprivation after pretreatment with resveratrol (50 mg/kg) for 2 weeks, while the mice in the SD+DMSO group only underwent sleep deprivation. After sleep deprivation, we evaluated spatial learning and memory function using the Morris water maze test. We used general molecular biology techniques to detect changes in levels of pro-inflammatory cytokines and Sirt1/miR-134 pathway-related synaptic plasticity proteins. We found that resveratrol significantly reversed sleep deprivation-induced learning and memory impairment, elevated interleukin-1ß, interleukin-6, and tumor necrosis factor-α levels, and decreased brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin levels by activating the Sirt1/miR-134 pathway. In conclusion, resveratrol is a promising agent for preventing sleep deprivation-induced cognitive dysfunction by reducing pro-inflammatory cytokines and improving synaptic function via the Sirt1/miR-134 pathway.
Assuntos
Disfunção Cognitiva , MicroRNAs , Masculino , Camundongos , Animais , Resveratrol/farmacologia , Privação do Sono/complicações , Privação do Sono/metabolismo , Sirtuína 1/metabolismo , Dimetil Sulfóxido/metabolismo , Dimetil Sulfóxido/farmacologia , Camundongos Endogâmicos C57BL , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Hipocampo/metabolismo , MicroRNAs/metabolismo , Citocinas/metabolismo , CogniçãoRESUMO
INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.
RESUMO
BACKGROUND: The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown. METHODS: We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders. RESULTS: We identified 11 genetic loci (P < 8.3 × 10-9) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories. CONCLUSIONS: Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders.
Assuntos
Encefalopatias , Substância Branca , Humanos , Imagem de Tensor de Difusão , Estudo de Associação Genômica Ampla , Encéfalo , AnisotropiaRESUMO
OBJECTIVE: Investigate the sleep characteristics of patients with obstructive sleep apnea syndrome (OSAS) comorbidity with panic disorder (PD), exploring its potential association with serum C-reactive protein (CRP) levels. PATIENTS AND METHODS: Fifty-four patients (25 OSAS patients with PD and 29 without PD) and 25 healthy controls (HCs) were included. The Self-rating anxiety scale (SAS), self-rating depression scale (SDS), and Pittsburgh sleep quality index (PSQI) were used to assess the mood and sleep quality of the subjects. All patients had circulating CRP levels and polysomnography was performed. RESULTS: OSAS with PD had higher SAS, SDS, PSQI than the OSAS without PD. Compared to OSAS without PD, OSAS with PD had higher percentage of non- rapid eye movement sleep 1 and 2 (N1 and N2%), sleep latency, and a lower percentage of rapid eye movement sleep (REM%). Respiratory-related microarousal index, AHI, and time below 90% oxygen saturation (T90) were low, and the lowest oxygen saturation (LO2) was high. Serum CRP levels in OSAS patients with PD were lower than that in OSAS patients without PD, but higher than that in HCs. In OSAS patients with PD, serum CRP levels were negatively correlated with wake time after sleep onset and SAS scores but positively correlated with sleep efficiency and N2%. Serum CRP levels were positively correlated with T90 and negatively correlated with LO2. CONCLUSION: OSAS patients with PD had worse sleep quality, less severe OSAS, and low serum CRP levels. Serum CRP levels in OSAS patients with PD were associated with poorer sleep quality and duration of hypoxia rather than AHI.
Assuntos
Proteína C-Reativa , Transtorno de Pânico , Apneia Obstrutiva do Sono , Proteína C-Reativa/análise , Apneia Obstrutiva do Sono/sangue , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/patologia , Humanos , Transtorno de Pânico/sangue , Respiração , Qualidade do Sono , Inflamação/metabolismo , Inflamação/patologia , Masculino , Feminino , Pessoa de Meia-IdadeRESUMO
Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the association among inflammation, brain structure, and neurodegenerative disorders at genetic and transcriptomic levels. Genetic variants associated with inflammatory cytokines were selected from the latest and largest genome-wide association studies of European ancestry. Neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies (DLB) and brain structure imaging measures were selected as the outcomes. Two-sample Mendelian randomization analyses were conducted to identify the causal associations. Single-nucleus transcriptome data of the occipitotemporal cortex was further analyzed to identify the differential expressed genes in AD, which were tested for biological processes and protein interaction network. MR analysis indicated that genetically predicted TREM2 and sTREM2 were significantly associated with AD (TREM2: z-score = -9.088, p-value = 1.02 × 10-19; sTREM2: z-score = -7.495, p-value = 6.61 × 10-14). The present study found no evidence to support the causal associations between other inflammatory cytokines and the risks of AD, PD, ALS, or DLB. Genetically predicted TREM2 was significantly associated with the cortical thickness of inferior temporal (z-score = -4.238, p-value = 2.26 × 10-5) and pole temporal (z-score = -4.549, p-value = 5.40 × 10-6). In the occipitotemporal cortex samples, microglia were the main source of TREM2 gene and showed increasing expression of genes associated with inflammation and immunity. The present study has leveraged genetic and transcriptomic data to identify the association among TREM2, temporal lobe, and AD and the underlying cellular and molecular basis, thus providing a new perspective on the role of TREM2 in AD and insights into the complex associations among inflammation, brain structure, and neurodegenerative disorders, particularly AD.
Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Encefalite , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Esclerose Lateral Amiotrófica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doenças Neurodegenerativas/genética , Doença de Parkinson/genética , Encéfalo/metabolismo , Inflamação/genética , Citocinas/genética , Citocinas/metabolismoRESUMO
Growing evidence indicates that neuroinflammation plays a critical role in anxiety, depression, and cognitive impairment. Sleep loss disrupts the host's immune balance and increases neuroinflammation. This study explored whether chronic sleep deprivation aggravates lipopolysaccharide-induced anxiety, depression, and cognitive impairment and assessed the underlying mechanisms. Lipopolysaccharide (250 µg/kg) was administered to adult mice for 9 days, accompanied with daily intermittent sleep deprivation from 12:00 to 18:00 by using an activity wheel. Anxiety, depression, and cognitive function were evaluated using a task battery consisting of an open field, elevated plus maze, tail suspension, forced swimming, and Morris water maze tests. The levels of pro-inflammatory cytokines and synaptic plasticity-associated proteins were examined by enzyme-linked immunosorbent assay and western blot, respectively. The results showed that lipopolysaccharide increased anxiety- and depression-like behaviors, impaired cognitive function, uprelated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and decreased brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95), and synaptophysin (SYN), which were aggravated by chronic sleep deprivation. These results suggest that chronic sleep deprivation exerted adverse effects on lipopolysaccharide-induced anxiety, depression, and cognitive impairment, which was associated with changes in pro-inflammatory cytokines and synaptic plasticity associated proteins.
Assuntos
Disfunção Cognitiva , Citocinas , Camundongos , Animais , Citocinas/metabolismo , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Privação do Sono/complicações , Doenças Neuroinflamatórias , Disfunção Cognitiva/induzido quimicamente , Ansiedade/induzido quimicamente , Plasticidade Neuronal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Interleucina-6/metabolismo , HipocampoRESUMO
Objectives: To examine serum concentrations of neurotensin, pannexin-1 and sestrin-2, and their correlations with subjective and objective sleep quality and cognitive function in the patients with chronic insomnia disorder (CID). Methods: Sixty-five CID patients were enrolled continuously and fifty-six good sleepers in the same period were served as healthy controls (HCs). Serum levels of neurotensin, pannexin-1 and sestrin-2 were measured by enzyme-linked immunosorbent assays. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and polysomnography, and mood was evaluated by 17-item Hamilton Depression Rating Scale. General cognitive function was assessed with the Chinese-Beijing Version of Montreal Cognitive Assessment and spatial memory was evaluated by Blue Velvet Arena Test (BVAT). Results: Relative to the HCs, the CID sufferers had higher levels of neurotensin (t=5.210, p<0.001) and pannexin-1 (Z=-4.169, p<0.001), and lower level of sestrin-2 (Z=-2.438, p=0.015). In terms of objective sleep measures, pannexin-1 was positively associated with total sleep time (r=0.562, p=0.002) and sleep efficiency (r=0.588, p=0.001), and negatively with wake time after sleep onset (r=-0.590, p=0.001) and wake time (r=-0.590, p=0.001); sestrin-2 was positively associated with percentage of rapid eye movement sleep (r=0.442, p=0.016) and negatively with non-rapid eye movement sleep stage 2 in the percentage (r=-0.394, p=0.034). Adjusted for sex, age and HAMD, pannexin-1 was still associated with the above objective sleep measures, but sestrin-2 was only negatively with wake time (r=-0.446, p=0.022). However, these biomarkers showed no significant correlations with subjective sleep quality (PSQI score). Serum concentrations of neurotensin and pannexin-1 were positively associated with the mean erroneous distance in the BVAT. Adjusted for sex, age and depression, neurotensin was negatively associated with MoCA score (r=-0.257, p=0.044), pannexin-1 was positively associated with the mean erroneous distance in the BVAT (r=0.270, p=0.033). Conclusions: The CID patients had increased neurotensin and pannexin-1 and decreased sestrin-2 in the serum levels, indicating neuron dysfunction, which could be related to poor sleep quality and cognitive dysfunction measured objectively.
RESUMO
INTRODUCTION: Maternal sleep deprivation (MSD), which induces inflammation and synaptic dysfunction in the hippocampus, has been associated with learning and memory impairment in offspring. Melatonin (Mel) has been shown to have anti-inflammatory, antioxidant, and neuroprotective function. However, the beneficial effect of Mel on MSD-induced cognitive impairment and its mechanisms are unknown. METHODS: In the present study, adult offspring suffered from MSD were injected with Mel (20 mg/kg) once a day during postnatal days 61-88. The cognitive function was evaluated by the Morris water maze test. Levels of proinflammatory cytokines were examined by enzyme-linked immunosorbent assay. The mRNA and protein levels of synaptic plasticity associated proteins were examined using reverse transcription-polymerase chain reaction and western blotting. RESULTS: The results showed that MSD impaired learning and memory in the offspring mice. MSD increased the levels of interleukin (IL)-1creIL-6, and tumor necrosis factor-α and decreased the expression levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin in the hippocampus. Furthermore, Mel attenuated cognitive impairment and restored markers of inflammation and synaptic plasticity to control levels. CONCLUSIONS: These findings indicated that Mel could ameliorate learning and memory impairment induced by MSD, and these beneficial effects were related to improvement in inflammation and synaptic dysfunction.
Assuntos
Hipocampo , Melatonina , Transtornos da Memória , Plasticidade Neuronal , Privação do Sono , Animais , Melatonina/farmacologia , Melatonina/administração & dosagem , Privação do Sono/complicações , Privação do Sono/tratamento farmacológico , Privação do Sono/fisiopatologia , Camundongos , Masculino , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Feminino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Gravidez , Privação Materna , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológicoRESUMO
Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.
Assuntos
Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Fatores de Risco , Fatores de Coagulação Sanguínea/genética , Exoma , Estudo de Associação Genômica Ampla , Fatores de Processamento de Serina-Arginina/genética , Fosfoproteínas/genéticaRESUMO
Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.
RESUMO
BACKGROUND AND OBJECTIVE: Rumination, a common factor of chronic insomnia disorder (CID) caused by cognitive-emotional arousal, is associated with an increased amount of rapid eye movement (REM) sleep. However, the specific subtypes, such as phasic REM and tonic REM, that contribute to the increased REM sleep have not been reported. This study aimed to determine the association between rumination and different REM sleep subtypes in patients with CID. METHODS: This study enrolled 35 patients with CID and 27 age- and sex-matched healthy controls. The Immersion-Rumination Questionnaire evaluated participants' rumination, and the Insomnia Severity Index was used to assess insomnia severity. Finally, polysomnography was used to monitor objective sleep quality and quantification of different types of REM. RESULTS: The CID patients had higher rumination scores than the healthy controls. They had a shorter REM sleep duration, less phasic REM, a lower percentage of phasic REM time, and a higher percentage of tonic REM time. Spectral analysis revealed that the patients affected by insomnia had higher ß power during REM sleep, higher ß and σ power during phasic REM sleep, and higher ß, and γ power during tonic REM sleep. Partial correlation analysis showed that rumination in the CID patients correlated negatively with the duration of phasic REM sleep. Additionally, rumination correlated negatively with δ power in REM sleep and positively with ß power in REM sleep, tonic REM sleep, phasic REM sleep, N3and N2 sleep in the patients with CID. CONCLUSION: The CID patients had stronger rumination, reduced total and phasic REM sleep, and the stronger rumination was, the shorter phasic REM was and the higher fast (ß) wave power in REM sleep.
Assuntos
Transtorno do Comportamento do Sono REM , Distúrbios do Início e da Manutenção do Sono , Humanos , Sono REM , Distúrbios do Início e da Manutenção do Sono/complicações , Polissonografia , Nível de Alerta , Transtorno do Comportamento do Sono REM/complicaçõesRESUMO
OBJECTIVES: To explore the relationship between nocturnal levels of stress-related hormones and different sleep-wake states in chronic insomnia disorder (CID) patients. METHODS: Thirty-three CID patients and 34 good sleepers were enrolled and completed assessment of sleep log, Pittsburgh Sleep Quality Index and Insomnia Severity Index. During a-overnight polysomnography monitoring, the patients' vein bleeds were continually collected at different time points (pre-sleep, deep-sleep, 5-min or 30-min waking, and morning waking-up). The control subjects' bleeds were collected only at 22:00 and morning waking-up. The serum hormones were detected using enzyme-linked immunosorbent assay. RESULTS: Compared with at pre-sleep, the level of cortisol was significantly higher at morning waking-up respectively in two-group subjects (Ps < 0.001), with insignificant inter-group differences in cortisol, corticotropin releasing hormone and copeptin at the two time-points. In the patients, the nocturnal secretion curves of three hormones were similar, with the highest concentration at morning waking-up, followed by 30-min waking, 5-min waking, pre-sleep, and deep-sleep. The patients' cortisol (Z = 79.192, P < 0.001) and copeptin (Z = 12.333, P = 0.015) levels were statistically different at different time-points, with higher cortisol at morning waking-up relative to deep-sleep, pre-sleep and 5-min waking (Ps < 0.05), and at 30-min waking relative to deep-sleep and pre-sleep (Ps < 0.05), and higher copeptin at morning waking-up relative to deep-sleep (P < 0.05). CONCLUSIONS: In CID, the nocturnal wakes were instantaneously accompanied by high level, and deep sleep was accompanied by the lowest levels, of stress-related hormones, especially in cortisol, supporting the insomniac hypothesis of increased nocturnal pulse-release of cortisol.
Assuntos
Distúrbios do Início e da Manutenção do Sono , Humanos , Projetos Piloto , Hidrocortisona , Sono , PolissonografiaRESUMO
While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.
Assuntos
Sequenciamento do Exoma , Transtornos Mentais , Humanos , Transtornos Mentais/genética , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Predisposição Genética para Doença , Reino Unido , Fenótipo , Doenças Neurodegenerativas/genética , Estudos de Associação Genética , Idoso , Exoma/genéticaRESUMO
Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.
Assuntos
Estudo de Associação Genômica Ampla , Hipotálamo , Humanos , Hipotálamo/metabolismo , Hipotálamo/diagnóstico por imagem , Masculino , Feminino , Adulto , Transtornos Mentais/genética , Proteínas ADAMTS/genética , Pessoa de Meia-Idade , Análise da Randomização MendelianaRESUMO
The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan.
Assuntos
Doença de Alzheimer , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Estudo de Associação Genômica Ampla , Fenótipo , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
BACKGROUND: The corpus callosum (CC) is the main structure transferring information between the cerebral hemispheres. Although previous large-scale genome-wide association study (GWAS) has illustrated the genetic architecture of white matter integrity of CC, CC volume is less stressed. METHODS: Using MRI data from 33,861 individuals in UK Biobank, we conducted univariate and multivariate GWAS for CC fractional anisotropy (FA) and volume with PLINK 2.0 and MOSTest. All discovered SNPs in the multivariate framework were functionally annotated in FUMA v1.3.8. In the meanwhile, a series of gene property analyses was conducted simultaneously. In addition, we estimated genetic relationship between CC metrics and other neuropsychiatric traits and diseases. RESULTS: We identified a total of 36 and 82 significant genomic loci for CC FA and volume (P < 5 × 10-8). And 53 and 27 genes were respectively mapped by four mapping strategies. For CC volume, gene-set analysis revealed pathways mainly relating to cell migration; cell-type analysis found the top enrichment in neuroglia while for CC FA in GABAergic neurons. Furthermore, we found a lot of genetic overlap and shared loci between CC FA and volume and common neuropsychiatric diseases. DISCUSSION: Collectively, this study helps to better understand the genetic architecture of whole CC and CC subregions. However, the way to divide CC FA and volume in our study restricts the interpretations of our results. Future work will be needed to pay attention to the genetic structure of white matter volume, and an appropriate division of CC may help to better understand CC structure.
Assuntos
Corpo Caloso , Substância Branca , Humanos , Corpo Caloso/diagnóstico por imagem , Imagem de Tensor de Difusão , Estudo de Associação Genômica Ampla , Imageamento por Ressonância Magnética , Substância Branca/diagnóstico por imagem , AnisotropiaRESUMO
BACKGROUND: Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. METHODS: We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. RESULTS: Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. CONCLUSIONS: Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.
Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Esclerose Múltipla , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Parkinson/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Estudo de Associação Genômica Ampla , Proteômica , Encéfalo/metabolismo , Esclerose Múltipla/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Glicoproteínas de Membrana/metabolismo , 17-Hidroxiesteroide Desidrogenases/metabolismoRESUMO
The amygdala is a crucial interconnecting structure in the brain that performs several regulatory functions, yet its genetic architectures and involvement in brain disorders remain largely unknown. We carried out the first multivariate genome-wide association study (GWAS) of amygdala subfield volumes in 27,866 UK Biobank individuals. The whole amygdala was segmented into nine nuclei groups using Bayesian amygdala segmentation. The post-GWAS analysis allowed us to identify causal genetic variants in phenotypes at the SNP, locus, and gene levels, as well as genetic overlap with brain health-related traits. We further generalized our GWAS in Adolescent Brain Cognitive Development (ABCD) cohort. The multivariate GWAS identified 98 independent significant variants within 32 genomic loci associated (P < 5 × 10-8) with amygdala volume and its nine nuclei. The univariate GWAS identified significant hits for eight of the ten volumes, tagging 14 independent genomic loci. Overall, 13 of the 14 loci identified in the univariate GWAS were replicated in the multivariate GWAS. The generalization in ABCD cohort supported the GWAS results with the 12q23.2 (RNA gene RP11-210L7.1) being discovered. All of these imaging phenotypes are heritable, with heritability ranging from 15% to 27%. Gene-based analyses revealed pathways relating to cell differentiation/development and ion transporter/homeostasis, with the astrocytes found to be significantly enriched. Pleiotropy analyses revealed shared variants with neurological and psychiatric disorders under the conjFDR threshold of 0.05. These findings advance our understanding of the complex genetic architectures of amygdala and their relevance in neurological and psychiatric disorders.
Assuntos
Encefalopatias , Estudo de Associação Genômica Ampla , Adolescente , Humanos , Estudo de Associação Genômica Ampla/métodos , Predisposição Genética para Doença , Teorema de Bayes , Tonsila do Cerebelo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
INTRODUCTION: Growing evidence clearly demonstrates that maternal rodents exposure to sleep deprivation (SD) during late pregnancy impairs learning and memory in their offspring. Epigenetic mechanisms, particularly histone acetylation, are known to be involved in synaptic plasticity, learning, and memory. We hypothesize that the cognitive decline induced by SD during late pregnancy is associated with histone acetylation dysfunction, and this effect could be reversed by an enriched environment (EE). METHODS: In the present study, pregnant CD-1 mice were exposed to SD during the third trimester of pregnancy. After weaning, all offspring were randomly assigned to two subgroups in either a standard environment or an EE. When offspring were 3 months old, the Morris water maze was used to evaluate hippocampal-dependent learning and memory ability. Molecular biological techniques, including western blot and real-time fluorescence quantitative polymerase chain reaction, were used to examine the histone acetylation pathway and synaptic plasticity markers in the hippocampus of offspring. RESULTS: The results showed that the following were all reversed by EE treatment: maternal SD (MSD)-induced cognitive deficits including spatial learning and memory; histone acetylation dysfunction including increased histone deacetylase 2 (HDAC2) and decreased histone acetyltransferase (CBP), and the acetylation levels of H3K9 and H4K12; synaptic plasticity dysfunction including decreased brain-derived neurotrophic factor; and postsynaptic density protein-95. CONCLUSIONS: Our findings suggested that MSD could damage learning ability and memory in offspring via the histone acetylation pathway. This effect could be reversed by EE treatment.