首页 > 最新文献

European Neuropsychopharmacology最新文献

英文 中文
INTRODUCING MIND: THE METHYLATION, IMAGING AND NEURODEVELOPMENT CONSORTIUM 介绍心智:甲基化、成像和神经发育联盟
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.088
Epigenetic processes, such as DNA methylation (DNAm), show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of psychiatric and other brain-based phenotypes. However, we still know surprisingly little about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research is almost entirely comprised of cross-sectional studies in adults, with modest sample sizes (median N = 80) and a lack of replication.
To bridge this gap, we present here the new Methylation, Imaging and NeuroDevelopment (MIND) Consortium. MIND aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies.
MIND currently brings together 14 cohorts worldwide, comprising samples from North and South America, Europe, Africa and Australia, with (repeated) measures of DNAm in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging (MRI) across up to five time points across development (Npooled DNAm = 11,791; Npooled neuroimaging = 9,350; Npooled combined = 5,249). The MIND Consortium operates as an open network, welcoming researchers who have access to neuroimaging and epigenetic data (collected at 1+ time points before 18 years) to join.
In this talk, we introduce the consortium, presenting key characteristics of the samples and data types included. We discuss main considerations, challenges and opportunities in collaborative research on developmental neuroimaging epigenetics, including: (i) separating developmental from technical variability, (ii) modeling time-varying DNAm-brain associations in multi-cohort analyses, and (iii) addressing the dimensionality of neuroimaging epigenetic data. We conclude with key priorities for the consortium, current plans and future directions.
By triangulating associations across multiple developmental time points and study types, we aim to generate new insights about the dynamic relationship between peripheral DNA methylation and the brain, and to improve understanding of how these ultimately relate to neurodevelopmental and psychiatric phenotypes.
DNA甲基化(DNAm)等表观遗传过程显示出作为生物标记和基因-环境相互作用机制的潜力,可用于预测精神疾病和其他基于大脑的表型。然而,对于外周表观遗传模式与大脑本身的个体差异之间的关系,我们仍然知之甚少。要解决这个问题,一种越来越流行的方法是将表观遗传学和神经影像学数据结合起来;然而,目前的研究几乎都是针对成人的横断面研究,样本量不大(中位数 N = 80),而且缺乏复制。MIND 的目标是通过以下方式为新兴的神经影像表观遗传学领域带来发展重点:(i) 通过多队列分析促进合作性、有充分支持的发展研究;(ii) 通过建立共享管道和开放科学实践提高科学严谨性;(iii) 通过利用前瞻性、纵向儿科研究的数据,促进我们对不同发展时期(从出生到成年)DNA 甲基化-大脑动态的了解。MIND 目前汇集了全球 14 个队列,包括来自北美、南美、欧洲、非洲和澳大利亚的样本,通过磁共振成像(MRI)对外周组织(血液、口腔细胞和唾液)中的 DNAm 和神经影像进行(重复)测量,横跨发育过程中最多五个时间点(Npooled DNAm = 11,791; Npooled neuroimaging = 9,350; Npooled combined = 5,249)。MIND 联合会是一个开放的网络,欢迎能够获得神经影像学和表观遗传学数据(在 18 岁之前的 1 个以上时间点收集)的研究人员加入。我们将讨论发育神经影像表观遗传学合作研究的主要考虑因素、挑战和机遇,包括:(i) 将发育变异与技术变异分开,(ii) 在多队列分析中建立时变 DNAm 脑关联模型,(iii) 解决神经影像表观遗传学数据的维度问题。通过对多个发育时间点和研究类型之间的关联进行三角测量,我们旨在就外周 DNA 甲基化与大脑之间的动态关系提出新的见解,并进一步了解这些关联与神经发育和精神表型之间的最终关系。
{"title":"INTRODUCING MIND: THE METHYLATION, IMAGING AND NEURODEVELOPMENT CONSORTIUM","authors":"","doi":"10.1016/j.euroneuro.2024.08.088","DOIUrl":"10.1016/j.euroneuro.2024.08.088","url":null,"abstract":"<div><div>Epigenetic processes, such as DNA methylation (DNAm), show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of psychiatric and other brain-based phenotypes. However, we still know surprisingly little about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research is almost entirely comprised of cross-sectional studies in adults, with modest sample sizes (median N = 80) and a lack of replication.</div><div>To bridge this gap, we present here the new Methylation, Imaging and NeuroDevelopment (MIND) Consortium. MIND aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies.</div><div>MIND currently brings together 14 cohorts worldwide, comprising samples from North and South America, Europe, Africa and Australia, with (repeated) measures of DNAm in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging (MRI) across up to five time points across development (Npooled DNAm = 11,791; Npooled neuroimaging = 9,350; Npooled combined = 5,249). The MIND Consortium operates as an open network, welcoming researchers who have access to neuroimaging and epigenetic data (collected at 1+ time points before 18 years) to join.</div><div>In this talk, we introduce the consortium, presenting key characteristics of the samples and data types included. We discuss main considerations, challenges and opportunities in collaborative research on developmental neuroimaging epigenetics, including: (i) separating developmental from technical variability, (ii) modeling time-varying DNAm-brain associations in multi-cohort analyses, and (iii) addressing the dimensionality of neuroimaging epigenetic data. We conclude with key priorities for the consortium, current plans and future directions.</div><div>By triangulating associations across multiple developmental time points and study types, we aim to generate new insights about the dynamic relationship between peripheral DNA methylation and the brain, and to improve understanding of how these ultimately relate to neurodevelopmental and psychiatric phenotypes.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
STANDARDIZE QC PROCEDURE FOR SCRNA-SEQ 规范 SCNA SEQ 的 QC 程序
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.025
Single-cell RNA sequencing (scRNA-seq) has emerged as a pivotal technology for dissecting cellular heterogeneity and function. In an effort to assess the consistency and rigor of quality control (QC) measures across scRNA-seq studies, we systematically reviewed publications from high-impact journals, including Cell, Nature, Science, and their major sister journals. Our analysis revealed a lack of standardization in QC procedures, with significant variability in the parameters employed. Despite general agreement on the necessity of certain QC steps, such as the removal of low-quality cells and the detection of doublets, the specific criteria for these steps were often arbitrarily defined and not universally applied. Notably, the assessment of ambient RNA contamination and the precision of gene expression measurements were frequently overlooked, potentially leading to the inclusion of spurious data in downstream analyses. To address these inconsistencies, we propose a revised set of QC procedures and parameters, which yielded distinct results compared to the original publications when applied to existing datasets. Moreover, we also assessed the performance of the existing data-driven QC tools in distinguishing the low-quality cells from the high-quality cells. Our findings underscore the urgent need for a standardized approach to QC in scRNA-seq to ensure the reliability and reproducibility of biological insights derived from this powerful technology.
单细胞 RNA 测序(scRNA-seq)已成为剖析细胞异质性和功能的关键技术。为了评估scRNA-seq研究中质量控制(QC)措施的一致性和严谨性,我们系统地查阅了《细胞》、《自然》、《科学》等高影响力期刊及其主要姊妹期刊上发表的论文。我们的分析表明,质控程序缺乏标准化,所采用的参数差异很大。尽管大家普遍认为某些质控步骤是必要的,如去除低质量细胞和检测双顶体,但这些步骤的具体标准往往是随意定义的,并没有得到普遍应用。值得注意的是,对环境 RNA 污染和基因表达测量精度的评估经常被忽视,这可能导致下游分析中包含虚假数据。为了解决这些不一致的问题,我们提出了一套经过修订的质量控制程序和参数,在应用于现有数据集时,其结果与原始出版物的结果截然不同。此外,我们还评估了现有数据驱动质控工具在区分低质量细胞和高质量细胞方面的性能。我们的研究结果突出表明,迫切需要一种标准化的方法来对 scRNA-seq 进行质量控制,以确保从这项强大的技术中获得的生物学见解的可靠性和可重复性。
{"title":"STANDARDIZE QC PROCEDURE FOR SCRNA-SEQ","authors":"","doi":"10.1016/j.euroneuro.2024.08.025","DOIUrl":"10.1016/j.euroneuro.2024.08.025","url":null,"abstract":"<div><div>Single-cell RNA sequencing (scRNA-seq) has emerged as a pivotal technology for dissecting cellular heterogeneity and function. In an effort to assess the consistency and rigor of quality control (QC) measures across scRNA-seq studies, we systematically reviewed publications from high-impact journals, including Cell, Nature, Science, and their major sister journals. Our analysis revealed a lack of standardization in QC procedures, with significant variability in the parameters employed. Despite general agreement on the necessity of certain QC steps, such as the removal of low-quality cells and the detection of doublets, the specific criteria for these steps were often arbitrarily defined and not universally applied. Notably, the assessment of ambient RNA contamination and the precision of gene expression measurements were frequently overlooked, potentially leading to the inclusion of spurious data in downstream analyses. To address these inconsistencies, we propose a revised set of QC procedures and parameters, which yielded distinct results compared to the original publications when applied to existing datasets. Moreover, we also assessed the performance of the existing data-driven QC tools in distinguishing the low-quality cells from the high-quality cells. Our findings underscore the urgent need for a standardized approach to QC in scRNA-seq to ensure the reliability and reproducibility of biological insights derived from this powerful technology.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PROGRESS UPDATE FROM THE PGC PEDIGREE SEQUENCING WORKING GROUP: RESULTS AND NOVEL METHODOLOGIES PGC 血统测序工作组的最新进展:成果和新方法
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.081
<div><div><strong>Background:</strong> Examining rare variants in multiplex pedigrees offers a complementary approach to the case-control study design to identify genes robustly associated with psychiatric disorders. Affected individuals within a pedigree are likely influenced by the same rare variant(s), which can simplify the disease-gene discovery process. Also, pedigrees are less sensitive to confounding from population stratification or environmental effects compared to unrelated cohorts. The goal of the Pedigree Sequencing Working Group of the Psychiatric Genomics Consortium (PGC) is to evaluate the contribution of rare variants from whole genome sequencing (WGS) in densely affected pedigrees. To date, we have collated WGS data from 310 individuals in 50 pedigrees across a range of psychiatric diagnoses. Here we give a progress update of the working group as well as describing novel methodologies developed for analysing pedigree-based WGS data.</div><div><strong>Methods:</strong> As an example of the above, we evaluated WGS data from 61 samples across ten pedigrees recruited from Utah multiply affected with schizophrenia or bipolar disorder. For single nucleotide variants (SNVs) and indels, we applied a simple filtering approach to identify plausible causal variants within each pedigree. We prioritised variants with a full co-segregation pattern (carried by all affected samples in-family and absent from unaffected and marry-in samples) or a reduced co-segregation pattern (carried by all but one affected sample in-family and absent from unaffected and marry-in samples). In addition, we applied an in-house Bayesian methodology known as BICEP to further identify variants of interest that would have been lost to the strict filtering. For copy number variants (CNVs), we applied our pedigree-aware consensus framework known as PECAN to call variants from the WGS data. We then applied a simple filtering prioritisation as before.</div><div><strong>Results:</strong> For the SNV/indel analysis, our filtering approach identified an ultra-rare, deleterious variant in ATP2B2 that had a reduced co-segregation pattern with schizophrenia. Recently, this gene was reported as significantly associated with bipolar disorder from a large case-control analysis of ultra-rare variants. Additionally, BICEP identified an ultra-rare variant in TTBK1 that perfectly co-segregated with schizophrenia. De novo pathogenic variants in this gene have been reported for childhood-onset schizophrenia. Finally, PECAN identified a rare, exonic deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults.</div><div><strong>Discussion:</strong> Our results highlight how pedigree-based analyses can provide a useful orthogonal approach to case-control strategies in identifying plausible risk genes for r
背景:研究多倍系谱中的罕见变异为病例对照研究设计提供了一种补充方法,以确定与精神疾病密切相关的基因。一个谱系中受影响的个体很可能受到相同罕见变异的影响,这可以简化疾病基因的发现过程。此外,与无血缘关系的队列相比,血缘关系对人群分层或环境影响的混杂敏感性较低。精神疾病基因组学联盟(PGC)的谱系测序工作组的目标是评估全基因组测序(WGS)对密集患病谱系中罕见变异的贡献。迄今为止,我们已经整理了 50 个血统中 310 个个体的 WGS 数据,涉及一系列精神病诊断。在此,我们将介绍工作组的最新进展,并介绍为分析基于谱系的 WGS 数据而开发的新方法:作为上述研究的一个实例,我们评估了从犹他州多发性精神分裂症或躁郁症患者中招募的 10 个血统中 61 个样本的 WGS 数据。对于单核苷酸变异(SNV)和嵌合变异,我们采用了一种简单的筛选方法,以确定每个血统中可信的因果变异。我们优先考虑具有完全共分离模式(家族中所有受影响样本均携带,而未受影响样本和婚配样本不携带)或降低共分离模式(除一个受影响样本外,家族中所有受影响样本均携带,而未受影响样本和婚配样本不携带)的变异。此外,我们还应用了一种称为 BICEP 的内部贝叶斯方法,以进一步确定在严格筛选过程中会丢失的感兴趣变异。对于拷贝数变异(CNV),我们采用了名为 PECAN 的血统感知共识框架,从 WGS 数据中调用变异。然后,我们像以前一样进行了简单的优先筛选:在SNV/indel分析中,我们的筛选方法在ATP2B2中发现了一个超罕见的有害变异,该变异与精神分裂症的共分离模式降低。最近,在一项对超罕见变异进行的大型病例对照分析中,发现该基因与双相情感障碍有显著相关性。此外,BICEP 还在 TTBK1 中发现了一个与精神分裂症完全共分离的超罕见变异。据报道,该基因中的新致病变体可导致儿童期精神分裂症。最后,PECAN 发现了一个罕见的外显子缺失,在其中一个血统中与精神分裂症完全共分离。该 CNV 与 PITRM1 重叠,而 PITRM1 与一种复杂的表型有关,包括共济失调、发育迟缓和受影响成人的精神分裂症样发作:我们的研究结果突显了在确定罕见变异的可信风险基因时,基于血统的分析如何为病例对照策略提供了一种有用的正交方法。事实上,一些导致表型风险的超罕见变异可能只有通过研究富含精神疾病诊断的多重谱系才能得到很好的描述。此外,我们还证明了其他优先排序策略(如贝叶斯方法)有助于发现严格筛选分析所忽略的其他风险变异。
{"title":"PROGRESS UPDATE FROM THE PGC PEDIGREE SEQUENCING WORKING GROUP: RESULTS AND NOVEL METHODOLOGIES","authors":"","doi":"10.1016/j.euroneuro.2024.08.081","DOIUrl":"10.1016/j.euroneuro.2024.08.081","url":null,"abstract":"&lt;div&gt;&lt;div&gt;&lt;strong&gt;Background:&lt;/strong&gt; Examining rare variants in multiplex pedigrees offers a complementary approach to the case-control study design to identify genes robustly associated with psychiatric disorders. Affected individuals within a pedigree are likely influenced by the same rare variant(s), which can simplify the disease-gene discovery process. Also, pedigrees are less sensitive to confounding from population stratification or environmental effects compared to unrelated cohorts. The goal of the Pedigree Sequencing Working Group of the Psychiatric Genomics Consortium (PGC) is to evaluate the contribution of rare variants from whole genome sequencing (WGS) in densely affected pedigrees. To date, we have collated WGS data from 310 individuals in 50 pedigrees across a range of psychiatric diagnoses. Here we give a progress update of the working group as well as describing novel methodologies developed for analysing pedigree-based WGS data.&lt;/div&gt;&lt;div&gt;&lt;strong&gt;Methods:&lt;/strong&gt; As an example of the above, we evaluated WGS data from 61 samples across ten pedigrees recruited from Utah multiply affected with schizophrenia or bipolar disorder. For single nucleotide variants (SNVs) and indels, we applied a simple filtering approach to identify plausible causal variants within each pedigree. We prioritised variants with a full co-segregation pattern (carried by all affected samples in-family and absent from unaffected and marry-in samples) or a reduced co-segregation pattern (carried by all but one affected sample in-family and absent from unaffected and marry-in samples). In addition, we applied an in-house Bayesian methodology known as BICEP to further identify variants of interest that would have been lost to the strict filtering. For copy number variants (CNVs), we applied our pedigree-aware consensus framework known as PECAN to call variants from the WGS data. We then applied a simple filtering prioritisation as before.&lt;/div&gt;&lt;div&gt;&lt;strong&gt;Results:&lt;/strong&gt; For the SNV/indel analysis, our filtering approach identified an ultra-rare, deleterious variant in ATP2B2 that had a reduced co-segregation pattern with schizophrenia. Recently, this gene was reported as significantly associated with bipolar disorder from a large case-control analysis of ultra-rare variants. Additionally, BICEP identified an ultra-rare variant in TTBK1 that perfectly co-segregated with schizophrenia. De novo pathogenic variants in this gene have been reported for childhood-onset schizophrenia. Finally, PECAN identified a rare, exonic deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults.&lt;/div&gt;&lt;div&gt;&lt;strong&gt;Discussion:&lt;/strong&gt; Our results highlight how pedigree-based analyses can provide a useful orthogonal approach to case-control strategies in identifying plausible risk genes for r","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HARNESSING GENOMIC DATA FOR PRECISION MEDICINE IN ALZHEIMER'S DISEASE: CHALLENGES AND OPPORTUNITIES 利用基因组数据对阿尔茨海默病进行精准医疗:挑战与机遇
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.055
{"title":"HARNESSING GENOMIC DATA FOR PRECISION MEDICINE IN ALZHEIMER'S DISEASE: CHALLENGES AND OPPORTUNITIES","authors":"","doi":"10.1016/j.euroneuro.2024.08.055","DOIUrl":"10.1016/j.euroneuro.2024.08.055","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PREDICTION OF ANTIDEPRESSANT SIDE EFFECTS IN THE GENETIC LINK TO ANXIETY AND DEPRESSION STUDY 焦虑和抑郁遗传关联研究中抗抑郁药副作用的预测
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.065
Antidepressants are the most common treatment for moderate or severe depression. Side effects are crucial indicators for antidepressants, but their expression varies widely among individuals.
In this study, we leveraged genetic and phenotypic data from self-reported questionnaires in the Genetic Link to Anxiety and Depression (GLAD) study to predict side effects and discontinuation (due to side effect) across three antidepressant classes (SSRI, SNRI, tricyclic antidepressants (TCA)) at the first and the last (most recent) year of prescription. About 260 predictors spanning genetic, clinical, comorbidity, demographic, and antidepressant information were included. XGBoost, random forest, cubist, elastic net, and support vector machine (with RBF and polynomial kernel) were trained, and their performance was compared.
The final dataset comprised 5358 individuals, with 4354 in the first and 3414 in the last year of prescription. The average prevalence of side effects and discontinuation was 74.1% and 28.7%, respectively. In the initial year, the best AUROC for predicting SSRI discontinuation and side effects were 0.65 and 0.60. In the last year of SSRI prescription, the highest AUROC reached 0.73 for discontinuation and 0.87 for side effects. Models for predicting discontinuation and side effects of SNRI and TCA showed comparable performance. The history of side effects and discontinuation of antidepressant use were the most influential predictors of the outcomes in the last year. When examining 30 common antidepressant side effect symptoms, most of them were differentially prevalent between antidepressant classes.
Our findings demonstrate the feasibility of predicting antidepressant side effects using a self-reported questionnaire, particularly for the last prescription. These results contribute valuable insights for the development of clinical decisions aimed at optimising treatment selection with enhanced tolerability.
抗抑郁药是治疗中度或重度抑郁症最常用的药物。在这项研究中,我们利用焦虑和抑郁的遗传联系(GLAD)研究中自我报告问卷中的遗传和表型数据,预测了三种抗抑郁药(SSRI、SNRI、三环类抗抑郁药(TCA))在处方第一年和最后一年(最近一年)的副作用和停药(由于副作用)情况。该研究纳入了约 260 个预测因子,涵盖遗传、临床、合并症、人口统计学和抗抑郁药信息。对 XGBoost、随机森林、立方体、弹性网和支持向量机(RBF 和多项式核)进行了训练,并比较了它们的性能。副作用和停药的平均发生率分别为 74.1%和 28.7%。在第一年,预测 SSRI 停药和副作用的最佳 AUROC 分别为 0.65 和 0.60。在处方 SSRI 的最后一年,预测停药和副作用的最高 AUROC 分别为 0.73 和 0.87。预测 SNRI 和 TCA 的停药和副作用的模型表现相当。有副作用史和停用抗抑郁药是对去年治疗结果影响最大的预测因素。我们的研究结果表明,使用自我报告问卷预测抗抑郁药副作用是可行的,尤其是对最近一次处方的副作用。这些结果为临床决策的制定提供了有价值的见解,旨在优化治疗选择,提高耐受性。
{"title":"PREDICTION OF ANTIDEPRESSANT SIDE EFFECTS IN THE GENETIC LINK TO ANXIETY AND DEPRESSION STUDY","authors":"","doi":"10.1016/j.euroneuro.2024.08.065","DOIUrl":"10.1016/j.euroneuro.2024.08.065","url":null,"abstract":"<div><div>Antidepressants are the most common treatment for moderate or severe depression. Side effects are crucial indicators for antidepressants, but their expression varies widely among individuals.</div><div>In this study, we leveraged genetic and phenotypic data from self-reported questionnaires in the Genetic Link to Anxiety and Depression (GLAD) study to predict side effects and discontinuation (due to side effect) across three antidepressant classes (SSRI, SNRI, tricyclic antidepressants (TCA)) at the first and the last (most recent) year of prescription. About 260 predictors spanning genetic, clinical, comorbidity, demographic, and antidepressant information were included. XGBoost, random forest, cubist, elastic net, and support vector machine (with RBF and polynomial kernel) were trained, and their performance was compared.</div><div>The final dataset comprised 5358 individuals, with 4354 in the first and 3414 in the last year of prescription. The average prevalence of side effects and discontinuation was 74.1% and 28.7%, respectively. In the initial year, the best AUROC for predicting SSRI discontinuation and side effects were 0.65 and 0.60. In the last year of SSRI prescription, the highest AUROC reached 0.73 for discontinuation and 0.87 for side effects. Models for predicting discontinuation and side effects of SNRI and TCA showed comparable performance. The history of side effects and discontinuation of antidepressant use were the most influential predictors of the outcomes in the last year. When examining 30 common antidepressant side effect symptoms, most of them were differentially prevalent between antidepressant classes.</div><div>Our findings demonstrate the feasibility of predicting antidepressant side effects using a self-reported questionnaire, particularly for the last prescription. These results contribute valuable insights for the development of clinical decisions aimed at optimising treatment selection with enhanced tolerability.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
META-ANALYSIS OF RARE CNV GENOME-WIDE ASSOCIATION STUDIES ACROSS MAJOR PSYCHIATRIC DISORDERS IN EUR, AFR/AFAM, AND ASN/ASAM POPULATIONS 对欧洲、非洲/非洲医学会和亚洲医学会/亚洲医学会人群中主要精神疾病的罕见 CNV 全基因组关联研究的荟萃分析
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.070
Genome-wide association studies (GWAS) to date have been able to leverage large sample sizes to identify genomic loci that contribute to risk for various psychiatric disorders. However, GWAS of copy number variants (CNVs) have prioritized identifying risk loci within European populations due to the lack of power in diverse ancestry groups. In this study, we called CNVs in a diverse group of samples to create CNV datasets for 2 additional ancestry groups: African/African American (AFR/AFAM) and Asian/Asian American (ASN/ASAM). SNPweights was used to infer genome-wide genetic ancestry for each sample. We were then able to boost power at specific loci by using a meta-analysis to combine EUR, AFR/AFAM, and ASN/ASAM CNV analyses (N=571,803).
Rare copy number variants have been implicated in a cross-disorder European cohort (N=537,466) that includes major psychiatric disorders such as autism (ASD), schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD). This analysis was able to identify novel loci with the statistical power that comes with being the largest CNV study to date. Naturally, the inclusion of diverse samples in this analysis can further lead to novel discoveries. Additional CNV-GWAS were performed for cross-disorder datasets in AFR/AFAM (N=17,474) and ASN/ASAM (N=16,863) populations. Meta-analysis of all 3 populations used an inverse-variance weighting to account for the disparity of sample size between populations. We compared EUR CNV-GWAS and burden results with those from the meta-analysis as these were the most well-powered tests. The effect was a substantial increase in significance levels at specific loci that reached testable CNV frequencies in the diverse groups. Comparing the EUR analysis with the trans-ancestry analysis allows us to quantify the contribution of the diverse groups and provide insight into the genomic loci associated with psychiatric disorders in AFR/AFAM and ASN/ASAM populations once similar sample sizes are reached. This study highlights the importance of expanding diversity during data collection so that the genotype-phenotype relationships can benefit people worldwide.
迄今为止,全基因组关联研究(GWAS)能够利用大样本量来确定导致各种精神疾病风险的基因组位点。然而,拷贝数变异(CNVs)的全基因组关联研究由于缺乏对不同祖先群体的研究,一直优先考虑确定欧洲人群中的风险位点。在这项研究中,我们调用了一组不同样本中的 CNVs,为另外两个祖先群体创建了 CNV 数据集:非洲/非裔美国人(AFR/AFAM)和亚洲/亚裔美国人(ASN/ASAM)。SNPweights 用于推断每个样本的全基因组遗传祖先。然后,我们利用荟萃分析将欧洲人、非洲裔美国人/非洲裔美国人和亚裔美国人/亚裔美国人的 CNV 分析结合起来(N=571,803),从而提高了特定位点的分析能力。罕见拷贝数变异已牵涉到一个跨障碍的欧洲队列(N=537,466),其中包括自闭症(ASD)、精神分裂症(SCZ)、重度抑郁障碍(MDD)、双相情感障碍(BD)、创伤后应激障碍(PTSD)和注意力缺陷/多动障碍(ADHD)等主要精神障碍。这项分析能够发现新的基因座,其统计能力是迄今为止最大的 CNV 研究所具备的。当然,将不同的样本纳入这项分析还能进一步带来新的发现。我们还对AFR/AFAM(样本数=17,474)和ASN/ASAM(样本数=16,863)人群的交叉紊乱数据集进行了CNV-GWAS分析。对所有 3 个人群的 Meta 分析都采用了反方差加权法,以考虑不同人群样本量的差异。我们将 EUR CNV-GWAS 和负担结果与荟萃分析的结果进行了比较,因为这些是最有效的检测方法。结果显示,在不同群体中,达到可检测 CNV 频率的特定位点的显著性水平大幅提高。将EUR分析与跨种群分析进行比较,可以量化不同群体的贡献,并在样本量达到类似规模后,深入了解与AFR/AFAM和ASN/ASAM人群精神障碍相关的基因组位点。这项研究强调了在数据收集过程中扩大多样性的重要性,从而使基因型与表型之间的关系造福于全世界的人们。
{"title":"META-ANALYSIS OF RARE CNV GENOME-WIDE ASSOCIATION STUDIES ACROSS MAJOR PSYCHIATRIC DISORDERS IN EUR, AFR/AFAM, AND ASN/ASAM POPULATIONS","authors":"","doi":"10.1016/j.euroneuro.2024.08.070","DOIUrl":"10.1016/j.euroneuro.2024.08.070","url":null,"abstract":"<div><div>Genome-wide association studies (GWAS) to date have been able to leverage large sample sizes to identify genomic loci that contribute to risk for various psychiatric disorders. However, GWAS of copy number variants (CNVs) have prioritized identifying risk loci within European populations due to the lack of power in diverse ancestry groups. In this study, we called CNVs in a diverse group of samples to create CNV datasets for 2 additional ancestry groups: African/African American (AFR/AFAM) and Asian/Asian American (ASN/ASAM). SNPweights was used to infer genome-wide genetic ancestry for each sample. We were then able to boost power at specific loci by using a meta-analysis to combine EUR, AFR/AFAM, and ASN/ASAM CNV analyses (N=571,803).</div><div>Rare copy number variants have been implicated in a cross-disorder European cohort (N=537,466) that includes major psychiatric disorders such as autism (ASD), schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD). This analysis was able to identify novel loci with the statistical power that comes with being the largest CNV study to date. Naturally, the inclusion of diverse samples in this analysis can further lead to novel discoveries. Additional CNV-GWAS were performed for cross-disorder datasets in AFR/AFAM (N=17,474) and ASN/ASAM (N=16,863) populations. Meta-analysis of all 3 populations used an inverse-variance weighting to account for the disparity of sample size between populations. We compared EUR CNV-GWAS and burden results with those from the meta-analysis as these were the most well-powered tests. The effect was a substantial increase in significance levels at specific loci that reached testable CNV frequencies in the diverse groups. Comparing the EUR analysis with the trans-ancestry analysis allows us to quantify the contribution of the diverse groups and provide insight into the genomic loci associated with psychiatric disorders in AFR/AFAM and ASN/ASAM populations once similar sample sizes are reached. This study highlights the importance of expanding diversity during data collection so that the genotype-phenotype relationships can benefit people worldwide.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
THE IDENTICAL DEPRESSION PHENOTYPING CONSORTIUM: DECONSTRUCTION AND PREDICTION OF MDD AND TREATMENT RESPONSE 相同抑郁表型联盟:解构和预测 MDD 及治疗反应
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.063
The Identical Depression Phenotyping Consortium consists of studies in the UK (Genetic Links to Anxiety and Depression or GLAD and UK Biobank), the Australian Genetics of Depression study, and the Biobanks Netherlands Internet Collaboration (BIONIC). The three studies are using the same method of phenotyping depression with detailed demographics, clinical record linkage, and data on over 130,000 cases of Major Depressive Disorder. We propose a symposium focused on advancing predictive models in MDD and its treatment, emphasizing the integration of polygenic scores, family history, and clinical data.
Wang will present on Joint Multi-Family History and Multi-Polygenic Score Prediction of Major Depressive Disorder. Machine learning integrating these factors in GLAD (9,927 MDD cases, 4,452 controls) revealed significant prediction accuracies for MDD, the number of recurrent MDD episodes. These findings were replicated in UK Biobank (40,667 MDD cases, 70,755 controls). Next, Li will present on incorporating genetic and clinical predictors for antidepressant side effects in > 5K cases from the GLAD study. By employing machine learning models, they achieved significant success in predicting side effects and discontinuation rates, particularly when integrating data from prior prescriptions. Huider will present on genetic analyses of MDD on behalf of the BIONIC consortium presents a large-scale genetic analyses of MDD and its symptoms to explore depression heterogeneity within the Netherlands, utilizing uniform in-depth phenotyping in > 30K cases. This ambitious project highlights the importance of large, homogeneous datasets in deciphering the complex genetics of depression. Finally, Mitchell will present on Using polygenic risk scores to characterise treatment resistant MDD in to explore the association of TRD with biological predictors such a polygenic score (PGS) and CYP2C19 and CYP2D16 metaboliser profiles, measured personality traits, and environmental predictors such as social support and exposure to stressful life events. Lastly, they tested for any gene-environment interactions across predictors. Their research identifies genetic factors that correlate with long-term treatment outcomes, providing a basis for personalized medicine in treating depression.
This symposium aims to showcase cutting-edge research that integrates genetic, familial, and clinical data to predict and manage major depressive disorder more effectively. Discussant Hatoum will consider the implications of integration of genetic prediction with machine learning approaches and the possibilities for clinical utility.
同种抑郁症表型研究联盟由英国的研究(焦虑和抑郁的遗传链接或 GLAD 和英国生物库)、澳大利亚抑郁症遗传学研究和荷兰生物库互联网合作(BIONIC)组成。这三项研究采用相同的方法对抑郁症进行表型分析,包括详细的人口统计学数据、临床记录链接以及超过 13 万例重度抑郁症病例的数据。我们提议召开一次专题讨论会,重点讨论 MDD 及其治疗的预测模型,强调多基因评分、家族史和临床数据的整合。在GLAD(9927例MDD病例,4452例对照)中整合了这些因素的机器学习显示,对MDD、MDD反复发作次数的预测准确率很高。这些发现在英国生物库(40667 例 MDD 病例,70755 例对照)中得到了验证。接下来,Li 将介绍在 GLAD 研究的 5K 个病例中纳入抗抑郁药物副作用的遗传和临床预测因素。通过采用机器学习模型,他们在预测副作用和停药率方面取得了巨大成功,尤其是在整合先前处方数据时。Huider将代表BIONIC联盟介绍MDD的遗传分析,该联盟利用对> 3万个病例的统一深入表型,对MDD及其症状进行了大规模遗传分析,以探索荷兰国内抑郁症的异质性。这一雄心勃勃的项目凸显了大型同质数据集在解读抑郁症复杂遗传学方面的重要性。最后,米切尔将发表题为 "使用多基因风险评分来描述耐药性MDD "的报告,探讨TRD与生物预测因素(如多基因评分(PGS)、CYP2C19和CYP2D16代谢物特征)、人格特征测量结果以及环境预测因素(如社会支持和生活压力事件)之间的关系。最后,他们测试了各种预测因素之间的基因与环境之间的相互作用。他们的研究确定了与长期治疗效果相关的遗传因素,为治疗抑郁症的个性化医疗提供了基础。本次研讨会旨在展示整合遗传、家族和临床数据的前沿研究,以便更有效地预测和管理重度抑郁障碍。讨论者 Hatoum 将探讨基因预测与机器学习方法相结合的意义以及临床应用的可能性。
{"title":"THE IDENTICAL DEPRESSION PHENOTYPING CONSORTIUM: DECONSTRUCTION AND PREDICTION OF MDD AND TREATMENT RESPONSE","authors":"","doi":"10.1016/j.euroneuro.2024.08.063","DOIUrl":"10.1016/j.euroneuro.2024.08.063","url":null,"abstract":"<div><div>The Identical Depression Phenotyping Consortium consists of studies in the UK (Genetic Links to Anxiety and Depression or GLAD and UK Biobank), the Australian Genetics of Depression study, and the Biobanks Netherlands Internet Collaboration (BIONIC). The three studies are using the same method of phenotyping depression with detailed demographics, clinical record linkage, and data on over 130,000 cases of Major Depressive Disorder. We propose a symposium focused on advancing predictive models in MDD and its treatment, emphasizing the integration of polygenic scores, family history, and clinical data.</div><div>Wang will present on Joint Multi-Family History and Multi-Polygenic Score Prediction of Major Depressive Disorder. Machine learning integrating these factors in GLAD (9,927 MDD cases, 4,452 controls) revealed significant prediction accuracies for MDD, the number of recurrent MDD episodes. These findings were replicated in UK Biobank (40,667 MDD cases, 70,755 controls). Next, Li will present on incorporating genetic and clinical predictors for antidepressant side effects in &gt; 5K cases from the GLAD study. By employing machine learning models, they achieved significant success in predicting side effects and discontinuation rates, particularly when integrating data from prior prescriptions. Huider will present on genetic analyses of MDD on behalf of the BIONIC consortium presents a large-scale genetic analyses of MDD and its symptoms to explore depression heterogeneity within the Netherlands, utilizing uniform in-depth phenotyping in &gt; 30K cases. This ambitious project highlights the importance of large, homogeneous datasets in deciphering the complex genetics of depression. Finally, Mitchell will present on Using polygenic risk scores to characterise treatment resistant MDD in to explore the association of TRD with biological predictors such a polygenic score (PGS) and CYP2C19 and CYP2D16 metaboliser profiles, measured personality traits, and environmental predictors such as social support and exposure to stressful life events. Lastly, they tested for any gene-environment interactions across predictors. Their research identifies genetic factors that correlate with long-term treatment outcomes, providing a basis for personalized medicine in treating depression.</div><div>This symposium aims to showcase cutting-edge research that integrates genetic, familial, and clinical data to predict and manage major depressive disorder more effectively. Discussant Hatoum will consider the implications of integration of genetic prediction with machine learning approaches and the possibilities for clinical utility.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
THE ALLELIC ARCHITECTURE OF RARE VARIATION IN AUTISM AND OTHER NEURODEVELOPMENTAL CONDITIONS 自闭症和其他神经发育疾病中罕见变异的等位基因结构
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.046
<div><div>The fields of autism and neurodevelopmental disorder (NDD) genetics are rapidly advancing. Catalyzed by the power of large cohorts and integration of all classes of de novo and inherited protein-coding variation, dozens of genes have emerged to harbor variants that confer high relative risk for autism, and hundreds of genes have been associated with NDDs more broadly. Through examination of protein-truncating variants (PTVs), predicted damaging missense variation, and copy number variants (CNVs), our prior analyses have begun to map the allelic diversity of perturbations within 72 autism-associated genes and 373 genes associated with NDDs, finding intriguing evidence of genes with significantly higher mutation rates and differences in the distribution of clinical phenotypes in autism compared to NDD (Fu et al., 2022; Satterstrom et al., 2020). Despite this progress, cohort sizes remain insufficient for disentangling the shared and distinct genetic architectures of autism, NDDs, and other neuropsychiatric conditions, as well as associating genes with more subtle impacts on neurodevelopment.</div><div>To advance these boundaries, we present the largest to-date study of rare coding variants, consisting of 62,013 autistic individuals, including 38,088 probands and 9,567 unaffected siblings from complete trio and quartet families, respectively, and 23,925 additional autism cases without parental information contrasted against 26,931 controls. By aggregating across the Autism Sequencing Consortium (ASC), the Simons Simplex Collection (SSC), the Simons Foundation Powering Autism Research (SPARK), and individuals from a leading diagnostic laboratory (GeneDx), this dataset totals almost 200,000 individuals, nearly a three-fold increase over prior studies. When we stratified the clinically-referred GeneDx autistic probands by co-occurring DD/ID status, we found synonymous, missense, and PTV de novo mutation rates in autism probands without DD/ID from GeneDx that were nearly identical to individuals ascertained for a diagnosis of autism in the ASC, SSC, and SPARK research studies (0.296 vs 0.294, 0.767 vs 0.763, and 0.141 vs 0.145 respectively), while GeneDx autism probands with DD/ID exhibited mutation rates similar to those observed in previous research studies of DD.</div><div>Further analyses of these data solidified previous observations of significant enrichment of de novo PTVs among autism probands of 3x compared to siblings among the genes most intolerant to PTVs in the human genome (i.e., lowest decile of LOEUF from gnomAD). We have also incorporated Alpha Missense (AM) pathogenicity estimates to complement our prior MPC scores for predicting damaging missense variation and identifying de novo missense variants acting with effect sizes comparable to de novo PTVs in constrained genes, with analysis of regional missense constraint within genes ongoing. We further leveraged the TADA Bayesian statistical method to jointly model these data in
自闭症和神经发育障碍(NDD)遗传学领域发展迅速。在大型队列和整合各类新发和遗传蛋白编码变异的推动下,数十个基因中出现了可导致自闭症高相对风险的变异,数百个基因与更广泛的 NDD 相关。通过研究蛋白质截断变异(PTVs)、预测的破坏性错义变异和拷贝数变异(CNVs),我们之前的分析已开始绘制 72 个自闭症相关基因和 373 个 NDDs 相关基因中扰乱的等位基因多样性图谱,发现了基因突变率显著高于 NDD 的有趣证据,以及自闭症与 NDD 相比临床表型分布的差异(Fu 等人,2022 年;Satterstrom 等人,2020 年)。尽管取得了这些进展,但队列规模仍然不足以区分自闭症、NDD 和其他神经精神疾病的共同和不同遗传结构,也不足以将对神经发育有更微妙影响的基因联系起来。为了推进这些研究,我们展示了迄今为止最大规模的罕见编码变异研究,研究对象包括 62,013 名自闭症患者,其中包括 38,088 名原发性患者和 9,567 名未受影响的兄弟姐妹,他们分别来自完整的三人家庭和四人家庭,另外还有 23,925 名没有父母信息的自闭症病例与 26,931 名对照组患者。通过汇总自闭症测序联盟(ASC)、Simons Simplex Collection (SSC)、Simons Foundation Powering Autism Research (SPARK)以及一家领先的诊断实验室(GeneDx)的数据,该数据集的总人数接近 20 万,比之前的研究增加了近三倍。当我们将临床转介的GeneDx自闭症受试者按并发DD/ID状态进行分层时,我们发现GeneDx中无DD/ID的自闭症受试者的同义突变率、错义突变率和PTV从头突变率几乎与ASC、SSC和SPARK研究中确诊为自闭症的个体相同(分别为0.296 vs 0.294、0.767 vs 0.763和0.141 vs 0.145)。对这些数据的进一步分析证实了之前的观察结果,即在人类基因组中最不耐受PTVs的基因中(即:LOEUF的最低十分位数),3倍于同胞的自闭症疑似患者的从头PTVs显著富集、即 gnomAD 中 LOEUF 最低十分位数)。我们还纳入了阿尔法错义(AM)致病性估计,以补充我们先前的 MPC 评分,从而预测破坏性错义变异,并识别在受限基因中作用效应大小与新生 PTV 相当的新生错义变异,目前正在对基因内的区域错义受限进行分析。我们进一步利用 TADA 贝叶斯统计方法,在一个统一的框架内对这些数据进行联合建模,充分利用罕见 PTV、损伤性错义变异和 CNV 的遗传信息。这种方法发现了数百个与自闭症相关的基因,我们观察到,在新的相关基因中,除全新 PTV 外,其他变异类别的贡献率正在稳步上升。我们正在进行分析,以了解这些基因对自闭症和相关神经精神疾病的表型表现产生影响的基因网络、发育时间和生物功能。
{"title":"THE ALLELIC ARCHITECTURE OF RARE VARIATION IN AUTISM AND OTHER NEURODEVELOPMENTAL CONDITIONS","authors":"","doi":"10.1016/j.euroneuro.2024.08.046","DOIUrl":"10.1016/j.euroneuro.2024.08.046","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The fields of autism and neurodevelopmental disorder (NDD) genetics are rapidly advancing. Catalyzed by the power of large cohorts and integration of all classes of de novo and inherited protein-coding variation, dozens of genes have emerged to harbor variants that confer high relative risk for autism, and hundreds of genes have been associated with NDDs more broadly. Through examination of protein-truncating variants (PTVs), predicted damaging missense variation, and copy number variants (CNVs), our prior analyses have begun to map the allelic diversity of perturbations within 72 autism-associated genes and 373 genes associated with NDDs, finding intriguing evidence of genes with significantly higher mutation rates and differences in the distribution of clinical phenotypes in autism compared to NDD (Fu et al., 2022; Satterstrom et al., 2020). Despite this progress, cohort sizes remain insufficient for disentangling the shared and distinct genetic architectures of autism, NDDs, and other neuropsychiatric conditions, as well as associating genes with more subtle impacts on neurodevelopment.&lt;/div&gt;&lt;div&gt;To advance these boundaries, we present the largest to-date study of rare coding variants, consisting of 62,013 autistic individuals, including 38,088 probands and 9,567 unaffected siblings from complete trio and quartet families, respectively, and 23,925 additional autism cases without parental information contrasted against 26,931 controls. By aggregating across the Autism Sequencing Consortium (ASC), the Simons Simplex Collection (SSC), the Simons Foundation Powering Autism Research (SPARK), and individuals from a leading diagnostic laboratory (GeneDx), this dataset totals almost 200,000 individuals, nearly a three-fold increase over prior studies. When we stratified the clinically-referred GeneDx autistic probands by co-occurring DD/ID status, we found synonymous, missense, and PTV de novo mutation rates in autism probands without DD/ID from GeneDx that were nearly identical to individuals ascertained for a diagnosis of autism in the ASC, SSC, and SPARK research studies (0.296 vs 0.294, 0.767 vs 0.763, and 0.141 vs 0.145 respectively), while GeneDx autism probands with DD/ID exhibited mutation rates similar to those observed in previous research studies of DD.&lt;/div&gt;&lt;div&gt;Further analyses of these data solidified previous observations of significant enrichment of de novo PTVs among autism probands of 3x compared to siblings among the genes most intolerant to PTVs in the human genome (i.e., lowest decile of LOEUF from gnomAD). We have also incorporated Alpha Missense (AM) pathogenicity estimates to complement our prior MPC scores for predicting damaging missense variation and identifying de novo missense variants acting with effect sizes comparable to de novo PTVs in constrained genes, with analysis of regional missense constraint within genes ongoing. We further leveraged the TADA Bayesian statistical method to jointly model these data in ","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MENDELIAN RANDOMIZATION – WHAT ARE THE PROMISES? 门德尔随机化--有哪些承诺?
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.028
With the availability of sufficiently large data from genome wide association analyses for varied phenotypes, a technique, Mendelian Randomization, has become common when searching for causal factors. Essentially, this technique uses genetic factors as proxies for modifiable exposures to explore causal relationships. There are several conditions, which are required for a valid andimpactful Mendelian Randomization estimation. In this symposium, we explore these conditions in more detail, in addition to providing some examples for meaningful explorations in psychiatric genetics.
随着针对各种表型的全基因组关联分析提供了足够多的数据,一种名为 "孟德尔随机化"(Mendelian Randomization)的技术已成为寻找因果关系的常用方法。从本质上讲,这种技术使用遗传因素作为可改变暴露的替代物来探索因果关系。要进行有效且有影响的孟德尔随机化估计,需要满足几个条件。在本次研讨会上,我们将更详细地探讨这些条件,并举例说明精神遗传学中的一些有意义的探索。
{"title":"MENDELIAN RANDOMIZATION – WHAT ARE THE PROMISES?","authors":"","doi":"10.1016/j.euroneuro.2024.08.028","DOIUrl":"10.1016/j.euroneuro.2024.08.028","url":null,"abstract":"<div><div>With the availability of sufficiently large data from genome wide association analyses for varied phenotypes, a technique, Mendelian Randomization, has become common when searching for causal factors. Essentially, this technique uses genetic factors as proxies for modifiable exposures to explore causal relationships. There are several conditions, which are required for a valid andimpactful Mendelian Randomization estimation. In this symposium, we explore these conditions in more detail, in addition to providing some examples for meaningful explorations in psychiatric genetics.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
POLYGENIC ARCHITECTURE AND DISEASE RISK PREDICTION 多基因结构和疾病风险预测
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.008
{"title":"POLYGENIC ARCHITECTURE AND DISEASE RISK PREDICTION","authors":"","doi":"10.1016/j.euroneuro.2024.08.008","DOIUrl":"10.1016/j.euroneuro.2024.08.008","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
European Neuropsychopharmacology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1