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TRACKING THE LONGITUDINAL COURSE IN YOUNG PEOPLE AT HIGH RISK OF BIPOLAR DISORDER 追踪躁郁症高危青少年的纵向病程
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.019
Philip Mitchell , Gloria Roberts , Janice Fullerton , Michael Breakspear , Neve Thompson
Young people with a first-degree relative with bipolar disorder (BD) have a 10-15% risk of developing this illness, but currently we have little understanding of the specific clinical and/or biological features which predict such an outcome. Our group in Sydney established the Bipolar Disorder Kids and Sibs high-risk cohort over a decade ago (with 170 high risk young people, 130 controls and 65 who had already developed BD) and have collaborated closely with the US multi-site consortium led by John Nurnberger. We have followed this Australian sample regularly over time, with particular interest in neuroimaging, genetic (including epigenetic), neuropsychological and clinical findings. We have scanned subjects on 3 occasions (baseline, 2 and 10 years), having already published on changes over the first two years. We reported significant weakening in the high-risk subjects of structural connectivity in a network encompassing the left inferior and middle frontal areas, left striatal and thalamic structures, the left fusiform, and right parietal and occipital regions. These findings were more pronounced in those who had developed a first episode of hypo(mania) over those two years. We have also explored for clinical predictors of hypo(mania) onset, finding particular depressive features to be a strong predictor of this outcome. We will present clinical and biological findings of our 10-year follow-up. More studies of long-term biological and clinical changes over time, and predictors of the onset of hypo(mania) are needed to enable rational development of early intervention studies in those at increased familial risk of BD.
有一级亲属患有躁郁症(BD)的年轻人有 10-15% 的患病风险,但目前我们对预测这种结果的具体临床和/或生物学特征知之甚少。我们在悉尼的研究小组十多年前建立了双相情感障碍儿童和兄弟姐妹高风险队列(包括170名高风险青少年、130名对照组和65名已经患上双相情感障碍的青少年),并与约翰-努恩伯格(John Nurnberger)领导的美国多站点研究小组密切合作。我们一直定期跟踪这一澳大利亚样本,尤其关注神经影像学、遗传学(包括表观遗传学)、神经心理学和临床研究结果。我们对受试者进行了 3 次扫描(基线、2 年和 10 年),并已发表了前两年的变化情况。我们发现,在高危人群中,包括左侧额叶下部和中部区域、左侧纹状体和丘脑结构、左侧纺锤体以及右侧顶叶和枕叶区域在内的网络结构连通性明显减弱。这些发现在两年内首次出现低(躁)狂症的患者中更为明显。我们还探索了低躁狂症发病的临床预测因素,发现特定的抑郁特征是预测这一结果的有力因素。我们将介绍 10 年随访的临床和生物学研究结果。我们需要对长期的生物学和临床变化以及低(躁)狂发病的预测因素进行更多的研究,以便对那些BD家族风险增加的人群进行合理的早期干预研究。
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引用次数: 0
YOUTH AT RISK OF BIPOLAR DISORDER: TRACKING TRAJECTORIES, OUTCOMES AND BIOMARKERS USING NEUROIMAGING, GENOMICS AND EPIGENOMICS 躁郁症风险青少年:利用神经影像学、基因组学和表观基因组学追踪轨迹、结果和生物标志物
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.021
Janice Fullerton , Bronwyn Overs , Gloria Roberts , Sonia Hesam-Shariati , Kate Ridgeway , Tayla Williams , Neve Thomson , Kerrie Pierce , Howard Edenberg , Holly Wilcox , Emma Stapp , Melvin McInnis , Leslie Hulvershorn , John Nurnberger , Philip Mitchell
<div><div>Longitudinal prospective studies in high-risk populations are key for identifying pre-morbid risk factors for the development of psychopathology. The Australia-US collaborative Bipolar high-risk study comprises 3 groups of participants aged 12-30 years: ‘high-risk’ (with a sibling or parent with bipolar-I or -II), controls with no family history, and an unrelated group of BD-probands; with clinical, demographic and biological data. Familial risk is sometimes considered a surrogate for genetic risk (that is indexed via inherited DNA variants), but we know that this is a simplification of the ‘heritable’ component, which might comprise both direct and indirect genetic effects as well as the impact of family environment. We have used multiple analytic approaches to define and characterize features of disease risk, using neuroimaging, genomics and epigenomics. Analysis of magnetic resonance imaging (MRI) data from 217 unrelated Australian ‘Bipolar Kids and Sibs study’ participants (baseline n=217, follow-up n=152) finds accelerated cortical thinning over time (two scans, 2 years apart) in high-risk subjects (n=105) compared to controls (n=112), suggesting an early brain over-growth followed by normalisation towards the typical age of BD onset. Accelerated thickness and volume reductions over time were observed in ‘high-risk’ individuals across multiple cortical regions, relative to controls, including right lateral orbitofrontal thickness (β=.033, p < .001) and inferior frontal volume (β=.021, p < .001). We also find that bipolar polygenic risk (PsychArray) interacts with stress to increase suicide risk. We examined polygenic risk for both suicide attempt and risky behaviour on structural variance in cortical parcellations that have previously shown replicable associations with suicide attempts, finding that structural differences in the anterior cingulate, parahippocampal, and cuneus warrant further investigation as potential biomarkers for suicide attempts, particularly within the context of BD. Examination of epigenetic markers (450k/EPIC array) shows that genome-wide methylation patterns are broadly impacted by polygenic risk; highlighting an important interplay between genomically inherited risk and the potential biological encoding of environmental exposures. We are now collecting a 3rd MRI scan to capture nonlinear cortical developmental trajectories, and a 2nd blood sample to extend our baseline epigenetic work, derive serum measures and examine mRNA transcription patterns as potential biomarkers of emergent psychopathology. Brain regions associated with both genetic and clinical measures of psychopathology may serve as viable biomarkers, with clinical utility for the identification of individuals who are at greatest risk of developing psychopathology or suicidal intent. Future work will enable integration of these features into a prediction model of disease, to identify biological subgroups on the trajectory towards mental il
对高危人群进行纵向前瞻性研究,是确定精神病理学发展的病前风险因素的关键。澳大利亚和美国合作开展的躁郁症高危人群研究包括三组 12-30 岁的参与者:"高危人群"(兄弟姐妹或父母中有一人患有躁郁症 I 或 II)、无家族史的对照组和无亲属关系的躁郁症患者组;这些参与者都有临床、人口统计学和生物学数据。家族风险有时被认为是遗传风险的替代物(通过遗传的 DNA 变异来表示),但我们知道,这只是对 "遗传 "成分的简化,"遗传 "成分可能包括直接和间接的遗传效应以及家庭环境的影响。我们采用多种分析方法,利用神经影像学、基因组学和表观基因组学来定义和描述疾病风险特征。通过分析217名无亲属关系的澳大利亚 "双相儿童和兄弟姐妹研究 "参与者的磁共振成像(MRI)数据(基线人数为217人,随访人数为152人)发现,与对照组(人数为112人)相比,高风险受试者(人数为105人)的大脑皮层随着时间的推移(两次扫描,间隔2年)加速变薄,这表明大脑在早期过度生长,随后在双相情感障碍的典型发病年龄趋于正常。与对照组相比,"高危 "人群的多个皮质区域的厚度和体积随着时间的推移加速减少,包括右侧眶额叶厚度(β=.033,p <.001)和下额叶体积(β=.021,p <.001)。我们还发现,躁郁症多基因风险(PsychArray)与压力相互作用,增加了自杀风险。我们对自杀未遂和危险行为的多基因风险进行了研究,研究结果表明,前扣带回、海马旁和楔叶的结构差异作为自杀未遂的潜在生物标志物值得进一步研究,尤其是在双相情感障碍的背景下。对表观遗传标记物(450k/EPIC 阵列)的研究表明,全基因组的甲基化模式受到多基因风险的广泛影响;这凸显了基因遗传风险与环境暴露的潜在生物编码之间的重要相互作用。目前,我们正在收集第三次核磁共振成像扫描结果,以捕捉大脑皮层的非线性发育轨迹,并收集第二次血液样本,以扩展我们的基线表观遗传学工作,得出血清测量结果,并研究 mRNA 转录模式,作为新出现的精神病理学的潜在生物标志物。与精神病理学遗传和临床测量相关的脑区可作为可行的生物标志物,在临床上用于识别最有可能发展成精神病理学或自杀意图的个体。未来的工作将能够把这些特征整合到疾病预测模型中,以确定精神疾病轨迹上的生物亚群。
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引用次数: 0
LEVERAGING CONTEXT-SPECIFIC EPIGENOMIC REGULATORY NETWORKS (EPINETS) TO DISSECT THE GENETICS OF NEUROPSYCHIATRIC DISORDERS 利用特定情境表观基因组调控网络(epinets)剖析神经精神疾病的遗传学问题
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.024
Ting-Ting Fu, Bhavana Kapalli, Jawahar Mahendran, Neha Rao, Lei Hou
Expression quantitative locus (eQTL) mapping provides deep insights into the function of disease-associated variants from Genome-wide association studies (GWAS). However, previous studies and our research reported misalignment between eQTLs and GWAS signals, likely due to bulk eQTLs mapped in non-pathology-relevant contexts and lack of cell-type resolution. Alternatively, unraveling the links between cis-regulatory elements (CREs) and genes in various cellular contexts offers an independent strategy to associate GWAS variants with their target genes beyond eQTL mapping. The state-of-the-art approaches, such as experimental assays (e.g., Promoter Capture Hi-C and macro-C) and computational models (e.g., ABC and EpiMap), provide linking resources based on different pieces of evidence, however, are each confined to limited brain cell types or cellular states.
Addressing this challenge, our study proposes a machine-learning approach to predict CRE-gene associations by combining protein-protein interactions and transcription factor (TF) binding predictions based on ATAC-seq, an assay measuring genomic accessibility. This computational approach facilitates the discovery of CRE-gene connections across different contexts (combinations of cell types and various conditions) whenever ATAC-seq data are available, enriching our understanding of the cis-regulatory networks between TF-CRE-gene.
We have amassed over 130 cell-sorted and single-cell ATAC-seq datasets encompassing a variety of brain cell types—excitatory neurons, inhibitory neurons, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), astrocytes, microglia, immune cells, and brain vascular cells—under a range of conditions including chemical perturbations, genetic modifications, infections, and disease status. Utilizing this extensive data collection and our integrative pipeline, we have constructed an atlas of TF-CRE-gene linking, namely cEpiNets. We finally employ the atlas to evaluate the enrichment of GWAS signals in CRE modules under various cellular contexts and to prioritize target genes and key drivers across a spectrum of neuropsychiatric disorders.
表达定量基因座(eQTL)图谱能让人从全基因组关联研究(GWAS)中深入了解疾病相关变异的功能。然而,先前的研究和我们的研究都报告了 eQTL 与 GWAS 信号之间的不一致,这可能是由于大量 eQTL 映射在非病理学相关的环境中以及缺乏细胞类型分辨率。另外,揭示顺式调控元件(CRE)与各种细胞环境中基因之间的联系也是一种独立的策略,可将 GWAS 变异与其 eQTL 图谱之外的靶基因联系起来。最先进的方法,如实验检测(如 Promoter Capture Hi-C 和 macro-C)和计算模型(如 ABC 和 EpiMap),提供了基于不同证据的关联资源,但每种方法都局限于有限的脑细胞类型或细胞状态。为了应对这一挑战,我们的研究提出了一种机器学习方法,通过结合基于 ATAC-seq 的蛋白质-蛋白质相互作用和转录因子(TF)结合预测来预测 CRE 与基因的关联。只要有ATAC-seq数据,这种计算方法就能帮助发现不同情况下(细胞类型和各种条件的组合)的CRE-基因关联,从而丰富我们对TF-CRE-基因之间顺式调控网络的理解。我们已经积累了 130 多个细胞分选和单细胞 ATAC-seq 数据集,涵盖了各种脑细胞类型--兴奋性神经元、抑制性神经元、少突胶质细胞、少突胶质祖细胞 (OPC)、星形胶质细胞、小胶质细胞、免疫细胞和脑血管细胞--在一系列条件下,包括化学扰动、基因修饰、感染和疾病状态。利用这些广泛的数据收集和我们的整合管道,我们构建了一个 TF-CRE 基因连接图谱,即 cEpiNets。最后,我们利用该图集评估了各种细胞环境下 CRE 模块中 GWAS 信号的富集情况,并对一系列神经精神疾病的目标基因和关键驱动因素进行了优先排序。
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引用次数: 0
LEVERAGING COMORBIDITY TO REFINE PTSD ASSOCIATIONS AND DISSECT GENETIC RISK 利用合并症细化 ptsd 关联并分析遗传风险
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.014
Leveraging comorbidity to refine PTSD associations and dissect genetic risk
利用合并症来完善创伤后应激障碍的关联性并剖析遗传风险
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引用次数: 0
INNATE AND ADAPTIVE IMMUNITY IN PSYCHIATRY: INSIGHTS FROM GENETIC ASSOCIATION STUDIES AND PERIPHERAL BLOOD IMMUNOPHENOTYPING 精神病学中的先天免疫和适应性免疫:遗传关联研究和外周血免疫分型的启示
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.027
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引用次数: 0
CURRENT CHALLENGES AND OPPORTUNITIES IN DATA-DRIVEN APPROACHES IN NEUROPSYCHIATRIC DISORDERS 当前神经精神疾病数据驱动方法面临的挑战和机遇
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.053
Chunyu Liu (Chair) , Zhongming Zhao (Co-chair) , Eric Gamazon (Discussant)
<div><div>As the technological landscape evolves, neuropsychiatric research increasingly relies on data-driven methodologies to uncover the mysteries of the human brain malfunction and genetic risk in neuropsychiatric disorders. This symposium brings together experts and stakeholders for a focused dialogue on the pressing challenges and innovative solutions within this rapidly progressing domain. Through a series of thought-provoking presentations, we will delve into the nuances of data integration, the intricacies of handling big data, and the critical aspects of ensuring research reproducibility and clinical applicability.</div><div>Dr. Chunyu Liu from the State University of New York (SUNY) Upstate Medical University will present a compelling discussion on the paramount importance of quality control in single-cell RNA-seq data. His presentation will underscore the necessity of stringent data evaluation and filtering protocols to bolster the precision of genomic analyses. The talk will provide participants with a solid foundation on the principles of data quality, which is pivotal for the reproducibility and credibility of research findings.</div><div>Dr. Zhongming Zhao from the University of Texas Health Science Center at Houston (UTHealth Houston) will present an in-depth exploration of cutting-edge machine-learning algorithms for the integration of omics, genetic, neuroimaging, and phenotypic data. His session will be centered on the elucidation of Alzheimer's Disease's molecular mechanisms and the identification of potential therapeutic targets. This presentation will demonstrate the transformative power of data analytics in shaping the future of neuropsychiatric therapeutics.</div><div>Dr. Peter Kochunov from the UTHealth Houston, will tackle the multifaceted challenges of data integration, scalability, and reproducibility within the scope of large-scale population imaging genetic studies. His expertise will offer a strategic guide for navigating the complexities of big data, ensuring the robustness of research outcomes, and bridging the gap between scientific discoveries and their clinical translation.</div><div>Dr. Xing-Ming Zhao from Fudan University will conclude the symposium with an insightful examination of the challenges and strategies related to data integration in psychiatric disorder research. His work will emphasize the significance of synthesizing diverse data streams, such as clinical assessments, neuroimaging, and genetic information, to achieve a comprehensive view of neuropsychiatric conditions. This session will highlight the potential of integrated data approaches to surmount the obstacles faced in the field.</div><div>Dr. Eric Gamazon from Vanderbilt University will serve as the discussant to summarize the talks and offer his own insight into harnessing large biobank data of diverse ancestries.</div><div>The symposium will weave these presentations into a coherent narrative, progressively building upon each topic to pro
随着技术的发展,神经精神疾病研究越来越依赖于数据驱动的方法来揭示人脑功能失常和神经精神疾病遗传风险的奥秘。本次研讨会汇聚了专家和利益相关者,就这一快速发展领域中的紧迫挑战和创新解决方案展开集中对话。通过一系列发人深省的演讲,我们将深入探讨数据整合的微妙之处、处理大数据的复杂性以及确保研究可重复性和临床适用性的关键方面。他的演讲将强调严格的数据评估和过滤协议对提高基因组分析精度的必要性。来自德克萨斯大学休斯顿健康科学中心(UTHealth Houston)的赵忠明博士将深入探讨用于整合 omics、遗传、神经影像和表型数据的前沿机器学习算法。他的演讲将围绕阐明阿尔茨海默病的分子机制和确定潜在治疗靶点展开。来自休斯顿UTHealth 的 Peter Kochunov 博士将探讨大规模群体成像基因研究中数据整合、可扩展性和可重复性等多方面的挑战。他的专业知识将为驾驭复杂的大数据、确保研究成果的稳健性以及弥合科学发现与临床转化之间的差距提供战略指导。来自复旦大学的赵兴明博士将以对精神疾病研究中与数据整合相关的挑战和策略的深入探讨结束本次研讨会。他的工作将强调综合不同数据流(如临床评估、神经影像学和遗传信息)以全面了解神经精神疾病的重要性。来自范德比尔特大学的 Eric Gamazon 博士将作为讨论者对发言进行总结,并就如何利用不同血统的大型生物库数据提出自己的见解。研讨会将把这些发言编织成一个连贯的叙事,在每个主题的基础上逐步展开,全面概述数据驱动的神经精神疾病研究目前面临的挑战和未来前景。本次研讨会将通过营造合作环境和激发创新思维来推动这一领域的发展。与会者将深刻了解神经精神疾病数据驱动研究中的关键问题。此外,他们还将获得多功能工具包,以提高研究水平,为推动神经精神科学的发展做出贡献。
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引用次数: 0
MULTI-ANCESTRY FINE-MAPPING REFINES BIPOLAR DISORDER RISK GENES 多基因精细图谱完善躁郁症风险基因
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.035
Maria Koromina , Kai Yuan , Sanan Venkatesh , Kevin S. O'Connell , Friederike David , Psychiatric Genomics Consortium Bipolar Disorder Working Group , Jonathan Coleman , Georgios Voloudakis , Panos Roussos , Niamh Mullins
Genome wide association studies (GWAS) have identified hundreds of loci contributing to bipolar disorder (BD) risk. However, translating genome-wide significant (GWS) loci into causal genes and mechanisms for BD is challenging due to linkage disequilibrium (LD) between risk variants, and incomplete understanding of the non-coding regulatory mechanisms in the brain. Recently, the Psychiatric Genomics Consortium Bipolar Disorder Working Group has performed GWAS meta-analyses of BD in cohorts of European (N cases = 131,969), East Asian (N cases = 5,969), African American (N cases = 7,076) and Latino (N cases = 13,022) ancestries, as well as a multi-ancestry meta-analysis (Total N = 158,036 cases, N= 2,796,499 controls) by including datasets with different ascertainment strategies. These analyses led to the identification of 298 GWS risk loci for BD, further emphasizing the need to identify the true causal variants and elucidate their biological mechanisms at the cellular level.
Here, we implemented SuSiEx, a statistical fine-mapping method leveraging differences in the LD architecture among different genetic ancestries, to prioritize likely causal SNPs, within these 298 GWS risk loci for BD. Then, we mapped these SNPs to their relevant gene(s), and investigated their likely functional consequences by aggregating multiple lines of evidence: (i) integration of variant annotation and brain cell-type epigenomic data (PLAC-seq data), (ii) implementation of Summary data-based Mendelian Randomization (SMR) to functionally interpret the likely causal SNPs in the context of brain bulk tissue quantitative trait loci (QTLs) (expression, splicing and methylation QTLs), and (iii) refining the cell-type specific context of likely causal SNPs via SMR, by leveraging a novel (unpublished) resource of brain single nuclei eQTLs.
Our comprehensive fine-mapping analysis prioritized 113 likely causal SNPs, from 298 GWS loci for BD using LD estimates from all 4 represented populations in the multi-ancestry GWAS. By integrating expression, splicing or methylation QTLs, preliminary results based on a previous BD GWAS indicated that the following genes, among others, are strongly implicated in BD: FURIN, FADS1, DCC, MED24, TTC12, SP4, POU6F2, TRANK1, and DDRD2. Additionally, our preliminary results showed that fine-mapped SNPs for BD can mediate their likely causal effect in specific brain cell-types, specifically inhibitory and excitatory neurons. Taken together, the abovementioned genes represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Finally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, thus highlighting the potential clinical utility of fine-mapping.
全基因组关联研究(GWAS)发现了数百个导致躁狂症(BD)风险的基因位点。然而,由于风险变异之间的连锁不平衡(LD)以及对大脑中非编码调控机制的不完全了解,将全基因组重要(GWS)位点转化为双相情感障碍的因果基因和机制具有挑战性。最近,精神病基因组学联盟躁郁症工作组对欧洲人(病例数=131969)、东亚人(病例数=5969)、非洲裔美国人(病例数=7076)和拉丁裔美国人(病例数=13022)血统队列中的躁郁症进行了GWAS荟萃分析,并通过纳入不同确定策略的数据集进行了多队列荟萃分析(总病例数=158036,对照数=2796499)。通过这些分析,我们确定了298个BD的GWS风险位点,进一步强调了确定真正的致病变异并在细胞水平阐明其生物学机制的必要性。在这里,我们采用了SuSiEx--一种利用不同遗传祖先之间LD结构差异的统计精细映射方法,在这298个BD的GWS风险位点中优先选择可能的致病SNPs。然后,我们将这些 SNPs 映射到其相关基因上,并通过整合多种证据来研究其可能的功能性后果:(i)整合变异注释和脑细胞类型表观基因组数据(PLAC-seq 数据);(ii)实施基于摘要数据的孟德尔随机化(SMR),在脑大块组织定量性状位点(QTLs)(表达、剪接和甲基化 QTLs)的背景下从功能上解释可能的致病 SNPs;(iii)通过 SMR,利用新颖的(未发表的)脑单核 eQTLs 资源,完善可能的致病 SNPs 的细胞类型特定背景。我们的综合精细图谱分析从 298 个 GWS 位点中优先筛选出 113 个可能是 BD 病因的 SNPs,这些 SNPs 采用了多种群 GWAS 中所有 4 个代表性种群的 LD 估计值。通过整合表达、剪接或甲基化 QTLs,基于之前 BD GWAS 的初步结果显示,以下基因与 BD 密切相关:FURIN、FADS1、DCC、MED24、TTC12、SP4、POU6F2、TRANK1 和 DDRD2。此外,我们的初步研究结果表明,BD 的精细映射 SNPs 可在特定脑细胞类型(特别是抑制性和兴奋性神经元)中介导其可能的因果效应。综上所述,上述基因是有希望进行功能实验以了解生物学机制和治疗潜力的候选基因。最后,我们证明了精细图谱效应大小可以提高BD多基因风险评分在不同祖先人群中的表现和可转移性,从而突出了精细图谱的潜在临床实用性。
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引用次数: 0
WHAT IS THE IMPACT OF COMPOUND HETEROZYGOUS EVENTS INVOLVING DELETIONS AND SEQUENCE-LEVEL VARIANTS IN AUTISM? 涉及缺失和序列变异的复合杂合事件对自闭症有什么影响?
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.080
Worrawat Engchuan , Brett Trost , Marla Mendes de Aquino , David Mager , Mehdi Zarrei , Rulan Shaath , Rayssa de Melo Wanderley , Faraz Ali , Nickie Safarian , Alex Chan , Shania Wu , Stephen W. Scherer , Elemi Breetvelt , Jacob Vorstman
<div><div>The majority of human genes maintain normal biological function when they become haploid due to a genomic deletion. However, pathogenicity may still arise when the remaining allele is affected by additional functional variation. Here, we describe analytical strategies for examining a specific type of compound heterozygosity, namely the co-occurrence of a deletion and a sequence-level variant affecting the other allele, hereafter referred to as deletion compound heterozygosity (DelCH). We report preliminary results in using these strategies to assess DelCH in Autism Spectrum Disorder (ASD).</div><div>We analyzed whole-genome sequencing data from MSSNG, Simons Simplex Collection, and SPARK cohorts (collectively 11,636 autistic individuals and 22,962 family members).</div><div>We developed multiple analytical strategies to examine rare (event rate < 1%) DelCH:<ul><li><span>1)</span><span><div>The burden analysis uses conditional logistic regression for group-level comparisons of DelCH rates between a) probands and their deletion-transmitting parents, with inherited deletion as a random effect variable, or b) probands and their family members, with family ID as a random effect variable;</div></span></li><li><span>2)</span><span><div>The transmission disequilibrium test (TDT) compares the rates with which deletion-non-transmitting parents transmit sequence-level variants within genes affected by deletions to their autistic offspring. Association is indicated by transmission of non-synonymous variants at a rate higher than predicted by chance. This approach was repeated in unaffected siblings as an additional control analysis.</div></span></li></ul></div><div>Each strategy has different strengths and weaknesses. The first burden analysis (1a) achieves perfect matching of deleted sequence and unambiguous phasing of variants but is restricted to proband-parent pairs. The second burden analysis (1b) benefits from a larger sample size but cannot distinguish between de novo and inherited variation. In addition, unambiguous phasing is possible only for SNVs within deletion boundaries. In contrast, while the TDT (2) can include SNVs outside deletion boundaries, thereby increasing statistical power, de novo events are not analyzed.</div><div>Our preliminary findings show variability in results as a function of the analytical strategy. Findings from the burden analysis suggest a modest enrichment of DelCH in ASD which was inversely proportional to the variant frequency thresholds applied.</div><div>Given that the mechanism consists of two rare events at the same locus, on the population level the role of DelCH in ASD etiology is likely modest, requiring large samples sizes for sufficient statistical power. In addition to this “lightning striking twice”, data preparation is demanding, as every subject has unique deletion regions in which sequence-level variants on the other allele are tallied. Variant selection metrics include allele frequency thres
当基因组缺失导致单倍体时,大多数人类基因都能保持正常的生物功能。然而,当剩余等位基因受到额外功能变异的影响时,致病性仍然可能产生。在此,我们将介绍一种特定类型复合杂合性的分析策略,即缺失和影响另一个等位基因的序列级变异的共同发生,以下简称缺失复合杂合性(DelCH)。我们分析了来自 MSSNG、Simons Simplex Collection 和 SPARK 队列的全基因组测序数据(共有 11,636 名自闭症患者和 22,962 名家庭成员)。我们开发了多种分析策略来研究罕见(事件发生率为 1%)的 DelCH:1)负担分析使用条件逻辑回归对以下两种情况的 DelCH 发生率进行群体水平的比较:a)将遗传性缺失作为随机效应变量,比较受试者与其缺失传播父母之间的 DelCH 发生率;或 b)将家庭 ID 作为随机效应变量,比较受试者与其家庭成员之间的 DelCH 发生率;2)传播不平衡检验(TDT)比较缺失非传播父母将受缺失影响的基因内的序列水平变异传播给其自闭症后代的比率。如果非同义变异的传递率高于偶然预测的传递率,则表明存在关联。作为额外的对照分析,在未受影响的兄弟姐妹中重复了这一方法。第一种负荷分析(1a)实现了删除序列的完美匹配和变异体的明确分期,但仅限于原核父母配对。第二种负担分析(1b)受益于更大的样本量,但无法区分从头变异和遗传变异。此外,只有在缺失边界内的 SNV 才有可能进行明确的分期。与此相反,虽然 TDT(2)可以包括缺失边界以外的 SNV,从而提高统计能力,但却无法分析从新发生的事件。负担分析的结果表明,DelCH 在 ASD 中的富集程度不高,与应用的变异频率阈值成反比。鉴于其机制由同一位点上的两个罕见事件组成,在人群水平上,DelCH 在 ASD 病因学中的作用可能不大,需要大样本量才能获得足够的统计能力。除了 "雷击两次 "之外,数据准备工作也要求很高,因为每个受试者都有独特的缺失区域,其中另一个等位基因上的序列级变异需要统计。变异选择指标包括等位基因频率阈值、常染色体显性缺失性预测阈值以及与缺失边界相关的变异包含规则。我们的研究结果表明,改变其中任何一个指标都会影响研究结果,因此需要慎重考虑。了解 DelCH 的潜在作用可能有助于建立更全面的 ASD 相关遗传变异库。DelCH可以解释为什么个别ASD患者会出现遗传自非受影响父母的缺失。最后,在遗传分析中研究DelCH可能有助于发现隐性ASD基因,否则这些基因将无法被发现。
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引用次数: 0
THE POLYGENETIC ARCHITECTURE OF AUTISM 自闭症的多基因结构
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.045
Jing Zhang , Jakob Grove , Caitlin Carey , Jack Fu , F. Kyle Satterstrom , Susan Kuo , Ajay Nadig , Swapnil Awasthi , Kaitlin Samocha , Anders Børglum , Elise Robinson
Autism is highly heritable and has been associated with multiple classes of genetic variation. Common genetic variation contributes substantially to autism. Previously, with 18,381 autistic individuals and 27,969 non-autistic individuals, five genome-wide significant loci were identified. Now with 38,717 autistic individuals and 232,725 non-autistic individuals, we report an updated genome-wide association study (GWAS) of autism with 12 genome-wide significant loci. We observe a moderate genetic correlation (0.675, SE=0.0434) between Europe-based (Nautistic=22,643; Nnon-autistic=204,389) and United States-based (Nautistic =16,074; Nnon-autistic=28,346) autism cohorts, which contributes to the decline of the estimated single nucleotide polymorphism (SNP) heritability (from 0.118 (SE=0.010) to 0.068 (SE=0.003)). The genetic correlation between autism with intellectual disability (ID) (Nautistic=6,590; Nnon-autistic= 43,071; h2=0.062; SE=0.012) and autism without ID (Nautistic=23,173; Nnon-autistic= 204,679; h2=0.089; SE=0.005) is 0.658 (SE=0.086). In the United States family-based cohorts, the genetic correlation between autism with ID (Nfamily=3,993; h2=0.159; SE=0.033) and autism without ID (Nfamily=4,357; h2=0.171; SE=0.031) is 0.812 (SE=0.157). Autism without ID was positively genetically correlated with educational attainment (0.163; P=4.84 × 10-11) and intelligence (0.233; P=1.95 × 10-11). Autism with ID genetically correlated with neither educational attainment (0.036; P=0.409) nor intelligence (-0.072; P=0.235). As ID alone is negatively genetically correlated with intelligence, the lack of correlation between autism with ID and intelligence strongly suggests that autism with ID is genetically different from ID alone. This difference has implications for both research and clinical nosology. Rare and de novo variants contribute substantially to autism in some individuals. Through rare variant analyses, 72 genes have been associated with autism at a genome-wide significant level to date. While de novo protein truncating variants (PTVs) and copy number deletions have been associated with autism, we report preliminary findings that the burden of inherited PTVs and copy number deletions among autistic individuals was elevated compared to their non-autistic siblings (P=4.00 × 10-5). Integration of multiple genetic factors will help us better understand the etiology of autism.
自闭症具有高度遗传性,与多种基因变异有关。常见的遗传变异对自闭症有很大的影响。此前,我们在 18,381 名自闭症患者和 27,969 名非自闭症患者中发现了五个全基因组重要位点。现在,我们以 38,717 名自闭症患者和 232,725 名非自闭症患者为研究对象,报告了一项最新的自闭症全基因组关联研究(GWAS),其中发现了 12 个具有重要意义的全基因组位点。我们观察到自闭症欧洲队列(Nautistic=22,643;Nnon-autistic=204,389)和美国队列(Nautistic=16,074;Nnon-autistic=28,346)之间存在中等程度的遗传相关性(0.675,SE=0.0434),这导致估计的单核苷酸多态性(SNP)遗传率下降(从 0.118(SE=0.010)降至 0.068(SE=0.003))。有智力障碍的自闭症(Nautistic=6 590;Nnon-autistic=43 071;h2=0.062;SE=0.012)与无智力障碍的自闭症(Nautistic=23 173;Nnon-autistic=204 679;h2=0.089;SE=0.005)之间的遗传相关性为 0.658(SE=0.086)。在美国以家庭为基础的队列中,有 ID 的自闭症(Nfamily=3,993;h2=0.159;SE=0.033)与无 ID 的自闭症(Nfamily=4,357;h2=0.171;SE=0.031)之间的遗传相关性为 0.812(SE=0.157)。无智障自闭症与教育程度(0.163;P=4.84 × 10-11)和智力(0.233;P=1.95 × 10-11)呈正相关。带有智障的自闭症与教育程度(0.036;P=0.409)和智力(-0.072;P=0.235)均无遗传相关性。由于单纯的智障与智力在基因上呈负相关,自闭症伴智障与智力之间缺乏相关性强烈表明,自闭症伴智障在基因上与单纯的智障不同。这种差异对研究和临床命名都有影响。罕见变异和新变异对某些个体的自闭症有重大影响。通过罕见变异分析,迄今已有 72 个基因与自闭症有全基因组意义上的关联。虽然从头蛋白质截断变异(PTVs)和拷贝数缺失与自闭症有关,但我们报告的初步研究结果表明,与非自闭症患者的兄弟姐妹相比,自闭症患者的遗传PTVs和拷贝数缺失的负担更高(P=4.00 × 10-5)。整合多种遗传因素将有助于我们更好地了解自闭症的病因。
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引用次数: 0
UPDATE FROM THE “PEDIGREE-BASED WHOLE GENOME SEQUENCING OF AFFECTIVE AND PSYCHOTIC DISORDERS" CONSORTIUM 基于谱系的情感障碍和精神障碍全基因组测序 "的最新进展联合会
IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.euroneuro.2024.08.082
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引用次数: 0
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European Neuropsychopharmacology
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