Genetic Analysis of Attention Deficit Hyperactivity Disorder

注意力缺陷多动障碍的遗传分析

• 批准号: 8565530
• 负责人: Maximilian Muenke
• 金额: $ 84.14万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565530
• 关键词: 11q; 11q22; 8p23.1; Accounting; Address; Adolescent; Adult; Affect; Alcohols; Attention deficit hyperactivity disorder; Behavior; Behavior Disorders; Behavioral Genetics; Biological Markers; Child; Classification; Clinical; Collaborations; Comorbidity; Complex; Conduct Disorder; DRD2 gene; Demographic Factors; Development; Disease; Drug usage; Drug user; Educational Status; Environmental Risk Factor; Evaluation; Foundations; Future; Genes; Genetic; Genetic Techniques; Genetic Variation; Genomics; Goals; Haplotypes; Health; Illicit Drugs; Individual; International; Intervention; Lead; Legal; Life; Low income; Medicine; Methods; Modeling; Molecular; NCAM1 gene; Network-based; Nuclear Family; Oppositional Defiant Disorder; Outcome; Pathway interactions; Patients; Persons; Pharmacogenetics; Phenotype; Predisposition; Process; Research; Research Design; Research Personnel; Risk; Sampling; Seminal; Severities; Shapes; Signal Transduction; Structure; Substance Use Disorder; Susceptibility Gene; Symptoms; Synapses; Therapeutic; Tobacco; Trees; Underemployment; Variant; World Health Organization; adverse outcome; alpha-latrotoxin receptor; base; clinical practice; cohort; drug seeking behavior; epidemiological model; genetic analysis; novel; response; segregation; social; success; synaptogenesis; systematic review; treatment response

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental behavioral disorder, affecting about 10% of children and adolescents worldwide.It frequently persists into adulthood and can have serious life-long health consequences. Affected individuals are at increased risk for poor educational achievement, low income, underemployment, legal difficulties, and impaired social relationships. The annual societal burden of ADHD was conservatively estimated to reach $42.5 billion in the U.S. In addition, ADHD increases the risk of substance use disorder (SUD) and disruptive (externalizing) disorders such as oppositional defiant disorder (ODD), conduct disorder (CD). SUD is characterized by compulsive drug seeking behavior and drug use in the face of severe adverse consequences. The World Health Organization estimates that there are worldwide at least two billion alcohol users, one billion tobacco users and almost 185 million illicit drug users. Genetic factors are strongly implicated in ADHD. During the last four years, our research on the genetics of ADHD made seminal advances to understand: 1) the innate susceptibility to ADHD and associated comorbidities, 2) the interaction of genetic, demographic and environmental factors underpinning the risk of developing ADHD, 3) how much these factors shape the response of ADHD patients to pharmacological interventions (pharmacogenetics of ADHD), 4) the overrepresentation of functional and ontological gene-based networks implicated in determining synapse structure, and 5) the use of advanced genetic-epidemiological models with potential for use in clinical practice (translational genomics). Thus far, we have identified variants of the latrophilin 3 gene (LPHN3) predisposing to ADHD86 and showed that LPHN3 variants interact with a haplotype on chromosome 11q, doubling ADHD susceptibility. This haplotype encompasses the NCAM1, TTC12, ANKK1, and DRD2 genes. Characterizing this interaction better predicts ADHD severity, long-term outcome and response to treatment and informs how the over-representation of these genes in particular ontogenetic pathways might be involved in processes related to synapse formation. Further, using classification tree-based recursive partitioning models in four independent cohorts, we not only built but also demonstrated that an oligogenic model influenced by demographic and environmental factors could predict the risk of developing ADHD and disruptive behaviors. These findings represent one of the most robustly replicated genetic study on ADHD ever. Our success has depended on several aspects of our research design: 1) Careful, thorough clinical characterization and use of a highly consistent phenotype in all the studies. This has been fundamental for evaluating genetic components in complex and heterogeneous conditions; 2) The use of a combination of approaches including linkage and segregation studies of large, multigenerational and nuclear families from several cohorts with thousands of indviduals (total n=6360, 2627 with ADHD); 3) The development and application of complex and/or novel statistical genetic techniques that address the limitations of subjective evaluations and the lack of biological markers. For example, given the complexity of the genetics of behavior, we chose a multivariate classification method, latent class analysis (LCA) to better serve our genetic studies. This analysis allowed us to include quantitative information of co-morbidities, identify milder phenotypes, and account for correlations between co-morbid and ADHD symptoms; 4) The systematic review of genetic regions of strong genetic signal in our samples. From our previous linkage studies we identified multiple regions of strong genetic signal, namely 4q13.2, 5q33.3, 8p23.1, 11q22, and 17p11). We expect that the discovery of these new molecular substrates will lead to the use of genetic variation as a predictor of clinical severity, dysfunctional comorbidity and individual treatment response in ADHD. This project was based on an international collaboration of nine groups from among the top researchers in the field of ADHD and disruptive behaviors. Our results could provide the foundation for key functional analyses of the genetics of ADHD and related conditions in the future.

注意力缺陷/多动障碍 (ADHD) 是最常见的神经发育行为障碍，影响全球约 10% 的儿童和青少年。它经常持续到成年期，并可能产生严重的终生健康后果。受影响的个人面临更大的教育成就差、收入低、就业不足、法律困难和社会关系受损的风险。据保守估计，在美国，ADHD 每年的社会负担将达到 425 亿美元。此外，ADHD 还会增加物质使用障碍 (SUD) 和破坏性（外化）障碍的风险，例如对立违抗障碍 (ODD)、品行障碍 (CD) 。 SUD 的特点是在面临严重不良后果的情况下强迫性寻求药物行为和吸毒。世界卫生组织估计，全球至少有 20 亿酒精使用者、10 亿烟草使用者和近 1.85 亿非法药物使用者。 遗传因素与多动症密切相关。在过去四年中，我们对 ADHD 遗传学的研究取得了重大进展，以了解：1）对 ADHD 和相关合并症的先天易感性，2）遗传、人口和环境因素的相互作用导致 ADHD 的风险，3）这些因素在多大程度上影响了 ADHD 患者对药物干预的反应（ADHD 的药物遗传学），4) 涉及确定的功能和本体基因网络的过度代表性突触结构，5) 使用具有临床实践潜力的先进遗传流行病学模型（翻译基因组学）。 到目前为止，我们已经鉴定出易患 ADHD86 的 latrophilin 3 基因 (LPHN3) 变体，并表明 LPHN3 变体与染色体 11q 上的单倍型相互作用，使 ADHD 易感性加倍。该单倍型包含 NCAM1、TTC12、ANKK1 和 DRD2 基因。表征这种相互作用可以更好地预测 ADHD 的严重程度、长期结果和对治疗的反应，并告知这些基因（特别是个体发育途径）的过度表达如何参与与突触形成相关的过程。此外，在四个独立队列中使用基于分类树的递归划分模型，我们不仅建立了而且证明了受人口和环境因素影响的寡基因模型可以预测患 ADHD 和破坏性行为的风险。这些发现代表了有史以来最可靠的多动症基因研究之一。 我们的成功取决于我们研究设计的几个方面：1) 仔细、彻底的临床特征以及在所有研究中使用高度一致的表型。这对于评估复杂和异质条件下的遗传成分至关重要。 2) 采用多种方法相结合，包括对来自多个队列的数千人的大型、多代和核心家庭进行连锁和隔离研究（总共 n=6360 人，其中 2627 人患有 ADHD）； 3）复杂和/或新颖的统计遗传技术的开发和应用，解决主观评估的局限性和生物标记的缺乏。例如，考虑到行为遗传学的复杂性，我们选择了多元分类方法，即潜在类别分析（LCA），以更好地服务于我们的遗传学研究。这项分析使我们能够纳入合并症的定量信息，识别较温和的表型，并解释合并症和 ADHD 症状之间的相关性； 4）对样本中强遗传信号的遗传区域进行系统回顾。 从我们之前的连锁研究中，我们确定了多个强遗传信号区域，即 4q13.2、5q33.3、8p23.1、11q22 和 17p11）。 我们预计这些新分子底物的发现将导致使用遗传变异作为 ADHD 临床严重程度、功能失调合并症和个体治疗反应的预测因子。该项目基于多动症和破坏性行为领域顶尖研究人员的九个小组的国际合作。我们的结果可以为未来 ADHD 和相关疾病的遗传学关键功能分析奠定基础。