Genetic Analysis of Attention Deficit Hyperactivity Disorder

注意力缺陷多动障碍的遗传分析

• 批准号: 10274163
• 负责人: Paul Liu
• 金额: $ 321.77万
• 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/10274163
• 关键词: 11q; 11q22; ANKK1 gene; Adhesions; Adolescent; Adult; Affect; Alcohols; Attention deficit hyperactivity disorder; Behavior; Behavior Disorders; Binding Sites; Brain; Brain region; Brazil; Canada; Child; Chromosomes; Colombia; Conduct Disorder; Confidence Intervals; Conserved Sequence; DRD2 gene; Data; Development; Diagnosis; Disease; Drug user; Educational Status; Embryonic Development; Enhancers; Epidemiology; FLRT3 gene; Family; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Genetic Transcription; Genomic Segment; Genotype; Germany; Goals; Haplotypes; Health; Illicit Drugs; Impairment; Incidence; Individual; Investigation; Knock-out; Lead; Legal; Life; Ligands; Link; Low income; Maintenance; Manuscripts; Measures; Membrane Proteins; Metabolism; Modeling; Mus; Myelin; NCAM1 gene; Neurons; Neuropsychology; Norway; Oppositional Defiant Disorder; Paper; Patients; Penetrance; Persons; Pharmaceutical Preparations; Play; Population Attributable Risks; Postsynaptic Membrane; Predisposition; Prevalence; Public Health; Publishing; Reporting; Research; Risk; Role; Severities; Shapes; South Korea; Spain; Sphingolipids; Substance Use Disorder; Surface; Susceptibility Gene; Symptoms; System; Therapeutic; Time; Twin Multiple Birth; Underemployment; Untranslated RNA; Variant; Work; World Health Organization; Zebrafish; addiction; alpha-latrotoxin receptor; axon guidance; base; cell motility; cohort; comorbidity; disease natural history; drug seeking behavior; endophenotype; genetic analysis; genetic variant; genome-wide; genome-wide linkage; member; myelination; neurodevelopment; noradrenergic; personalized medicine; predicting response; risk variant; segregation; social relationships; socioeconomic disadvantage; socioeconomics; tobacco user; transcription factor

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental behavioral disorder, affecting about 5.3% 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 significant socioeconomic disadvantages, such as poor educational achievement, low income, underemployment, legal problems, and impaired social relationships. In addition, ADHD increases the risk of co-morbid disruptive disorders, such as oppositional defiant disorder (ODD), conduct disorder (CD) and substance use disorder (SUD). Over the last two decades, our research has made significant contributions to the genetics of ADHD. We collected families clustering ADHD and associated comorbidities from disparate regions around the world. Using genome-wide data, we found evidence of linkage of ADHD to chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11.93. Linkage and association analyses revealed co-segregation between ADHD and disruptive behaviors linking genetics to the natural history of the disease. The Mendelian co-segregation of ADHD with these genomic regions and their high genotypic penetrance identify them as major loci predisposing to ADHD. Fine mapping of the region at 4q13.2 identified variants in the adhesion G protein-coupled receptor L3 gene (ADGRL3, also known as latrophilin 3 or LPHN3) that predispose to ADHD. ADGRL3 encodes a member of the latrophilin subfamily of adhesion G-protein coupled receptors and is highly expressed in brain regions implicated in the dopaminergic and noradrenergic systems. ADGRL3 endogenous ligand has been identified as FLRT3, a postsynaptic membrane protein involved in axon guidance and neuronal cell migration during embryonic development. Mouse and zebrafish knockout models support ADGRL3 implication in ADHD pathophysiology. We and others have found a significant homogeneous genetic effect of ADGRL3 variants predisposing to ADHD in children, adolescents, and adults using cohorts of thousands of individuals from Colombia, Germany, Norway, Spain, South Korea, Brazil, U.S., and Canada. To the best of our knowledge, ADGRL3 this is the most replicated gene associated with ADHD. As a measure of the epidemiological impact, the population attributable risk of ADGRL3 susceptibility variants has been estimated at 8.99 (95% confidence interval = 3.90-14.12), which means that the incidence of ADHD would be reduced by 9% if we were able to control for the effect of this gene. We have reported evidence of a genetic interaction between ADGRL3 variants and a haplotype in chromosome 11q. This negative epistasis doubles the risks of developing ADHD, worsens ADHD severity, and predicts the response to stimulant medication. The haplotype at 11q encompasses the NCAM1 gene, which encodes a surface molecule with a fundamental role in neural development; DRD2, which has been previously associated with ADHD; and TTC12 and ANKK1, two relatively unknown genes associated with co-morbid disruptive symptoms. More recently, we identified a non-coding, three-marker ADGRL3 risk haplotype associated with ADHD, disruptive disorders and neuropsychological endophenotypes. This haplotype is harbored at a highly conserved sequence that functions as a brain specific transcriptional enhancer. Functional analysis of risk allele substitutions in this enhancer demonstrated disruption of YY1 repressor binding site, an important neurodevelopmental transcription factor. We have now concluded an investigation supporting a main role for ADGRL3 in the development of SUD. SUD and addiction represent a global public health problem of substantial socioeconomic implications. The World Health Organization estimates a worldwide prevalence of at least two billion alcohol users, one billion tobacco users and almost 185 million illicit drug users. The close association between ADHD and SUD, as summarized by family, twin, and genome-wide linkage and association studies, suggests that genetic factors play a crucial role in shaping the susceptibility to both ADHD and SUD. While ADGRL3 has been extensively studied in association with ADHD and disruptive behaviors (in the context of ADHD), a direct link between ADGRL3 and SUD had not been investigated. In this manuscript, we provide evidence supporting a possible functional role for ADGRL3 in modulating drug seeking behavior. We speculate that ADGRL3 variants may underlie a differential genetic susceptibility SUD and that a timely diagnosis and treatment of ADHD with stimulant medication might reduce the occurrence and/or severity of SUD. Confirmation of such hypothesis would have substantial public health implications. Another study concluded this year involves a possible involvement of sphingolipid metabolism in the development of ADHD. Based on data suggesting that ADHD patients might present with atypical central myelination and given the essential role of sphingolipids in myelin formation and maintenance, we interrogated sphingolipid metabolism gene variants for a possible association with ADHD. We found statistically significant associations between ADHD and variants in GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOLV5 and CERK genes. Variants in GALC, SMPD1 and CERS6 were successfully replicated in additional ADHD cohorts. The paper reporting these findings have now been published (Henriquez-Henriquez et al., 2020).

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5.3%的儿童和青少年。它经常持续到成年，并可能产生严重的终身健康后果。受影响的个人面临更大的社会经济不利因素的风险，如教育成绩差、收入低、就业不足、法律的问题和社会关系受损。此外，ADHD增加了共病破坏性障碍的风险，如对立违抗性障碍（ODD），行为障碍（CD）和物质使用障碍（SUD）。 在过去的二十年里，我们的研究对ADHD的遗传学做出了重大贡献。我们收集了来自世界各地不同地区的ADHD和相关合并症的家庭。使用全基因组数据，我们发现ADHD与染色体4q13.2，5q33.3，8q11.23，11 q22和17p11.93连锁的证据。连锁和关联分析揭示了ADHD和破坏性行为之间的共分离，将遗传学与疾病的自然史联系起来。ADHD与这些基因组区域的孟德尔共分离和它们的高基因型多态性将它们鉴定为ADHD易感的主要位点。 对4q13.2区域的精细定位确定了粘附G蛋白偶联受体L3基因（ADGRL 3，也称为latrophilin 3或LPHN 3）的变体，这些变体易患ADHD。ADGRL 3编码粘附G蛋白偶联受体的亲脂蛋白亚家族的成员，并且在涉及多巴胺能和去甲肾上腺素能系统的脑区域中高度表达。ADGRL 3内源性配体已被鉴定为FLRT 3，其是在胚胎发育期间参与轴突引导和神经元细胞迁移的突触后膜蛋白。小鼠和斑马鱼基因敲除模型支持ADGRL 3在ADHD病理生理学中的意义。 我们和其他人使用来自哥伦比亚，德国，挪威，西班牙，韩国，巴西，美国，和加拿大据我们所知，ADGRL 3是与ADHD相关的复制最多的基因。作为流行病学影响的量度，ADGRL 3易感性变体的人群归因风险估计为8.99（95%置信区间= 3.90-14.12），这意味着如果我们能够控制该基因的影响，ADHD的发病率将降低9%。 我们已经报道了ADGRL 3变体和染色体11 q单倍型之间遗传相互作用的证据。这种负上位性使患ADHD的风险加倍，使ADHD的严重程度增加，并预测对兴奋剂药物的反应。11 q的单倍型包括NCAM 1基因，其编码在神经发育中具有基本作用的表面分子; DRD 2，其先前与ADHD相关;以及TTC 12和ANKK 1，两个相对未知的与共病破坏性症状相关的基因。最近，我们发现了一个非编码的三标记ADGRL 3风险单倍型与ADHD，破坏性障碍和神经心理学内表型。这种单倍型是窝藏在一个高度保守的序列，作为大脑特异性转录增强子的功能。在这个增强子中的风险等位基因置换的功能分析表明YY 1阻遏物结合位点，一个重要的神经发育转录因子的破坏。 我们现在已经完成了一项调查，支持ADGRL 3在SUD发展中的主要作用。SUD和成瘾是一个具有重大社会经济影响的全球公共卫生问题。世界卫生组织估计，全世界至少有20亿酗酒者、10亿烟草使用者和近1.85亿非法药物使用者。ADHD和SUD之间的密切关联，如家庭，双胞胎和全基因组连锁和关联研究所总结的，表明遗传因素在形成ADHD和SUD的易感性方面起着至关重要的作用。虽然ADGRL 3已被广泛研究与ADHD和破坏性行为（在ADHD的背景下），ADGRL 3和SUD之间的直接联系尚未调查。在这份手稿中，我们提供的证据支持ADGRL 3在调节药物寻求行为中可能的功能作用。我们推测ADGRL 3变异体可能是SUD差异遗传易感性的基础，及时诊断和使用兴奋剂药物治疗ADHD可能会减少SUD的发生和/或严重程度。证实这种假设将对公共卫生产生重大影响。 今年结束的另一项研究涉及鞘脂代谢可能参与ADHD的发展。基于数据表明ADHD患者可能存在非典型的中央髓鞘形成，并考虑到鞘脂在髓鞘形成和维持中的重要作用，我们询问了鞘脂代谢基因变异与ADHD的可能关联。我们发现ADHD与GALC，CERS 6，SMPD 1，SMPDL 3B，CERS 2，FADS 3，GALLV 5和CERK基因的变异之间存在统计学显著相关性。GALC，SMPD 1和CERS 6的变体在其他ADHD队列中成功复制。报道这些发现的论文现已发表（Henriquez-Henriquez et al.，2020年）。