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Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission.

来自单个和多个事件家族的 ADHD trios 的全外显子组测序涉及新的候选基因,并突出多基因传递。

  • 影响因子:3.36
  • DOI:10.1038/s41431-020-0619-7
  • 作者列表:"Al-Mubarak BR","Omar A","Baz B","Al-Abdulaziz B","Magrashi AI","Al-Yemni E","Jabaan A","Monies D","Abouelhoda M","Abebe D","Ghaziuddin M","Al-Tassan NA
  • 发表时间:2020-04-01
Abstract

Several types of genetic alterations occurring at numerous loci have been described in attention deficit hyperactivity disorder (ADHD). However, the role of rare single nucleotide variants (SNVs) remains under investigated. Here, we sought to identify rare SNVs with predicted deleterious effect that may contribute to ADHD risk. We chose to study ADHD families (including multi-incident) from a population with a high rate of consanguinity in which genetic risk factors tend to accumulate and therefore increasing the chance of detecting risk alleles. We employed whole exome sequencing (WES) to interrogate the entire coding region of 16 trios with ADHD. We also performed enrichment analysis on our final list of genes to identify the overrepresented biological processes. A total of 32 rare variants with predicted damaging effect were identified in 31 genes. At least two variants were detected per proband, most of which were not exclusive to the affected individuals. In addition, the majority of our candidate genes have not been previously described in ADHD including five genes (NEK4, NLE1, PSRC1, PTP4A3, and TMEM183A) that were not previously described in any human condition. Moreover, enrichment analysis highlighted brain-relevant biological themes such as "Glutamatergic synapse", "Cytoskeleton organization", and "Ca2+ pathway". In conclusion, our findings are in keeping with prior studies demonstrating the highly challenging genetic architecture of ADHD involving low penetrance, variable expressivity and locus heterogeneity.

摘要

在注意缺陷多动障碍 (ADHD) 中已经描述了在众多位点发生的几种类型的遗传改变。然而,罕见单核苷酸变异 (SNVs) 的作用仍在研究中。在这里,我们试图确定具有预测有害作用的罕见 SNVs 可能导致 ADHD 风险。我们选择研究多动症家族 (包括多发病) 来自一个血缘关系率高的人群,其中遗传危险因素倾向于积累,因此增加了检测危险等位基因的机会。我们采用全外显子组测序 (WES) 询问 16 例 ADHD 三联体的整个编码区。我们还对最终的基因列表进行了富集分析,以确定过度表达的生物过程。在 31 个基因中共鉴定出 32 个具有预测损伤效应的罕见变异。每个先证者至少检测到两种变异,其中大部分不局限于受累个体。此外,我们的大多数候选基因以前没有在 ADHD 中描述过,包括五个基因 (NEK4 、 NLE1 、 PSRC1 、 PTP4A3 和 TMEM183A) 以前没有在任何人类条件下描述过的。此外,富集分析突出了 “谷氨酸能突触” 、 “细胞骨架组织” 和 “Ca2 + 通路” 等脑相关的生物学主题。总之,我们的研究结果与以前的研究一致,证明了 ADHD 的高度挑战性的遗传结构,涉及低 penetr率、可变表达率和位点异质性。

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影响因子:2.12
发表时间:2020-01-12
来源期刊:Trials
DOI:10.1186/s13063-019-3872-8
作者列表:["Katja Becker","Tobias Banaschewski","Daniel Brandeis","Christina Dose","Christopher Hautmann","Martin Holtmann","Thomas Jans","Lea Jendreizik","Carolin Jenkner","Katja John","Johanna Ketter","Sabina Millenet","Ursula Pauli-Pott","Tobias Renner","Marcel Romanos","Anne-Katrin Treier","Elena von Wirth","Anne-Kathrin Wermter","Manfred Döpfner"]

METHODS:Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a psychosocially impairing and cost-intensive mental disorder, with first symptoms occurring in early childhood. It can usually be diagnosed reliably at preschool age. Early detection of children with ADHD symptoms and an early, age-appropriate treatment are needed in order to reduce symptoms, prevent secondary problems and enable a better school start. Despite existing ADHD treatment research and guideline recommendations for the treatment of ADHD in preschool children, there is still a need to optimise individualised treatment strategies in order to improve outcomes. Therefore, the ESCApreschool study (Evidence-Based, Stepped Care of ADHD in Preschool Children aged 3 years and 0 months to 6 years and 11 months of age (3;0 to 6;11 years) addresses the treatment of 3–6-year-old preschool children with elevated ADHD symptoms within a large multicentre trial. The study aims to investigate the efficacy of an individualised stepwise-intensifying treatment programme. Methods The target sample size of ESCApreschool is 200 children (boys and girls) aged 3;0 to 6;11 years with an ADHD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a diagnosis of oppositional defiant disorder (ODD) plus additional substantial ADHD symptoms. The first step of the adaptive, stepped care design used in ESCApreschool consists of a telephone-assisted self-help (TASH) intervention for parents. Participants are randomised to either the TASH group or a waiting control group. The treatment in step 2 depends on the outcome of step 1: TASH responders without significant residual ADHD/ODD symptoms receive booster sessions of TASH. Partial or non-responders of step 1 are randomised again to either parent management and preschool teacher training or treatment as usual. Discussion The ESCApreschool trial aims to improve knowledge about individualised treatment strategies for preschool children with ADHD following an adaptive stepped care approach, and to provide a scientific basis for individualised medicine for preschool children with ADHD in routine clinical care. Trial registration The trial was registered at the German Clinical Trials Register (DRKS) as a Current Controlled Trial under DRKS00008971 on 1 October 2015. This manuscript is based on protocol version 3 (14 October 2016).

影响因子:3.16
发表时间:2020-03-02
DOI:10.1016/j.bbr.2019.112382
作者列表:["Kibby MY","Dyer SM","Lee SE","Stacy M"]

METHODS:Prefrontal volume reductions commonly are demonstrated in ADHD, but the literature examining prefrontal volume in reading disorders (RD) is scant despite their also having executive functioning (EF) deficits. Furthermore, only a few anatomical studies have examined the frontal lobes in comorbid RD/ADHD, though they have EF deficits similar to RD and ADHD. Hence, we examined frontal gyri volume in children with RD, ADHD, RD/ADHD and controls, as well as their relationship to EF for gyri found to differ between groups. We found right inferior frontal (RIF) volume was smaller in ADHD, and smaller volume was related to worse behavioral regulation. Left superior frontal (LSF) volume was larger in RD than ADHD, and its size was negatively related to basic reading ability. Left middle frontal (LMF) volume was largest in RD/ADHD overall. Further, its volume was not related to basic reading nor behavioral regulation but was related to worse attentional control, suggesting some specificity in its EF relationship. When examining hypotheses on the etiology of RD/ADHD, RD/ADHD was commensurate with ADHD in RIF volume and both RD and ADHD in LSF volume (being midway between the groups), consistent with the common etiology hypothesis. Nevertheless, they also had an additional gyrus affected: LMF, consistent with the cognitive subtype hypothesis in its specificity to RD/ADHD. The few other frontal aMRI studies on RD/ADHD supported both hypotheses as well. Given this, future research should continue to focus on frontal morphology in its endeavors to find neurobiological contributors to the comorbidity between RD and ADHD.

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影响因子:5.77
发表时间:2020-01-24
来源期刊:Psychological medicine
DOI:10.1017/S0033291719004148
作者列表:["Mooney MA","Bhatt P","Hermosillo RJM","Ryabinin P","Nikolas M","Faraone SV","Fair DA","Wilmot B","Nigg JT"]

METHODS:BACKGROUND:Mechanistic endophenotypes can inform process models of psychopathology and aid interpretation of genetic risk factors. Smaller total brain and subcortical volumes are associated with attention-deficit hyperactivity disorder (ADHD) and provide clues to its development. This study evaluates whether common genetic risk for ADHD is associated with total brain volume (TBV) and hypothesized subcortical structures in children. METHODS:Children 7-15 years old were recruited for a case-control study (N = 312, N = 199 ADHD). Children were assessed with a multi-informant, best-estimate diagnostic procedure and motion-corrected MRI measured brain volumes. Polygenic scores were computed based on discovery data from the Psychiatric Genomics Consortium (N = 19 099 ADHD, N = 34 194 controls) and the ENIGMA + CHARGE consortium (N = 26 577). RESULTS:ADHD was associated with smaller TBV, and altered volumes of caudate, cerebellum, putamen, and thalamus after adjustment for TBV; however, effects were larger and statistically reliable only in boys. TBV was associated with an ADHD polygenic score [β = -0.147 (-0.27 to -0.03)], and mediated a small proportion of the effect of polygenic risk on ADHD diagnosis (average ACME = 0.0087, p = 0.012). This finding was stronger in boys (average ACME = 0.019, p = 0.008). In addition, we confirm genetic variation associated with whole brain volume, via an intracranial volume polygenic score. CONCLUSION:Common genetic risk for ADHD is not expressed primarily as developmental alterations in subcortical brain volumes, but appears to alter brain development in other ways, as evidenced by TBV differences. This is among the first demonstrations of this effect using molecular genetic data. Potential sex differences in these effects warrant further examination.

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