ADGRL3 (LPHN3) variants are associated with a refined phenotype of ADHD in the MTA study.
ADGRL3 (LPHN3) variants are associated with a refined phenotype of ADHD in the MTA study.
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DOI：
10.1002/mgg3.230
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发表时间：
2016-09
影响因子：
2
通讯作者：
Muenke M
中科院分区：
文献类型：
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作者：
Acosta MT;Swanson J;Stehli A;Molina BS;MTA Team;Martinez AF;Arcos-Burgos M;Muenke M
ADHD是影响所有年龄段个体的最常见的神经精神疾病。受影响个体的长期结局以及与重度合并症（如SUD或行为障碍）的相关性是主要问题。遗传关联已被广泛描述。多项研究表明，ADGRL 3（LPHN 3）基因中的内含子变异与ADHD相关，尤其是与不良结局相关。在这项研究中，我们在ADHD儿童的多模式治疗研究（MTA）中评估了这种关联，该研究最初是一项为期14个月的随机临床试验，共有579名诊断为DSM-IV ADHD-混合型（ADHD-C）的儿童，过渡到16年的前瞻性观察随访，并在2年评估时增加了289名同学作为当地规范性对照组（LNCG）。入学时的诊断评估是基于儿童-父母诊断访谈计划（DISC-P），多年来在几个点重复进行。对于附加遗传学研究，从MTA组的232例和LNCG组的139例中采集血样。在205名MTA参与者中，14.6%的人在青春期保留了DISC-P对ADHD-C的诊断。在127名LNCG参与者中，88.2%的人仍未被DISC-P诊断。我们对ADGRL 3基因中的15个多态性SNP标记进行了基因分型，并将30例在青春期继续诊断为ADHD‐C的病例的等位基因频率与其他参与者进行了比较。观察到rs 2345039 ADGRL 3变异体相关性的复制（P值= 0.004，FDR校正= 0.03;比值比= 2.25，CI上限1.28-3.97）。在从儿童期到青春期持续诊断ADHD‐C的极端表型中检测到ADGRL 3变异体赋予的易感性，为ADGRL 3和ADHD的关联不是虚假的提供了额外的支持。在纵向队列中探索遗传效应，其中记录了精炼的，年龄依赖性的表型，对于了解ADHD的自然史至关重要。
ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long‐term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes. In this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14‐month randomized clinical trial of 579 children diagnosed with DSM‐IV ADHD‐Combined Type (ADHD‐C), that transitioned to a 16‐year prospective observational follow‐up, and 289 classmates added at the 2‐year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children‐Parent (DISC‐P), which was repeated at several points over the years. For an add‐on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG. For the 205 MTA participants, 14.6% retained the DISC‐P diagnosis of ADHD‐C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC‐P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD‐C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28–3.97). The detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD‐C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age‐dependent phenotypes are documented, is crucial to understand the natural history of ADHD.