A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication
A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication
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DOI：
10.1038/mp.2010.6
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发表时间：
2010-11-01
影响因子：
11
通讯作者：
Muenke, M.
中科院分区：
文献类型：
--
作者：
Arcos-Burgos, M.;Jain, M.;Muenke, M.
注意力缺陷多动障碍（ADHD）具有非常高的遗传率（0.8），表明约80%的表型变异是由于遗传因素。我们使用统计和功能方法的整合来发现一种导致ADHD的新基因。对于我们的统计方法，我们首先进行了一项基于群体隔离中大型多代家庭的连锁研究，然后使用基于家庭的设计对目标区域进行精细定位。在来自世界不同地区的五个样本中进行了基于家庭和人口的关联研究。进行脑成像研究以评估基因功能。连锁研究发现了一个基因组区域，该区域位于Latrophilin 3基因（LPHN 3）中。在全世界范围的样本中（总n=6360，2627例ADHD病例和2531例对照），LPHN 3和ADHD的统计学关联得到证实。功能研究表明，LPHN 3变体在与注意力和活动相关的关键大脑区域中表达，影响与ADHD有关的神经回路的代谢，并与对兴奋剂药物的反应有关。ADHD与一个新的非候选基因（LPHN 3）的连锁和复制关联为ADHD的遗传学，神经生物学和治疗提供了新的见解。Molecular Psychiatry（2010）15，1053-1066; doi：10.1038/mp.2010.6; 2010年2月16日在线发表
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD. Molecular Psychiatry (2010) 15, 1053-1066; doi:10.1038/mp.2010.6; published online 16 February 2010