National Human Genome Research Institute, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
Mol Psychiatry. 2010 Nov;15(11):1053-66. doi: 10.1038/mp.2010.6. Epub 2010 Feb 16.
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.
注意缺陷多动障碍（ADHD）的遗传性很高（0.8），表明大约 80%的表型变异是由遗传因素引起的。我们使用统计和功能方法的整合来发现一个新的基因，该基因与 ADHD 有关。对于我们的统计方法，我们从人口隔离的大型多代家族的连锁研究开始，然后使用基于家族的设计对目标区域进行精细映射。来自世界不同地区的五个样本的基于家族和基于人群的关联研究用于复制。进行脑成像研究以评估基因功能。连锁研究发现了一个Latrophilin 3 基因（LPHN3）中包含的基因组区域。在全球样本（总 n=6360，其中 2627 例 ADHD 病例和 2531 例对照）中，LPHN3 与 ADHD 的统计关联得到确认。功能研究表明，LPHN3 变体在与注意力和活动相关的关键大脑区域表达，影响与 ADHD 相关的神经回路中的代谢，并且与对兴奋剂药物的反应相关。ADHD 与新的非候选基因（LPHN3）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。
