Genomewide linkage analyses of neurocognitive traits in sibling pairs with ADHD

描述（由申请人提供）：该提案响应FOA PAS-06-204，其目标是使用新策略，包括中间表型，以识别复杂疾病（如注意力缺陷多动障碍（ADHD））的基因。虽然ADHD的遗传性是公认的，但在识别易感基因方面进展缓慢。位于从基因到行为的通路中的“内表型”可能会增加分子遗传学研究的力量，因为它们相对于疾病的复杂性降低，并且它们有可能划分异质性神经生物学过程。前额叶-纹状体和相关神经网络功能的神经认知测量已被广泛讨论为ADHD的候选内表型，因为它们在受影响的个体及其亲属中的受损状态。然而，在分子遗传学研究中，它们还没有被系统地研究。目前的建议旨在评估前额叶认知，注意力和处理速度的损伤在多大程度上是ADHD的有用内表型。我们的中心假设是，这些损伤是一个潜在的特征，或特征，部分重叠/s与遗传的病理生理障碍。因此，我们希望他们将有助于寻找ADHD基因。为了验证这一假设，我们的目标是利用数据已经从我们受影响的兄弟姐妹对连锁研究多动症。我们建议使用生物统计建模，以减少我们的神经认知电池的一小部分因素的基础上，他们的家族架构。我们将把这些因素纳入ADHD的多变量连锁分析，使用的策略，将使我们能够确定共同和单独贡献每一个表型的基因座。在探索性分析中，我们将在表型和基因型水平上研究我们最有希望的连锁峰。这项工作将推进我们研究的长期目标，即确定增加ADHD及其相关神经认知障碍风险的基因变异，并阐明这种疾病的神经生物学。我们的方法是创新的，因为多变量全基因组连锁尚未用于探索ADHD内表型。这一提议意义重大，因为发现ADHD及其相关神经认知障碍的基因将有助于确定新的干预和预防生物靶点。开发更好的ADHD模型和治疗方法是一个重要的公共卫生目标，因为这种疾病的高患病率及其与学术和职业失败，药物滥用，犯罪，驾驶事故和医疗保健过度使用的相关性。

DESCRIPTION (provided by applicant): This proposal responds to FOA PAS-06-204, the goal of which is to use novel strategies, including intermediate phenotypes, to identify genes for complex conditions such as attention deficit-hyperactivity disorder (ADHD). Although the heritability of ADHD is well-established, progress in identifying susceptibility genes has been slow. "Endophenotypes" that lie in the pathway from genes to behavior may increase the power of molecular genetic studies because of their reduced complexity relative to the disorder and their potential to partition heterogeneous neurobiological processes. Neurocognitive measures of functioning in prefrontal-striatal and related neural networks have been widely discussed as candidate endophenotypes for ADHD due to their impaired status in affected individuals and their relatives. Yet, they have not been investigated systematically in molecular genetics studies. The current proposal aims to evaluate the extent to which impairments in prefrontal cognition, attention and processing speed are useful endophenotypes for ADHD. Our central hypothesis is that these impairments index a latent trait, or traits, that partially overlap/s with the heritable pathophysiology of the disorder. Thus, we expect that they will be useful for finding ADHD genes. To test this hypothesis, we aim to capitalize on data already available from our affected sibling pair linkage study of ADHD. We propose to use biometrical modeling to reduce our neurocognitive battery to a small number of factors based on their familial architecture. We will incorporate these factors into a multivariate linkage analysis of ADHD, using a strategy that will allow us to identify loci that contribute jointly and separately to each phenotype. In exploratory analyses, we will investigate our most promising linkage peak at the phenotypic and genotypic levels. This work will advance the long-term goals of our research, which are to identify gene variants that increase the risk for ADHD and its correlated neurocognitive impairments and to clarify the neurobiology of the disorder. Our approach is innovative because multivariate genomewide linkage has not been used to explore ADHD endophenotypes. This proposal is significant because finding genes for ADHD and its correlated neurocognitive impairments will facilitate the identification of novel biological targets for intervention and prevention. Developing better models of and treatments for ADHD is an important public health goal due to the high prevalence of the condition and its association with academic and occupational failure, substance abuse, criminality, driving accidents and health care over-utilization.