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，其目标是使用包括中间表型在内的新策略来识别复杂疾病（如注意缺陷多动障碍（ADHD））的基因。虽然ADHD的遗传性已经得到了证实，但在确定易感基因方面进展缓慢。“内表型”存在于从基因到行为的通路中，可能会增加分子遗传学研究的力量，因为它们相对于疾病降低了复杂性，并且有可能划分异质神经生物学过程。由于受影响个体及其亲属的受损状态，前额叶纹状体和相关神经网络功能的神经认知测量作为ADHD的候选内表型被广泛讨论。然而，它们在分子遗传学研究中尚未得到系统的研究。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有用的内表型。我们的中心假设是，这些损伤表明了一种或多种潜在的特征，这些特征与该疾病的可遗传病理生理部分重叠。因此，我们期望它们将有助于发现ADHD基因。为了验证这一假设，我们的目标是利用我们从ADHD的受影响兄弟姐妹联系研究中获得的数据。我们建议使用生物识别模型将我们的神经认知电池减少到基于家族结构的少数因素。我们将把这些因素纳入多动症的多变量关联分析中，使用一种策略，使我们能够确定共同或单独影响每种表型的基因座。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，即识别增加ADHD及其相关神经认知障碍风险的基因变异，并阐明该疾病的神经生物学。我们的方法是创新的，因为多元全基因组关联尚未用于探索ADHD的内表型。这一建议意义重大，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的生物学靶点。由于ADHD的高患病率及其与学业和职业失败、药物滥用、犯罪、驾驶事故和医疗保健过度利用的关联，开发更好的ADHD模型和治疗方法是一项重要的公共卫生目标。

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.