An Affected SibPair Study of ADHD in Costa Rica

描述（由申请人提供）：这是一项旨在确定引起注意缺陷多动障碍（ADHD）的基因的染色体定位的建议，ADHD是一种遗传性疾病，始于儿童期，其特征是注意力、注意力集中和注意力不集中。这一目标将通过对哥斯达黎加中央谷遗传同质人群中有多个受影响兄弟姐妹（受影响同胞对或ASP家庭）的家庭进行研究来实现（CVCR）。ADHD家族很可能从一个或几个共同的祖先遗传了ADHD的易感性。ADHD基因将通过使用连锁和关联研究搜索ADHD患者具有相同血统（IBD）的基因组区域来绘制。研究样本将包括有两个或两个以上兄弟姐妹患有ADHD的家庭及其父母（总共约300个家庭）。诊断评估将包括对患者、家庭成员和教师的采访，以及对医疗记录的审查。最终诊断将通过由专家诊断ADHD的“最佳估计”共识过程来实现。将获得所有家庭的家谱，只有当他们的大多数祖先（等于或>5/8的曾祖父母）是CVCR起源时，这些家庭才被纳入研究。将对样本进行基因分型，以确定被认为在ADHD易感性中起作用的候选基因，以及使用分布在整个基因组中的标记。功效分析表明，即使在病因异质性的情况下，在拟议的研究样本中检测到ADHD易感基因的概率也很高。这项研究的创新之处在于，它结合了在遗传隔离人群中使用连锁和关联研究，以及使用最先进的统计方法来提高样本的功效和精度。一旦ADHD基因被定位，精细定位研究就可以开始，最终导致定位克隆的努力。在CVCR中进行的初步研究显示了本申请中描述的采样、诊断和基因分型方法的可行性。将通过在CVCR中建立的持续合作来促进采样。

DESCRIPTION (provided by applicant): This is a proposal to identify the chromosomal location of genes responsible for attention deficit hyperactivity disorder (ADHD), an inherited disorder that begins in childhood and is characterized by problems with attention, concentration, and distractibility. This goal will be achieved by studies of families with multiple affected siblings (affected sib pair or ASP families) in the genetically homogeneous population of the Central Valley of Costa Rica (CVCR). ADHD families in this population have likely inherited a susceptibility to ADHD from one or a few common ancestors. ADHD genes will be mapped by searching for genome regions that ADHD patients share identical by descent (IBD), using linkage and association studies. The study sample will consist of families with two or more siblings affected with ADHD and their parents (approximately 300 families total). Diagnostic assessment will include interviews of patients, family members, and teachers, and review of medical records. Final diagnoses will be achieved through a "best estimate" consensus process conducted by experts in diagnosing ADHD. Genealogies will be obtained for all families, who will be included in the study only if the majority of their ancestors (equal to or >5/8 great-grandparents) are of CVCR origin. The samples will be genoyped for candidate genes thought to play a role in ADHD susceptibility, as well as using markers distributed throughout the genome. Power analyses show a high probability of detecting ADHD susceptibility genes in the proposed study sample, even given etiological heterogeneity. This study is innovative in that it combines the use of linkage and association studies in a genetically isolated population, as well as using cutting edge statistical approaches to increase the power and refine the precision of the sample. Once ADHD genes are localized, fine-mapping studies can begin, ultimately leading to positional cloning efforts. Preliminary studies conducted in the CVCR show the feasibility of the sampling, diagnostic, and genotyping approaches described in this application. The sampling will be facilitated by ongoing collaborations established in the CVCR.