MOLECULAR GENETIC EPIDEMIOLOGY STUDY OF ADHD/DRD4

利用人类基因组计划确定的大量标记位点，关联研究正在应用于许多复杂疾病的数据。一旦确定了一种关联，研究人员的问题是确定这种关联告诉我们关于疾病过程的什么。当被大量研究证实时，这种关联是统计学伪影的可能性很小。于是我们就有了两种解释：相关的等位基因在疾病中起着致病作用，或者该等位基因与另一个起作用的基因座（多态性）处于连锁不平衡状态。为了真正理解这种疾病，我们必须区分这些疾病，但如何区分呢？该项目旨在利用我们的能力，在严格的研究设计中确定的大量个体中快速准确地对基因座进行DNA测序，并应用这些信息来确定关联的原因。我们选择检查注意缺陷多动障碍（ADHD）和多巴胺受体基因DRD 4。我们首先报道了ADHD与该基因的D4.7等位基因的相关性，现在已经被我们和其他五项研究证实。ADHD影响约3-5%的学龄人口，被认为是儿童期最普遍的精神疾病。家庭，双胞胎和收养研究已经为ADHD建立了强大的遗传基础。候选基因的最初分子遗传学研究集中在神经递质多巴胺上，因为大多数患者对哌甲酯有反应。DRD 4基因座是高度可变的基因座，其中48 bp片段的7-重复形式出现在许多等位基因形式中。在DRD 4中还发现了其他多态性，其中一些具有已知的功能意义，但没有一个在ADHD研究中进行过评估。先证者将通过儿童发展中心的临床试验确定，当他们符合ADHD的严格诊断标准时。先证者、他们的父母和兄弟姐妹将被研究，他们的DNA将被测序为DRD 4。将对其他多巴胺通路基因座进行基因分型。在那些携带D4.7的家庭中，我们将确定DRD 4基因中存在的所有多态性的受影响个体中存在的单倍型。对于非D4.7家系，我们将检测与DRD 4区域的紧密连锁。如果D4.7仅仅是一个与致病多态性连锁不平衡的标记，那么后一个家族子集也应该显示出连锁的证据。

Utilizing the vast number of marker loci being identified by the Human Genome Project, association studies are being applied to data on many complex disorders. Once an association is identified the issue for investigators is to determine what the association tells us about the disease process. When confirmed by numerous studies, the possibility of he association being a statistical artifact is remote. We are then left with two explanations: the associated allele plays a causative role in the disorder or the allele is in linkage disequilibrium with another locus(polymorphism) which does play a role. In order to truly understand the disorder we will have to distinguish between these, but how? This project is designed to capitalize on our ability to rapidly and accurately sequence DNA for a locus over a large number of individuals ascertained within a rigorous research design, and apply that information to determine the reason for he association. We have chosen to examine Attention Deficit Hyperactivity Disorder (ADHD) and the dopamine receptor gene DRD4. We first reported the association of ADHD with the D4.7 allele of this gene, which has now been confirmed by us and five other studies. ADHD affects about 3-5% of the school-aged population and is considered the most prevalent psychiatric disorder of childhood. Family, twin, and adoption studies have established a strong genetic basis for ADHD. Initial molecular genetic investigations of candidate genes focused on the neurotransmitter dopamine because most patients are responsive to methylphenidate. The DRD4 locus is a highly variable locus where the 7- repeat form of a 48 bp segment occurs in many allelic forms. Other polymorphisms have been identified in DRD4, some of which have known functional significance, but none of which have been evaluated in ADHD studies. Probands will be ascertained through clinical trials at the Child Development Center, UCI when they meet rigorous diagnostic criteria for ADHD. Probands, their parents, and siblings will be studied and their DNA sequenced for DRD4. Other dopamine pathway loci will be genotyped. Within those families who carry D4.7 we will determine the haplotype(s) present in affected individuals for all of the polymorphisms present in the DRD4 gene. For the non-D4.7 families we will test or tight linkage with the DRD4 region. If D4.7 is merely a marker in linkage disequilibrium with a causative polymorphism, then this latter subset of families should also show evidence for linkage.