STRONG EVIDENCE FOR A CHROMOSOME 4 RISK LOCUS PREDISPOISNG TO ANXIETY DISORDERS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们对一组19个美国扩展家系（219名受试者）进行了10 cM连锁常染色体基因组扫描，这些家系通过惊恐障碍先证者确定。几种焦虑症，包括社交恐惧症，广场恐惧症和简单恐惧症-除了恐慌症-在这些家庭中分离。在以前对这个样本的分析中，连锁分析分别基于每个单独的分类情感诊断。考虑到焦虑症和它们可能共有的遗传易感性之间的实质性共病性，很明显，这种方法丢弃了相当多的信息。我们提出了一种新的方法，认为恐慌症，简单恐怖症，社交恐怖症，广场恐怖症作为相同的多变量，pupuncturegenetically影响，性状的表达。我们应用多点Haseman-Elston方法，使用这些表型的模糊聚类产生的隶属度作为Haseman-Elston回归中的因变量。染色体4 q31-q34上标记D4 S413周围的一个区域（多点和单点标称p值<0.00001）显示出连锁的强有力证据（全基因组显著性p<0.05）。已知同一区域是神经肽Y受体基因NPY 1 R（4 q31-q32）的位点，该基因最近与大鼠的抗焦虑作用有关。我们的研究结果支持了这样一种观点，即主要的焦虑症，包括恐惧症和恐慌症，都是复杂的特征，它们至少有一个共同的易感性位点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We conducted a 10 cM linkage autosomal genome scan in a set of 19 American extended pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders, including social phobia, agoraphobia, and simple phobias - in addition to panic disorder- segregate in these families. In previous analyses on this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Considering the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. We proposed a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced, trait. We applied the multipoint Haseman-Elston method, using the grades of membership generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34 around marker D4S413 (multipoint and single-point nominal p-values <0.00001) showed strong evidence of linkage (genome-wide significant at p<0.05). The same region is known to be the site of a neuropeptide Y receptor gene NPY1R (4q31-q32) that was recently implicated in anxiolytic-like effects in rats. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus.