Genetics of Anorexia Nervosa

描述(申请人提供)：神经性厌食症(AN)是一种慢性疾病，通常是致命的，影响0.3%的女性。没有FDA批准的治疗方法，死亡率为每十年5%。除了环境影响外，家庭和双胞胎研究表明，AN的遗传性很强。由于这种毁灭性疾病的病因尚不清楚，我们进行了一项初步研究，以检查其遗传基础。在一个私人基金会的支持下，我们的多中心合作已经从北美和欧洲的7个地点收集了196个多路家庭。在样本有限的情况下，这项先导研究从全基因组扫描中产生了四个提示性链接，其中一个非常接近全基因组意义(染色体1在70 cM，p-0.0001；Chr。1在202 cm处，LOD=3 46。P=0.00003；2在10 2 cm处，LOD=2.2 2，P=0.00070；13在102厘米处。LOD=2.5；p=0.00035)第一个暗示连锁来自样本的子集，即具有An限制亚型的个体。其他结果是通过将两个协变量，即来自饮食障碍调查-2的瘦的驱动力和来自耶鲁-布朗强迫量表的总分，纳入到基于协变量的连锁分析中。基于这些非常有希望的连锁发现，我们相信可以通过扩大试点样本来定位潜在的AN易感性基因。因此，需要为收集400个受影响的亲属对的多中心工作提供支持。在五年的时间里，11个合作小组(10个临床小组，1个分析小组)将从400个多基因家系收集诊断和其他表型数据和血液样本。匹兹堡大学就是这些研究小组之一。他们中的每一个都作为一群合作的R01提交了几乎相同的申请。微卫星将在基因组中以H 10厘米的间隔使用所有新的家族进行基因分型。将通过使用诊断和表型数据进行连锁分析，以确认来自试点研究的暗示关联，并确定新的感兴趣的基因组区域。诊断和遗传数据以及淋巴母细胞系(取自血液样本)将成为国家档案资源的一部分，用于通过NIMH遗传学倡议进行的遗传病研究。

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) is a chronic and often fatal disorder that affects 0.3% of women. There is no FDA-approved treatment, and the mortality rate is 5% per decade. In addition to environmental influence, family and twin studies demonstrate substantial heritability for AN. Because the etiology of this devastating illness is not known, we undertook a pilot study to examine its genetic underpinnings. With the support of a private foundation, our multicenter collaboration has collected 196 multiplex AN kindreds from 7 sites across North America and Europe. With a limited sample, this pilot study has produced four suggestive linkages from a genome-wide scan, one very close to genome-wide significance (Chromosome 1 at 70 cM, p - 0.0001; Chr. 1 at 202 cM, LOD = 3 46. p = 0.00003; Chr. 2 at 102 cM, LOD = 2.22: p = 0.00070; and Chr. 13 at 102 cM. LOD = 2.50; p = 0.00035) The first suggestive linkage results from a subset of the sample, namely individuals with the restricting subtype of AN. The other results were obtained by incorporating two covariates, drive-for-thinness from the Eating Disorders lnventory-2 and the total score from the Yale-Brown Obsessive Compulsive Scale, into covariate-based linkage analysis. Based on these very promising linkage findings, we believe genes underlying liability to AN can be mapped by augmenting the pilot sample. Thus support is requested for a multicenter effort to collect 400 affected relative pairs with AN. Over a five year period, the 11 collaborating groups (10 clinical, 1 analytic) will collect diagnostic and other phenotypic data and blood samples from 400 multiplex AN kindreds. The UNIVERSITY OF PITTSBURGH is one of these research groups. each of which is submitting a nearly identical application as a group of collaborating R01s. Microsatellites will be genotyped at H 10 cM intervals across the genome using all new families. Linkage analyses will be conducted by using diagnostic and phenotypic data to confirm suggestive linkages from the pilot study and to identify new genomic regions of interest. The diagnostic and genetic data and lymphoblastoid cell lines (derived from blood samples) will become part of a national archival resource for genetic studies of AN through the NIMH Genetics Initiative.