Identification of Sex-Specific Genes for Stuttering

描述(由申请人提供)：最近的研究表明，许多复杂表型的遗传结构中存在显著的性别特异性成分，包括我们报道的关于口吃的言语和语言障碍的结果。很少有基于连锁的性别特异性信号经历了足够的后续行动，从而导致基因鉴定和对信号背后的性别特异性的性质的理解。我们建议对之前的连锁图谱研究中确定的三个区域进行精细定位，对最大的要进行口吃连锁图谱绘制的家庭队列进行定位。性别特异性连锁分析导致在染色体7q上的一个区域与全基因组范围内的连锁有明显的证据，而在第21号染色体上的一个区域在全基因组范围内与雌性的连锁的显著证据。第三个被检查的区域(2Q)具有很高的跟进优先权，因为它与自闭症语言亚型研究中涉及的一个区域近乎完美地重叠。我们的具体目标是(1)使用SNPlex基因分型平台对这三个区域进行精细定位，SNP基因分型的初始密度随着距离连锁证据峰值的距离而降低；2)利用[最近Affymetrix基因表达阵列]在CEPH细胞系中调查7号和21号染色体上具有性别特异性连锁证据的区域与口吃的连锁和关联研究。复杂表型的精细作图和位置克隆研究本身就是高风险的。我们正在跟踪的三个信号中有两个具有性别特异性，这可能会增加研究的挑战(和风险)，但也为开发研究框架提供了机会，从而提高了成功的可能性。我们提出的这项研究建立在考克斯和乔里安博士实验室的现有优势、芝加哥大学开发的独特资源和大规模公开资源的基础上，以开发一个框架来确定复杂疾病的性别特异性基因，并确定一个或多个影响口吃风险的基因。

DESCRIPTION (provided by applicant): Recent studies have suggested a significant sex-specific component to the genetic architecture of many complex phenotypes, including results we reported for the speech and language disorder of stuttering. Few linkage-based sex-specific signals have undergone sufficient follow up to lead to gene identification and an understanding of the nature of the sex specificity underlying the signal. We propose here to conduct fine mapping of three regions identified in previous linkage mapping studies on the largest cohort of families to undergo linkage mapping for stuttering. Sex-specific linkage analyses led to identification of a region on chromosome 7q with genome-wide significant evidence for linkage in males and to a region on chromosome 21 with genome-wide significant evidence for linkage in females. The third region to be examined (2q) had high priority for follow up because of its near-perfect overlap with a region implicated in studies of a language subphenotype of autism. Our specific aims are (1) to conduct fine mapping over these 3 regions using the SNPlex genotyping platform, with initial density of SNP genotyping decreasing with distance from the peak evidence for linkage; 2) to investigate the regions on chromosomes 7 and 21 with the sex-specific evidence for linkage to stuttering with linkage and association studies in CEPH cell lines phenotyped for gene expression using [recent Affymetrix Gene Expression Array]. Fine mapping and positional cloning studies of complex phenotypes are inherently high risk. The sex-specific nature of 2 of the 3 signals we are following up may increase the challenges (and risks) of the research, but also offers opportunities for developing a research framework that will improve the likelihood for success. The research we propose builds on existing strengths in the laboratories of Drs. Cox and Gilliam, unique resources developed at The University of Chicago, and large-scale publicly available resources to develop a framework for the identification of sex-specific genes for complex disorders and to identify one or more genes affecting the risk of stuttering.