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具有重要的性别特异性成分，包括我们报道的口吃的语言和语言障碍的结果。很少有基于连锁的性别特异性信号经历了足够的随访，从而导致基因鉴定和理解信号背后的性别特异性的本质。在此，我们建议对先前连锁图谱研究中确定的三个区域进行精细图谱绘制，并对最大的家族队列进行口吃连锁图谱绘制。性别特异性连锁分析鉴定出染色体7q上的一个区域在男性中具有全基因组范围内显著的连锁证据，而染色体21上的一个区域在女性中具有全基因组范围内显著的连锁证据。要检查的第三个区域（2q）具有很高的后续优先级，因为它与自闭症语言亚表型研究中涉及的区域近乎完美地重叠。我们的具体目标是：(1)利用SNPlex基因分型平台对这3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峰值证据的距离而降低；2)利用[最近的Affymetrix基因表达阵列]对CEPH细胞系进行基因表达表型的连锁和关联研究，研究7号和21号染色体上的区域与口吃相关的性别特异性证据。复杂表型的精细制图和定位克隆研究本身就是高风险的。我们正在跟踪的3个信号中有2个的性别特异性可能会增加研究的挑战（和风险），但也为开发一个研究框架提供了机会，这将提高成功的可能性。我们建议的研究建立在博士实验室的现有优势之上。Cox和Gilliam，芝加哥大学开发的独特资源，以及大规模的公共资源，以开发一个框架，用于识别复杂疾病的性别特异性基因，并识别影响口吃风险的一个或多个基因。

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.