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. ? ? ?
