New complexities in the genetics of stuttering: significant sex-specific linkage signals

Abstract

Stuttering is a speech disorder long recognized to have a genetic component. Recent linkage studies mapped a susceptibility locus for stuttering to chromosome 12 in 46 highly inbred families ascertained in Pakistan. We report here on linkage studies in 100 families of European descent ascertained in the United States, Sweden, and Israel. These families included 252 individuals exhibiting persistent stuttering, 45 individuals classified as recovered from stuttering, and 19 individuals too young to classify. Primary analyses identified moderate evidence for linkage of the broader diagnosis of "ever stuttered" (including both persistent and recovered stuttering) on chromosome 9 (LOD = 2.3 at 60 cM) and of the narrower diagnosis of persistent stuttering on chromosome 15 (LOD = 1.95 at 23 cM). In contrast, sex-specific evidence for linkage on chromosome 7 at 153 cM in the male-only data subset (LOD = 2.99) and on chromosome 21 at 34 cM in the female-only data subset (LOD = 4.5) met genomewide criteria for significance. Secondary analyses revealed a significant increase in the evidence for linkage on chromosome 12, conditional on the evidence for linkage at chromosome 7, with the location of the increased signal congruent with the previously reported signal in families ascertained in Pakistan. In addition, a region on chromosome 2 (193 cM) showed a significant increase in the evidence for linkage conditional on either chromosome 9 (positive) or chromosome 7 (negative); this chromosome 2 region has been implicated elsewhere in studies on autism, with increased evidence for linkage observed when the sample is restricted to those with delayed onset of phrase speech. Our results support the hypothesis that the genetic component to stuttering has significant sex effects.

Figure 1

Nonparametric LOD scores obtained across the genome with use of the broad-affection classification of “ever stuttered” (A) and the narrow-affection classification of “persistent stuttering” (B).

Figure 2

Close-up of the chromosomes with the highest evidence for linkage in the primary analysis for each phenotype definition. Chromosome 9, with a LOD score of 2.3 at 60 cM (A), and chromosome 15, with a LOD score of 1.95 at 23 cM (B), showed the highest evidence for linkage by use of the broad and narrow phenotype definitions, respectively.

Figure  3

Sex-specific evidence for linkage. A, Analysis of the female-only data set (gray line) compared with the complete data set (black line) on chromosome 21, showing significant increase in the LOD score when only females are classified as affected. B, Similar significant increase in the evidence for linkage on chromosome 7 when the male-only data set (gray line) is compared with the complete data set (black line). C, Increased evidence for linkage also observed in the male-only data set (gray line) on chromosome 20.

Figure 4

Results of conditional analyses that showed a notable increase in evidence for linkage, with LOD scores >2.5. The X-axis corresponds to the distance in cM from the P terminus of the respective chromosome. The Y-axis corresponds to the nonparametric LOD score. For all conditional analyses, the weighting function used is indicated in each legend, along with the primary signal (in parentheses) from which the weights were generated.