A major susceptibility locus for specific language impairment is located on 13q21

Abstract

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.

Figure 1

Maximum two-point heterogeneity LOD scores for all six models, summarized over the entire genome. The three highest peaks are labeled by marker and model. A list of two-point results for all markers and models is located in the online-only supplementonline-only supplement. C = clinical diagnosis; R = reading discrepant; L = language impaired; “Rec” and “Dom” are recessive and dominant modes of inheritance, respectively.

Figure 2

Four-point analysis of the recessive reading model using markers D13S1317, D13S800, and D13S1306. This graph shows the overlap between our observed linkage and the CLSA (; originally published as Bradford et al. 2001). The horizontal bar indicates the Z_max-1 interval from the CLSA data set.

Figure 3

PPL across the length of chromosome 13 when the reading discrepancy phenotype is used. Note the height of the linkage peak relative to the background level of linkage across the chromosome.

Figure 4

Overlapping three-point analysis with the recessive language model of a selected region of chromosome 2. For the purposes of this graph, LOD scores were plotted by use of successive analyses anchored by each marker. The potential localization of DYX3 is shown by the black horizontal bar (Fagerheim et al. 1999).