Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment

Abstract

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are >/=1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).

Figure 1

LOD-score significance distributions for different linkage methods. Simulations demonstrate that the unweighted HE method (HEuw; solid lines) gives a better fit to the theoretical distribution (black line) than either the weighted HE (HEw; graph A) or the VC (graph B) methods (dotted lines). Data is shown for the total data set.

Figure 2

HE linkage to chromosome 16 within the wave 1 and wave 2 samples. Linkage to chromosome 16 within the replication sample (wave 2) was found, with the NWRtrans trait in a similar region to that seen in the genome screen (wave 1). The positions of all markers are shown by triangles. Markers that gave single-point LOD scores >1.0 are shown in black, markers that gave single-point LOD scores >2.0 are shown in blue, and the marker that gave the maximum single-point LOD score (D16S3040; HE MLS = 4.41, VC MLS = 2.73) is shown in red. Single-point data refers to the total data set. Plots are shown only for HE analyses and the NWRtrans trait. Note that the linkage in wave 1 differs from that reported in SLIC 2002, owing to the addition of missing data points and to the use of different genetic maps.

Figure 3

Linkage to chromosome 19 within the wave 1 and wave 2 samples. Linkage to chromosome 19 within the replication sample (wave 2) was found with the NWRtrans trait in a similar region to that of ELStrans seen in the genome screen (wave 1). The positions of all markers are shown by triangles. Markers that gave single-point LOD scores >1.0 (waves 1 and 2) are shown in black. Single-point data refers to the total data set. Plots are shown only for HE analyses and the NWRtrans and ELStrans traits. Note that the linkage in wave 1 differs from that reported in SLIC 2002, owing to the addition of missing data points and to the use of different genetic maps.

Figure 4

Linkage to chromosome 16 within the constituent groups. Linkage is demonstrated independently within each independent cohort. Traces are shown only for HE analyses and the NWRtrans trait.

Figure 5

Linkage to chromosome 19 within the constituent groups. Linkage is demonstrated independently within each independent cohort. A, Linkage to ELStrans on chromosome 19. B, Linkage to NWRtrans on chromosome 19. The Cambridge cohort shows linkage to ELStrans only, the Edinburgh cohort shows linkage to NWRtrans only, and the Guys/Aberdeen group shows linkage to both ELStrans and NWRtrans. In A and B, traces are shown for HE analyses and the ELStrans or NWRtrans trait, respectively.

Figure 6

Linkage of reading measures to chromosome 16. Linkage was also found between three measures of reading ability on chromosome 16q. Traces are shown for HE analyses only.