CMIP and ATP2C2 modulate phonological short-term memory in language impairment

Abstract

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.

Figure 1

Association in SLIC Cohort Association results for family-based quantitaive analysis and case-control analysis of nonword repetition across the SLI1 region. In the case-control analysis, cases and controls were selected on the basis of their nonword-repetition performance (see text). Gaps in data represent regions where there are no mapped genes. SNPS included in the screen genotype panel are shown as +, and SNPs included in the follow-up genotype panel are shown as x.

Figure 2

Nonword-Repetition Means for CMIP and ATP2C2 in SLIC and Replication Cohorts (A) CMIP. (B) ATP2C2. All means are for age- and sex-adjusted nonword-repetition scores standardized with a mean of 0 and a SD of 1. The three CMIP SNPs (rs12927866, rs4265801, and rs16955705) show genotype trends in the opposite direction from SLIC (A), whereas the three ATP2C2 SNPs (rs16973771, rs2875891, and rs8045507) show genotype trends in the same direction as SLIC (B).