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

Newbury, Dianne F. and Winchester, Laura and Addis, Laura and Paracchini, Silvia and Buckingham, Lyn-Louise and Clark, Ann and Cohen, Wendy and Cowie, Hilary and Dworzynski, Katharina and Everitt, Andrea and Goodyer, Ian M. and Hennessy, Elizabeth and Kindley, A. David and Miller, Laura L. and Nasir, Jamal and O'Hare, Anne and Shaw, Duncan and Simkin, Zoe and Simonoff, Emily and Slonims, Vicky and Watson, Jocelynne and Ragoussis, Jiannis and Fisher, Simon E. and Seckl, Jonathon R. and Helms, Peter J. and Bolton, Patrick F. and Pickles, Andrew and Conti-Ramsden, Gina and Baird, Gillian and Bishop, Dorothy V.M. and Monaco, Anthony P. (2009) CMIP and ATP2C2 modulate phonological short-term memory in language impairment. American Journal of Human Genetics, 85 (2). pp. 264-272. ISSN 0002-9297

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    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 × 10−7 at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 × 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.