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CMIP and ATP2C2 Modulate Phonological Short-Term Memory in Language Impairment |
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| Authors: | Dianne F Newbury Laura Winchester Laura Addis Silvia Paracchini Ann Clark Wendy Cohen Hilary Cowie Katharina Dworzynski Andrea Everitt Ian M Goodyer Elizabeth Hennessy A David Kindley Laura L Miller Anne O'Hare Duncan Shaw Zoe Simkin Emily Simonoff Vicky Slonims Jocelynne Watson Jiannis Ragoussis Jonathon R Seckl Peter J Helms Patrick F Bolton Andrew Pickles Gina Conti-Ramsden Gillian Baird Dorothy VM Bishop Anthony P Monaco |
| Institution: | 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK 2 Speech and Hearing Sciences, Queen Margaret University, Edinburgh EH21 6UU, UK 3 Department of Educational and Professional Studies, University of Strathclyde, Glasgow G13 1PP UK 4 Department of Speech and Language Therapy, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK 5 Department of Child and Adolescent Psychiatry, Institute of Psychiatry, London SE5 8AF, UK 6 Department of Child Health, University of Aberdeen, Aberdeen AB25 2GZ, UK 7 Developmental Psychiatry Section, University of Cambridge, Cambridge CB2 8AH, UK 8 The Raeden Centre and Grampian University Hospitals Trust, Aberdeen AB2 4PE, UK 9 Avon Longitudinal Study Parents and Children, Department of Social Medicine, University of Bristol, Bristol BS8 2BN, UK 10 Division of Clinical Developmental Sciences St. George's University of London, London SW17 0RE, UK 11 Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh EH9 1UW, UK 12 Human Communication and Deafness, School of Psychological Sciences, University of Manchester, Manchester M13 9PL, UK 13 Newcomen Centre, Guy's Hospital, London SE1 9RT, UK 14 The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK 15 Department of Child and Adolescent Psychiatry and Medical Research Council Centre for Social, Developmental, and Genetic Psychiatry, Institute of Psychiatry, London SE5 8AF, UK 16 Biostatistics Group, School of Epidemiology and Health Science, University of Manchester, UK 17 Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK 18 The SLI Consortium, UK |
| 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. |
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