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Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents

Molecular Psychiatry volume 16, pages 917–926 (2011)Cite this article

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Abstract

Disrupted-in-schizophrenia-1 (DISC1), contains two common non-synonymous single-nucleotide polymorphisms (SNPs)—Leu607Phe and Ser704Cys—that modulate (i) facets of DISC1 molecular functioning important for cortical development, (ii) fronto-temporal cortical anatomy in adults and (iii) risk for diverse psychiatric phenotypes that often emerge during childhood and adolescence, and are associated with altered fronto-temporal cortical development. It remains unknown, however, if Leu607Phe and Ser704Cys influence cortical maturation before adulthood, and whether each SNP shows unique or overlapping effects. Therefore, we related genotype at Leu607Phe and Ser704Cys to cortical thickness (CT) in 255 typically developing individuals aged 9–22 years on whom 598 magnetic resonance imaging brain scans had been acquired longitudinally. Rate of cortical thinning varied with DISC1 genotype. Specifically, the rate of cortical thinning was attenuated in Phe-carrier compared with Leu-homozygous groups (in bilateral superior frontal and left angular gyri) and accelerated in Ser-homozygous compared with Cys-carrier groups (in left anterior cingulate and temporal cortices). Both SNPs additively predicted fixed differences in right lateral temporal CT, which were maximal between Phe-carrier/Ser-homozygous (thinnest) vs Leu-homozygous/Cys-carrier (thickest) groups. Leu607Phe and Ser704Cys genotype interacted to predict the rate of cortical thinning in right orbitofrontal, middle temporal and superior parietal cortices, wherein a significantly reduced rate of CT loss was observed in Phe-carrier/Cys-carrier participants only. Our findings argue for further examination of Leu607Phe and Ser704Cys interactions at a molecular level, and suggest that these SNPs might operate (in concert with other genetic and environmental factors) to shape risk for diverse phenotypes by impacting on the early maturation of fronto-temporal cortices.

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Acknowledgements

This study was funded through the National Institutes of Health, National Institute of Health Intramural Research, and a UK Medical Research Council Clinical Research Training Fellowship (author AR—G0701370). We thank the participants who took part in this study. We are also grateful to the reviewers of this paper for their helpful comments. Dr Raznahan would like to thank Ms Shirley V Rojas for her tireless support on both sides of the laboratory door.

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  1. Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MA, USA

    A Raznahan, Y Lee, R Long, D Greenstein, L Clasen, A Addington, J L Rapoport & J N Giedd

  2. Department of Child and Adolescent Psychiatry, Kings College London, Institute of Psychiatry, London, UK

    A Raznahan

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Raznahan, A., Lee, Y., Long, R. et al. Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents. Mol Psychiatry 16, 917–926 (2011). https://doi.org/10.1038/mp.2010.72

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