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GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Molecular Psychiatry volume 10, pages 581–588 (2005)Cite this article

Abstract

Postmortem brain studies have shown deficits in the cortical γ-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5′ upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022–0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003–0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

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Acknowledgements

We thank all of the families who participated in the COS study. We also express our gratitude to Michael Egan, Bhaskar Kolachana, Lew Bigelow, Thomas Hyde and coworkers in the Clinical Brain Disorders Branch Sibling Study, who contributed to the original discovery of association with GAD1 in the adult schizophrenia datasets and whose generous sharing of proprietary information and laboratory resources led to our initiation of this study in our sample. Finally, we thank two anonymous reviewers for their helpful comments and suggestions.

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Authors and Affiliations

  1. Child Psychiatry Branch, NIMH, NIH, Bethesda, MD, USA

    A M Addington, M Gornick, A Sporn, N Gogtay, A Bobb, D Greenstein, M Lenane, P Gochman, N Baker & J L Rapoport

  2. Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA

    J Duckworth

  3. Clinical Brain Disorders Branch, NIMH, NIH, Bethesda, MD, USA

    R Balkissoon, R K Vakkalanka, D R Weinberger & R E Straub

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  1. A M Addington
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Correspondence to A M Addington.

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Supplementary Information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp)

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Addington, A., Gornick, M., Duckworth, J. et al. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry 10, 581–588 (2005). https://doi.org/10.1038/sj.mp.4001599

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