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Genetic Variations in the ADAMTS12 Gene are Associated with Schizophrenia in Puerto Rican Patients of Spanish Descent

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Abstract

ADAMTS12 belongs to the family of metalloproteinases that mediate a communication between specific cell types and play a key role in the regulation of normal tissue development, remodeling, and degradation. Members of this family have been implicated in neurodegenerative and neuroinflammatory, as well as in muscular-skeletal, cardiovascular, respiratory and renal diseases, and cancer. Several metalloproteinases have been associated with schizophrenia. In our previous study of the pedigree from a genetic isolate of Spanish origin in Puerto Rico, we identified a schizophrenia susceptibility locus on chromosome 5p13 containing ADAMTS12. This gene, therefore, is not only a functional but also a positional candidate gene for susceptibility to the disorder. In order to examine possible involvement of ADAMTS12 in schizophrenia, we performed mutation analysis of the coding, 5′- and 3′-untranslated, and putative promoter regions of the gene in affected members of the pedigree and identified 18 sequence variants segregated with schizophrenia. We then tested these variants in 135 unrelated Puerto Rican schizophrenia patients of Spanish origin and 203 controls and identified the intronic variant rs256792 (P = 0.0035; OR = 1.59; 95% CI = 1.16–2.17) and the two-SNP haplotype rs256603–rs256792 (P = 0.0023; OR = 1.62; 95% CI = 1.19–2.21) associated with the disorder. The association remained significant after correction for multiple testing. Our data support the hypothesis that genetic variations in ADAMTS12 influence the risk of schizophrenia.

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Acknowledgments

The authors thank patients and healthy volunteers for their participation in the study. We also thank Enrique Rossy-Fullana and Jose Carrión-Baralt for samples collection and administrative assistance. We thank Martina Durner and James Schmeidler for helpful discussions and Inga Peter for assistance with logistic regression analysis. We are grateful to Andrei Kurochkin and anonymous reviewers for critical reading of the manuscript and useful comments and suggestions. The study was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) to INB (Young Investigator Award), the National Institute of Mental Health (NIMH) to INB (RO3 Award MH082134), and The Department of Veterans Affairs (VA) to JMS (Merit Award). The funding sources had no role in study design, analysis and interpretation of the data, and writing the manuscript.

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Authors and Affiliations

  1. Department of Psychiatry, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1230, New York, NY, 10029, USA

    Irina N. Bespalova, Gary W. Angelo, Ben P. Ritter, Jason Hunter, Larry J. Siever & Jeremy M. Silverman

  2. James J. Peters Veterans Affairs Medical Center, Bronx, NY, 10468, USA

    Irina N. Bespalova, Gary W. Angelo, Ben P. Ritter, Larry J. Siever & Jeremy M. Silverman

  3. San Juan Veteran Affairs Medical Center, San Juan, PR, USA

    Maria L. Reyes-Rabanillo

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  1. Irina N. Bespalova
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  2. Gary W. Angelo
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  3. Ben P. Ritter
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  4. Jason Hunter
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  5. Maria L. Reyes-Rabanillo
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Correspondence to Irina N. Bespalova.

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Bespalova, I.N., Angelo, G.W., Ritter, B.P. et al. Genetic Variations in the ADAMTS12 Gene are Associated with Schizophrenia in Puerto Rican Patients of Spanish Descent. Neuromol Med 14, 53–64 (2012). https://doi.org/10.1007/s12017-012-8169-y

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  • DOI: https://doi.org/10.1007/s12017-012-8169-y

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