Genetic variations in the ADAMTS12 gene are associated with schizophrenia in Puerto Rican patients of Spanish descent
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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Findings from genetic association and GWAS analyses suggest that several metzincin protease genes, including ADAMTSL3, ADAMTS12, ADAMTS-16, ADAM22, and MMP16, may confer vulnerability to schizophrenia.
“First, converging results from several recent genetic association and genome-wide association studies indicate that genes encoding for a number of metzincin metalloproteases may represent vulnerability factors for SZ.”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Bespalova et al., 2012
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Bespalova, I. N., Angelo, G. W., Durner, M., Smith, C. J., Siever, L. J., Buxbaum, J. D., & Silverman, J. M. (2005) · Psychiatric Genetics · doi:10.1097/00041444-200509000-00012 · Cited by 16 · see citing works
Proteinases and Matrix Degradation
Okada, Y. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-3285-4.10007-5 · Cited by 12 · see citing works
Holliday, E., Mowry, B. J., & Nyholt, D. (2008) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30722 · Cited by 10 · see citing works
Association Between Paternal Schizophrenia and Low Birthweight: A Nationwide Population-Based Study
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Non-synonymous variants in the AMACR gene are associated with schizophrenia
Bespalova, I. N., Durner, M., Ritter, B. P., Angelo, G. W., Rossy-Fullana, E., Carrión‐Baralt, J. R., Schmeidler, J., & Silverman, J. M. (2010) · Schizophrenia Research · doi:10.1016/j.schres.2010.08.040 · Cited by 7 · see citing works
Association between paternal schizophrenia and low birthweight: ADAM12 may matter
Bernstein, H., Müller, S., Steiner, J. H., Farkas, N., Bogerts, B., & Lendeckel, U. (2010) · Asian Journal of Andrology · doi:10.1038/aja.2010.13 · Cited by 1 · see citing works
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3 of the 107 references couldn’t be matched to a known paper.
Cited by
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Berretta, S., Pantazopoulos, H., Markota, M., Brown, C., & Batzianouli, E. T. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2014.12.040 · Cited by 152 · see citing works
In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders
Pantazopoulos, H., & Berretta, S. (2015) · Neural Plasticity · doi:10.1155/2016/9847696 · Cited by 118 · see citing works
Molecular signature of extracellular matrix pathology in schizophrenia
Pantazopoulos, H., Katsel, P., Haroutunian, V. H., Chelini, G., Klengel, T., & Berretta, S. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.15009 · Cited by 79 · see citing works
ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response
Moncada-Pazos, Á., Obaya, Á. J., Prada, M. L., Heljäsvaara, R., Suárez, M. F., Colado, E., Noël, A., Cal, S., & López-Otı́n, C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.408625 · Cited by 50 · see citing works
New Insights into ADAMTS Metalloproteases in the Central Nervous System
Mohamedi, Y., Fontanil, T., Cobo, T., Cal, S., & Obaya, Á. J. (2020) · Biomolecules · doi:10.3390/biom10030403 · Cited by 39 · see citing works
ADAMTS-12: A Multifaced Metalloproteinase in Arthritis and Inflammation
Wei, J., Richbourgh, B., Jia, T., & Liu, C.-J. (2014) · Mediators of Inflammation · doi:10.1155/2014/649718 · Cited by 39 · see citing works
ADAMTS-12: Functions and Challenges for a Complex Metalloprotease
Mohamedi, Y., Fontanil, T., Cal, S., Cobo, T., & Obaya, Á. J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.686763 · Cited by 28 · see citing works
Neurocan is a New Substrate for the ADAMTS12 Metalloprotease: Potential Implications in Neuropathies
Fontanil, T., Mohamedi, Y., Moncada-Pazos, Á., Cobo, T., Vega, J. A., Cobo, J. L., García‐Suárez, O., Cobo, J. L., Obaya, Á. J., & Cal, S. (2019) · Cellular Physiology and Biochemistry · doi:10.33594/000000069 · Cited by 25 · see citing works
Hyalectanase Activities by the ADAMTS Metalloproteases
Fontanil, T., Mohamedi, Y., Casado, J. E., Obaya, Á. J., Cobo, T., & Cal, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062988 · Cited by 13 · see citing works
Effects of metalloprotease ADAMTS12 on cervical cancer cell phenotype and its potential mechanism
Zou, R., Gu, R., Tu, X., Chen, J., Liu, S., Xue, X., Li, W., & Zhang, Y. (2023) · Discover Oncology · doi:10.1007/s12672-023-00776-2 · Cited by 8 · see citing works
Alterations in ADAMTS12 gene expression in salivary glands of radioiodine-131-administered rats
Sadıç, M., Korkmaz, M., Gültekin, S. S., & Demircan, K. (2016) · Nuclear Medicine Communications · doi:10.1097/mnm.0000000000000556 · Cited by 7 · see citing works
Chondroitin Sulphate Proteoglycan Axonal Coats in the Human Mediodorsal Thalamic Nucleus
Pantazopoulos, H., Hossain, N. M., Chelini, G., Durning, P. T., Barbas, H., Zikopoulos, B., & Berretta, S. (2022) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2022.934764 · Cited by 5 · see citing works
Conditional GWAS revealing genetic impacts of lifestyle behaviors on low-density lipoprotein (LDL)
Liu, W., Cui, Z., Xu, P., Han, H., & Zhu, J. (2018) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2018.11.010 · Cited by 3 · see citing works
Chen, Q., Hu, T., & Hui, L. (2026) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-026-01166-y
- Authors
- Bespalova, I. N., Angelo, G. W., Ritter, B. P., Hunter, J., Reyes-Rabanillo, M. L., Siever, L. J., & Silverman, J. M.
- Affiliations
- James J. Peters VA Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- VA Caribbean Healthcare System (PR)
- Corresponding author
- Bespalova, Irina N.
- ORCID
- Silverman, Jeremy M.
- Venue
- NeuroMolecular Medicine
- Published
- 2012-02-10
- Volume
- 14
- Issue
- 1
- Pages
- 53-64
- ISSN
- 1535-1084 (ISSN-L)
- 1559-1174
- OpenAlex
- W2071291115
- Cited by
- 14
- References
- 107
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2012: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- NeuroMolecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (R03MH082134)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- ADAMTS12, schizophrenia, genetic susceptibility, metalloproteinases, haplotype association, intronic variants, Puerto Rican patients, positional candidate genes
- MeSH terms
- ADAMTS Proteins, Base Sequence, DNA Mutational Analysis, Exons, Female, Haplotypes, Hispanic or Latino, Humans, Introns, Male, Molecular Sequence Data, Pedigree, Promoter Regions, Genetic, Puerto Rico, Risk, Schizophrenia, Genetic Variation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, ADAM Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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