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Genetic Association Analysis of ITGB3 Polymorphisms with Age at Onset of Schizophrenia

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Abstract

Schizophrenia (SCZ) is a debilitating disorder with a prevalence of approximately 1 % worldwide. SCZ is known to have a high degree of genetic and clinical heterogeneity and is a major health problem worldwide. The integrin-β 3 subunit gene (ITGB3) gene at 17q21.32 has been implicated in psychiatric disorders. We therefore hypothesized that ITGB3 gene polymorphisms might also play a role in SCZ and age at onset (AAO) of SCZ. We investigated the genetic associations of 23 single-nucleotide polymorphisms (SNPs) of the ITGB3 gene with AAO in SCZ in two Caucasian samples (2,166 cases and 2,525 controls) using linear regression analysis and meta-analysis. We observed four ITGB3-SNPs associated with AAO in SCZ in a non-Genetic Association Information Network (GAIN) sample (p < 10−3). Three of these four SNPs were replicated in the GAIN sample. The SNP rs16941771 was most significantly associated with AAO (p = 7.47 × 10−5). Meta-analysis showed that 6 of 23 SNPs were associated with AAO. The haplotype analysis also supports the association of ITGB3 with AAO. Three disease-associated SNPs were located at species-conserved regions, indicating functional importance. This is the first report which shows that ITGB3 variants are associated with AAO in SCZ, providing direct evidence of the use of AAO as an intermediate phenotype to dissect the complex genetics of SCZ.

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Acknowledgments

Funding support for Genome-Wide Association Study of Schizophrenia was providedby funding from the NIH grant 5U01M0H79469 to Dr. PV Gejman and the genotypingof samples was provided through the Genetic Association Information Network (GAIN). The dataset used for the analyses described in this manuscript were obtainedfrom the database of Genotype and Phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v2.p1. Samples and associated phenotype data for the Genome-Wide Association Study of Schizophrenia were provided by Dr. PV Gejman. Funding support for the companion studies, Genome-Wide Association Study of Schizophrenia (GAIN) and Molecular Genetics of Schizophrenia - nonGAIN Sample (MGS_nonGAIN), wasprovided by Genomics Research Branch at NIMH and the genotyping and analysis ofsamples was provided through the Genetic Association Information Network (GAIN) and under the MGS U01s: MH79469 and MH79470. Assistance with data cleaning wasprovided by the National Center for Biotechnology Information. The MGS dataset(s) used for the analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession numbers phs000021.v2.p1 (GAIN) and phs000167.v1.p1(nonGAIN). Samples and associated phenotype data for the MGS GWAS study werecollected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH46276 (CR Cloninger), MH46289 (C Kaufmann), and MH46318 (MT Tsuang); andMGS Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257 (NG Buccola), MH59588 (BJMowry), MH59571 (PV Gejman), MH59565 (Robert Freedman), MH59587 (F Amin), MH60870 (WF Byerley), MH59566 (DW Black), MH59586 (JM Silverman), MH61675(DF Levinson), and MH60879 (CR Cloninger). Further details of collection sites, individuals, and institutions may be found in data supplement Table 1 of Sanders et al. (2008).

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All authors have reported no financial interests or potential conflicts of interest.

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Authors and Affiliations

  1. Departments of Psychiatry and Neurology and The Center of Excellence in Neuroscience, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Tania Bedard Arana, Cynthia Camarillo, Michael A. Escamilla & Chun Xu

  2. Departments of Psychiatry and Neurology, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Henry Weisman & Cecilia Devargas

  3. Texas Tech University Health Science Center, El Paso, TX, USA

    Nicholas Thompson

  4. Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN, 37614-1700, USA

    Ke-Sheng Wang & Xuefeng Liu

  5. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, People’s Republic of China

    Brenda Bin Su & Chun Xu

  6. University of Toronto, Toronto, Ontario, Canada

    ChunXiang Mao

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  1. Ke-Sheng Wang
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  2. Xuefeng Liu
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Correspondence to Ke-Sheng Wang or Chun Xu.

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Wang, KS., Liu, X., Arana, T.B. et al. Genetic Association Analysis of ITGB3 Polymorphisms with Age at Onset of Schizophrenia. J Mol Neurosci 51, 446–453 (2013). https://doi.org/10.1007/s12031-013-0059-8

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