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PKNOX2 is Associated with Formal Thought Disorder in Schizophrenia: a Meta-Analysis of Two Genome-wide Association Studies

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Abstract

Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia; however, little is known about the etiology of FTD. To identify new genetic loci associated with FTD, we conducted the first genome-wide association meta-analysis of two datasets of 835 cases of FTD and 2,694 controls with 729,454 single-nucleotide polymorphisms (SNPs). Logistic regression analysis of FTD as a binary trait, adjusted for age and sex, was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 61 SNPs associated with FTD with p < 10−4. The most significant association with FTD was observed with rs1783925 (p = 4.4 × 10−7) within PKNOX2 gene at 11q24.2 while the second interesting locus was rs2277644 (p = 1.18 × 10−5) within MYH13 at 17p13. Haplotype analyses of PKNOX2 and MYH13 loci further supported the associations with FTD. The third locus was PHF2 at 9q22.31 (the top SNP was rs12238738 with p = 2.08 × 10−5) while the fourth locus was GPC6 at 13q32 (the top SNP was rs17196161 with p = 3.12 × 10−5). In conclusion, we identified four new loci (PKNOX2, MYH13, PHF2, and GPC6) associated with FTD. These findings offer the potential for new insights into the pathogenesis of FTD and schizophrenia.

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Acknowledgments

Funding support for Genome-Wide Association Study of Schizophrenia was provided by funding from the NIH grant 5U01M0H79469 to Dr. PV Gejman and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The dataset 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 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), was provided by Genomics Research Branch at NIMH and the genotyping and analysis of samples was provided through the Genetic Association Information Network (GAIN) and under the MGS U01s: MH79469 and MH79470. Assistance with data cleaning was provided 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 were collected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH46276 (CR Cloninger), MH46289 (C Kaufmann), and MH46318 (MT Tsuang); and MGS Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257 (NG Buccola), MH59588 (BJ Mowry), 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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Authors and Affiliations

  1. 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 & Min Zeng

  2. Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, 63108, USA

    Qunyuan Zhang

  3. Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON, Canada

    Longyang Wu

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  1. Ke-Sheng Wang
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Correspondence to Ke-Sheng Wang.

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Wang, KS., Zhang, Q., Liu, X. et al. PKNOX2 is Associated with Formal Thought Disorder in Schizophrenia: a Meta-Analysis of Two Genome-wide Association Studies. J Mol Neurosci 48, 265–272 (2012). https://doi.org/10.1007/s12031-012-9787-4

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