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  • Original Research Article
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Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44

Molecular Psychiatry volume 10, pages 375–383 (2005)Cite this article

Abstract

Using restriction fragment length polymorphism and pyrosequencing methods, we genotyped two TNFA gene promoter SNPs (−G308A, −G238A) and analyzed the haplotype structure in 24 Canadian families of primarily Celtic origin. Our results demonstrate that after correction for multiple testing based on simulations of 10 000 replicates of unlinked/unassociated data, there is evidence for association (P=0.026) of a specific haplotype (−308A, −238G) with schizophrenia and schizophrenia spectrum disorders with a family-based trimmed haplotype linkage disequilibrium test (Trimhap). Stratifying the 22 families with genome scan data by TNFA promoter haplotypes followed by reanalysis of linkage to schizophrenia throughout the genome, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 (D1S1609) demonstrated a significant increase (P=0.025) in LOD score from 0.15 to 3.01 with a broad definition of the schizophrenia phenotype and a dominant mode of inheritance. This result replicates a previously reported positive result of linkage of schizophrenia spectrum disorders to this area of the genome. We also illustrated that simulation studies are pivotal in evaluating the significance of results obtained with newer statistical methods, when multiple, but not independent, tests are performed, and when sample stratification is utilized to reduce the impact of heterogeneity or assess the interaction between loci.

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Acknowledgements

This work was supported by grant R01 MH62440 from the National Institutes of Mental Health (LMB), the Canadian Institutes of Health Research (ASB), and The Bill Jefferies Schizophrenia Endowment Fund (ASB). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through contract N01-HG-65403 from the National Institutes of Health to The Johns Hopkins University.

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Authors and Affiliations

  1. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    V Saviouk & L M Brzustowicz

  2. Department of Psychiatry, University of Toronto, and Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    E W C Chow & A S Bassett

  3. Department of Psychiatry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA

    L M Brzustowicz

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  1. V Saviouk
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Correspondence to V Saviouk.

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Electronic-Database Information

Center for Inherited Disease Research (CIDR), http://www.cidr.jhmi.edu/ (for genotyping protocols)Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/.Pyrosequencing Technical Support, http://techsupport.pyrosequencing.com (for Pyrosequencing SNP Primer Design Software v 1.0.)UCSC Genome Browser, http://genome.cse.ucsc.edu/ (for July 2003 NCBI Build 34 of the human genome)Whitehead Institute, http://www.genome.wi.mit.edu/genome-software/other/primer3.html (for PRIMER3)

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Saviouk, V., Chow, E., Bassett, A. et al. Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44. Mol Psychiatry 10, 375–383 (2005). https://doi.org/10.1038/sj.mp.4001582

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