Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses

Glatt, Stephen J.; Wang, Richard S.; Yeh, Yu-Chi; Tsuang, Ming T.; Faraone, Stephen V.

doi:10.1016/j.schres.2004.07.015

« Previous Next »Schizophrenia Research
Volume 73, Issue 2 , Pages 281-290, 1 March 2005

Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses

Stephen J. Glatt
- Department of Psychiatry, Institute of Behavioral Genomics, University of California, San Diego, La Jolla, CA, United States
- Corresponding author. Tel.: +1 858 822 2433; fax: +1 858 822 2469.
Richard S. Wang
- Department of Psychiatry, Institute of Behavioral Genomics, University of California, San Diego, La Jolla, CA, United States
Yu-Chi Yeh
- Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, United States
- Department of General Psychiatry, Bali Mental Hospital of the Department of Health of Taiwan, Taipei County, Taiwan
Ming T. Tsuang
- Department of Psychiatry, Institute of Behavioral Genomics, University of California, San Diego, La Jolla, CA, United States
- Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, United States
- VA San Diego Healthcare System, La Jolla, CA, United States
Stephen V. Faraone
- Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, United States
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
- Department of Psychiatry, Harvard Medical School at the Massachusetts General Hospital; Boston, MA, Unites States

Received 2 April 2004; received in revised form 21 July 2004; accepted 23 July 2004.

Abstract

NOTCH4 initially received consideration as a risk gene for schizophrenia based on its location within a region on chromosome 6p that had previously shown strong evidence for genetic linkage with the illness. The initial published test for allelic association found strong evidence for involvement of this gene in schizophrenia, but subsequent studies failed to confirm this finding. Presently, we have used meta-analysis to derive a best estimate of the nature and magnitude of the associations between schizophrenia and five polymorphisms in and around the NOTCH4 gene. No significant association was detected between schizophrenia and repeat length of alleles at the (TAA)_n, (CTG)_n, or (TTAT)_n polymorphisms, or between the disease and specific risk alleles at these polymorphisms or at the SNP1 or SNP2 polymorphisms. Heterogeneity and stronger evidence of association with the putative risk alleles of the (TAA)_n, (CTG)_n, SNP1, and SNP2 polymorphisms was observed in family-based studies than in case-control studies, suggesting that these polymorphisms may reliably influence risk for schizophrenia under certain circumstances. Since more consistent and robust associations with schizophrenia risk have been observed for haplotypes of these polymorphisms [especially those containing SNP2 and (CTG)_n], additional large family-based or genomic-controlled studies would be helpful for definitively specifying the role of NOTCH4 haplotypes in risk for schizophrenia.

Keywords: Allelic association, Chromosome 6p, Major histocompatibility complex, Meta-analysis schizophrenia, NOTCH4