Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples

Received 2 May 2005; received in revised form 8 November 2005; accepted 8 February 2006. published online 24 April 2006.

Background

Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles.

Methods

In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807).

Results

The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations.

Conclusions

Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Key Words: RGS4 , schizophrenia , meta-analysis , association , polymorphism , linkage

a Departments of Human Genetics, Psychiatry, Neuroscience, and NeurobiologyUniversity of Pittsburgh, Pittsburgh, Pennsylvania

b Department of StatisticsCarnegie Mellon University, Pittsburgh, Pennsylvania

c Department of Psychological MedicineUniversity of Wales College of Medicine, Cardiff, Wales, United Kingdom

d Department of PsychiatryInstitute of Molecular Medicine, Trinity College, Dublin, Ireland

e Department of PsychiatryVirginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, Virginia

f Department of PsychiatryUniversity of Sao Paulo, Sao Paulo, Brazil

g Department of PsychiatryDr. Ram Manoher Lohia Hospital, New Delhi, India

h Department of Human GeneticsUniversity of Delhi South Campus, New Delhi, India

i Department of GeneticsRutgers University, Piscataway, New Jersey

j Department of PsychiatryUniversity of Toronto and Center for Addiction & Mental Health, Toronto, Ontario, Canada

k Zilkha Neurogenetic Institute and Department of Preventive MedicineKeck School of Medicine, University of Southern California, Los Angeles, California

l Department of PsychiatryInstitute of Psychiatry, London, United Kingdom

m Genes, Cognition, and Psychosis ProgramNational Institute of Mental Health, Bethesda, Maryland

n Vanderbilt Kennedy Center for Research on Human Development and Department of PharmacologyVanderbilt University, Nashville, Tennessee

o Department of PsychiatryWest China Hospital, Sichuan University, PR China

p Department of Mental HealthUniversity of Aberdeen, Foresterhill, Aberdeen, United Kingdom

q Department of PsychiatryUniversity of Washington, Seattle, Washington

Address reprint requests to Vishwajit L. Nimgaonkar, M.D., Ph.D., University of Pittsburgh–WPIC, Departments of Psychiatry and Human Genetics, 3811 O'Hara Street, Room 441, Pittsburgh, PA 15213

PII: S0006-3223(06)00233-2

doi:10.1016/j.biopsych.2006.02.015

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