Molecular Psychiatry (1998) 3, 141–149  1998 Stockton Press All rights reserved 1359–4184/98 $12.00 ORIGINAL RESEARCH ARTICLE A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia J Williams 1 , G Spurlock 1,2 , P Holmans 1,2 , R Mant 3 , K Murphy 1 , L Jones 1 , A Cardno 1 , P Asherson 4 , D Blackwood 5 , W Muir 5 , K Meszaros 6 , H Aschauer 6 , J Mallet 7 , C Laurent 7 , P Pekkarinen 8 , J Seppala 8 , CN Stefanis 9 , GN Papadimitriou 9 , F Macciardi 10 , M Verga 10 , C Pato 11 , H Azevedo 11 , M-A Crocq 12 , H Gurling 13 , G Kalsi 13 , D Curtis 13 , P McGuffin 1 and MJ Owen 1,2 1 Department of Psychological Medicine; 2 Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff; 3 The Institute of Opthalmology and Moorfields Eye Hospital, Department of Clinical Opthalmology, City Road, London; 4 Institute of Psychiatry, De Crespigny Park, London; 5 Department of Psychiatry, The University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh; 6 Department of General Psychiatry, University Hospital for Psychiatry, Wa ¨ hringer Gu ¨ rtel 18–20, A-1090 Vienna, Austria; 7 Laboratoire de Genetique Moleculaire de la Neurotransmission et des Processus Neurodegeneraties, CNRS-LGN, Batiment CERVI, Hopital de la Pitie Salpetriere, 83 Boulevard de l’Hopital, 75651 Paris Cedex 13, France; 8 National Public Health Institute, Departments of Human Molecular Genetics and Mental Health, Mannerheimintie 166, SF00300 Helsinki, Finland; 9 Athens University Medical School, Department of Psychiatry, Eginition Hospital, 72–74 Vas Sophias Ave, 11528 Athens, Greece; 10 Department of Neuroscience, Istituto Scientifico H San Raffaele, University of Milano – School of Medicine, via L, Prinetti 29, 20127 Milano, Italy; 11 Centre for Neuroscience, Universidade de Coimbra, Portugal; 12 Foundation for Applied Neuroscience, Research in Psychiatry, 66250 Rouffach, France; 13 Molecular Psychiatry Laboratory, Department of Psychiatry and Behavioural Sciences, Windeyer Institute for Medical Science, University College London Medical School, 46 Cleveland Street, London, UK We performed a meta-analysis of over 30 case-control studies of association between schizo- phrenia and a bi-allelic, Bal I polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07–1.35) in the combined sample of 5351 individ- uals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family- based association study of this polymorphism in 57 parent/proband trios, taken from unre- lated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35–5.86). Although no significant allelic association was observed, a significant association was detected with the 1–1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13–4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09–1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the Bal I polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it. Keywords: D3 receptor gene; meta-analysis; TDT; schizophrenia; association Introduction There is compelling evidence for a substantial genetic contribution to the aetiology of schizophrenia. 1,2 How- ever, the disorder appears genetically complex and is Correspondence: Dr J Williams, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK Received 7 July 1997; revised 2 December and 9 December 1997; accepted 22 December 1997 unlikely to be due to a single major gene. 3–5 Alternative genetic models stress the action of genes of minor effect, co-acting or inter-acting with other minor genes 6,7 or with a gene or genes of major effect. 8 Such genetic complexity and the consequent uncertainties surrounding the mode of transmission at any given locus, may impede traditional lod score linkage approaches. An additional, complementary approach to positional cloning, is offered by studies of genetic association of candidate genes. 9,10 Disturbances in dopamine neurotransmission and