ORIGINAL ARTICLE Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia S Mah 1,4 , MR Nelson 1,4 , LE DeLisi 2 , RH Reneland 1 , N Markward 1 , MR James 3 , DR Nyholt 3 , N Hayward 3 , H Handoko 3 , B Mowry 3 , S Kammerer 1 and A Braun 1 1 Sequenom Inc., San Diego, CA, USA; 2 Department of Psychiatry, New York University, New York, NY, USA and 3 Queensland Institute of Medical Research, Herston, QLD, Australia The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome- wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizo- phrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case– control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus. Molecular Psychiatry advance online publication, 10 January 2006; doi:10.1038/sj.mp.4001785 Keywords: single-nucleotide polymorphism; genome-wide association; chromosome 1q32; plexin; semaphorin Introduction Schizophrenia is one of the most severe and disabling of the mental disorders affecting up to 1% of the world’s population, regardless of gender, race, culture and class. 1 Family, twin and adoption studies strongly suggest a genetic basis for this illness with the heritability estimated at about 70%. 2 Among the genes that have been postulated as candidates from linkage and association studies are the regulator of G- protein signaling 4 on 1q22, 3 disrupted in schizo- phrenia (DISC) 1 and 2 on chromosome 1q42, 4 dystrobrevin-binding protein 1 on 6p22, 5 neuregulin 1 on 8p21, 6 D-amino-acid oxidase activator (G72) on 13q34, 7 catechol-O-methyltransferase on 22q11 8 and proline dehydrogenase 1 on 22q11. 9 Despite intensive research, results for most of these regions have been inconsistent. 10,11 There has been increasing interest in using whole- genome association as a method to identify genes involved in complex diseases. Genome-wide associa- tion studies using large numbers of single-nucleotide polymorphisms (SNPs) have been proposed and successfully applied to find genetic variations asso- ciated with myocardial infarction, 12 bone mineral density 13 and breast cancer. 14,15 In an effort to identify genes and variants that influence the risk of schizo- phrenia, we carried out a large-scale SNP association study using a multi-center collection of schizophrenia cases and controls. We identified a gene on chromo- some 1q32, plexin A2 (PLXNA2), as a candidate gene for schizophrenia. Several linkage studies previously reported schizophrenia susceptibility loci in the 1q22-42 region; 16–20 other studies, however, have been Received 17 May 2005; revised 19 October 2005; accepted 16 November 2005 Correspondence: Dr A Braun, Sequenom Inc., 3595 John Hopkins Court, San Diego, CA 92121, USA. E-mail: andibraun@earthlink.net 4 These authors contributed equally to this work. Molecular Psychiatry (2006), 1–8 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp