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. Author manuscript; available in PMC: 2009 Feb 1.
Published in final edited form as: Schizophr Res. 2007 Dec 21;99(1-3):365–366. doi: 10.1016/j.schres.2007.10.033

No association between schizophrenia and polymorphisms of the PlexinA2 gene in Chinese Han Trios

Stephane Budel 1, Sang-ohk Shim 1, Zeny Feng 2,3, Hongyu Zhao 2, Fuki Hisama 1, Stephen M Strittmatter 1
PMCID: PMC2276648  NIHMSID: NIHMS42692  PMID: 18096369

Letter to the Editors:

Multiple genetic, environmental and developmental factors have been implicated (Hyman, 1999; Riley et al., 2000) in the etiology of schizophrenia. Axon guidance molecules may be considered candidate genes to explain an early developmental abnormality underlying schizophrenia. Plexin A2, a member of the semaphorin receptor family, is an axon guidance receptor widely expressed in the brain (Takahashi et al., 1999). A genome-wide association study of European schizophrenic patients and controls and found a significant association between schizophrenia and 3 SNPs at the Plexin A2 locus (PLXNA2): rs841865, rs752016 and rs2498028 (Mah et al., 2006). Another study found no association of PLXNA2 and schizophrenia amongst Japanese (Fujii et al., 2007).

We sought to replicate this association in a DNA sample of 290 Chinese Han Trios (621 schizophrenic patients and 501 controls) obtained from the National Institute of Mental Health (NIMH; www.nimh.nih.gov). Families were excluded if both parents were schizophrenic. We genotyped the same three SNPs at the PLXNA2 locus: rs841865, rs752016 and rs2498028 using the TaqMan SNP Genotyping Assay (Applied Biosystems, California).

Genotype distribution was performed to test deviation from Hardy-Weinberg equilibrium using the Fisher exact test. LD between pairs of SNPs was measured as D’ using Haploview. Structures of haplotypes were analyzed from the parental genotypes based upon LD pattern using the expectation-maximization algorithm (Slatkin and Excoffier, 1996). Conventional TDT statistics were used to analyze transmission disequilibrium between the discrete trait schizophrenia or schizoaffective disorder and the SNPs (Spielman et al., 1993) using the trios from the NIMH with both available parents and one affected offspring. In addition, single marker and haplotype association with schizophrenia were tested using FBAT (Family-Based Association Test) software (Laird et al., 2000; Horvath et al., 2004). FBAT also implements haplotype-based association tests for family-based studies when markers are tightly linked. In our study, all markers were tested as they all had minor allele frequencies greater than 5%.

No Mendelian errors were observed in our analysis. The genotype frequencies of the three SNPs tested were in Hardy-Weinberg equilibrium. The association of single SNP and haplotypes with schizophrenia is shown in Figure 1. Results of single SNP-based association and hapltype-based association tests using FBAT are summarized (Fig. 1C, D). No statistical evidence suggests the association between schizophrenia and 3 SNPs at the PLXNA2 locus. Thus, using this population of Chinese Han trios, we were unable to replicate an association at the PLXNA2 locus and schizophrenia (Mah et al., 2006).

Figure 1. SNP and linkage analysis at the PlexinA2 locus in Chinese Han Trios.

Figure 1

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(A) The three markers selected were in Hardy Weinberg equilibrium (p > 0.05). oHet: observed heterozygotes; pHet: predicted number of heterozygotes; HWpVal: Hardy-Weinberg p value; %geno: Percent successful genotype; M.E.: Number of Mendelian errors; MAF: Minor Allele Frequency. (B) Linkage Disequilibrium (LD) plot. The relative position of the three SNPs are depicted. (C) Association of specific single markers with the disease. MA: Minor allele. (D) Haplotype association with schizophrenia.

In conclusion, we performed a comprehensive analysis of three particular SNPs at the PLXNA2 locus and failed to replicate a previously reported association of this locus and schizophrenia. Further studies are required to verify the potential role of axon guidance molecules in schizophrenia.

Acknowledgements

The authors thank N.I.H. and the Scottish Rite Association for funding, and Dr. Noam Harel, who assisted with proof-reading of the manuscript. Data and biomaterials were collected in three projects that participated in the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative. Most importantly, we thank the families who have participated in and contributed to these studies.

Data and biomaterials were collected in three projects that participated in the NationalInstitute of Mental Health (NIMH) Schizophrenia Genetics Initiative. From 1991-97, the Principal Investigators and Co-Investigators were: Harvard University, Boston, MA, U01MH46318, Ming T. Tsuang, M.D., Ph.D., D.Sc., Stephen Faraone, Ph.D., and JohnPepple, Ph.D.; Washington University, St. Louis, MO, U01 MH46276, C. RobertCloninger, M.D., Theodore Reich, M.D., and Dragan Svrakic, M.D.; Columbia University,New York, NY U01 MH46289, Charles Kaufmann, M.D., Dolores Malaspina, M.D., and Jill Harkavy Friedman, Ph.D. The data from the Han Chinese Schizophrenia Linkage Study were collected with funding from grant R01 MH59624 from the US National Institute of Mental Health to Ming T. Tsuang, MD, PhD (Principal Investigator). Other participants in the US were Stephen V. Faraone, PhD (Co-Principal Investigator), Shao Zhu, MD (Project Coordinator) and Xingjia Cui, MD (Project Coordinator). The project leaders in Taiwan were Hai-Gwo Hwu, M.D. (Taiwan Principal Investigator, National Taiwan University Hospital), Wei J. Chen, M.D. Sci.D. (Taiwan Co-Principal Investigator). Other participants in Taiwan were: Chih-Min Liu,M.D., Shih-Kai Liu, M.D.,Ming-Hsien Shieh, M.D., Tzung-Jeng Hwang, M.D., MPH, Ming-Ming Tsuang, M.D.,Wen Chen OuYang, M.D., Ph.D., Chun-Ying Chen, M.D., Chwen-Cheng Chen, M.D.,Ph.D. Jin-Jia Lin,M.D., Frank Huang-Chih Chou, M.D., PH.D., Ching-Mo Chueh, M.D.,Wei-Ming Liu, M.D., Chiao-Chicy Chen, M.D. Jia-Jiu Lo, M.D., Jia-Fu Lee, M.D., Ph.D.Seng Shen, M.D., Yung Feng, M.D. Shin-Pin Lin, M.D, Shi-Chin Guo, M.D, Ming-ChengKuo, M.D., Liang-Jen Chuo, M.D., Chih-Pin Lu, M.D., Deng-Yi Chen, M.D, Huan-Kwang Ferng, M.D., Nan-Ying Chiu, M.D., Wen-Kun Chen, M.D. Tien-Cheng Lee, M.D.Hsin-Pei Tang, M.D. Yih-Dar Lee, M.D., Wu-Shih Wang, M.D. For-Wey Long, M.D.,PhD., Tiao-Lai Huang, M.D., Jung-Kwang Wen, M.D., Cheng-Sheng Chen, M.D., Wen-Hsiang Huang, M.D., Shu-Yu Yang, M.D., Mei-Hua Hall, Cheng-Hsing Chen. M.D.The project leaders in the People’s Republic of China were Xiaogang Chen M.D., PhD(China Principal Investigator, Institute of Mental Heath, Xiang-ya Teaching Hospital,Central South University), and Xingqun Ni, M.D. (Original Principal Investigator, Sun YatsenUniversity). Other participants in China were: Liwen Tan, M.D., PhD, Liang Zhou,M.D., PhD, Jiajun Shi, M.D., PhD, Xiaoling He, M.D., PhD, Xiogzhao Zhu, M.D., PhD,Lingjian Li, M.D., PhD, Ming Wang, M.D., Tiansheng Guo, M.D., Xiaqi Shen, M.D., PhD.,Jinghua Yang, M.D. NH/Northwestern University, Evanston, IL, MH059571, Pablo V. Gejman, M.D.(Collaboration Coordinator; PI), Alan R. Sanders, M.D.; Emory University School of Medicine, Atlanta, GA,MH59587, Farooq Amin, M.D. (PI); University of California, San Francisco, CA,MH60870, William Byerley, M.D. (PI); University of Iowa, Iowa, IA,MH59566, Raymond Crowe, M.D. (PI), Donald Black, M.D.; Washington University, St. Louis, MO, U01, MH060879, C. Robert Cloninger, M.D. (PI); University of Colorado, Denver, CO, MH059565, Robert Freedman, M.D. (PI), Ann Olincy, M.D.; University of Pennsylvania, Philadelphia, PA, MH061675, Douglas Levinson M.D. (PI), Nancy Buccola APRN, BC, MSN, New Orleans, Louisiana; University of Queensland, Queensland, Australia, MH059588, Bryan Mowry, M.D. (PI); Mt. Sinai School of Medicine, New York, NY,MH59586, Jeremy Silverman, Ph.D. (PI). Most importantly, we thank the families who have participated in and contributed to these studies.

Footnotes

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