The epsin 4 gene is associated with psychotic disorders in families of Latin American origin

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Abstract

This study attempted to replicate evidence for association of the Epsin 4 gene (which encodes enthoprotin, a protein involved in vesicular transport) to schizophrenia in a new sample of families segregating schizophrenia drawn from the Latin American population. 1423 subjects (767 with a history of psychosis) from 337 Latino families were genotyped using three single nucleotide polymorphisms (SNPs) spanning the Epsin 4 gene. A family based association test was utilized to test for association of these SNPs to the phenotypes of psychosis and schizophrenia. Haplotypes defined by these three SNPs showed significant association to the phenotype of psychosis in this sample (global p value = 0.014, bi-allelic p value = 0.047). Variation in the Epsin 4 gene is significantly associated with psychotic disorder in this Latino population. This provides additional support for the involvement of enthoprotin in the pathogenesis of schizophrenia and other psychotic disorders.

Introduction

Several genome wide mapping studies over the last decade have provided convergent evidence that the chromosome 5q31 to 5q35 region contains a risk gene (or genes) for schizophrenia (Gurling et al., 2001, Straub et al., 1997) and for psychotic disorders (Sklar et al., 2004, Escamilla et al., 2006). Linkage studies, by their nature, identify wide regions which contain many genes, which require subsequent analyses to analyze specific genes for association to disease phenotypes. In 2005, Pimm et al. provided evidence that variation within or near a specific gene within this region, the Epsin 4 gene, which codes for a protein involved in transport and stability of neurotransmitter vesicles (Wasiak et al., 2002) was likely to be responsible for increasing risk for schizophrenia. The Pimm study utilized subjects whose ancestry was principally derived from the countries of England, Ireland, Scotland, and Wales and utilized a case/control analytic design. Two subsequent studies conducted in the Han Chinese population (Tang et al., 2006, Liou et al., 2006) provided contradictory evidence that this gene was associated with schizophrenia in this population. Of these three studies, only the study of Tang et al. (2006), used family based analyses, which protect against possible false positives or negatives that case/control studies are vulnerable to, and in this study a distinct haplotype was associated with schizophrenia. Given that we had obtained preliminary linkage evidence of a gene contributing to psychotic disorders and schizophrenia on chromosome 5q in our previous linkage study of subjects with Mexican and Central American ancestry (Escamilla et al., 2006), we used family based association statistics to test three SNPs (Single Polynucleotide Polymorphisms) spanning the Epsin 4 gene in a large sample of subjects, to determine if this gene was associated with schizophrenia and psychosis in Latino subjects.

Section snippets

Methods

The sample studied consisted of 1423 subjects from 337 Latin American families who had been recruited as part of a multisite genetic linkage study to detect genes related to schizophrenia in persons of Mexican or Central American ancestry (National Institute of Mental Health study “Genetics of Schizophrenia in the Latino Population” MH06881R01) (Moldin, 2003). All subjects had at least two out of four grandparents whose ancestry was from Mexico or from a Central American country (Costa Rica,

Results

All three SNPs showed evidence of being in linkage disequilibrium with each other, with r2 = 0.438 between rs254664 and rs1186930, r2 = 0.012 between rs1186930 and rs10046055, and r2 = 0.13 between rs254664 and rs10046055. The three marker haplotypes defined by these SNPs (rs254664 (C/T)–rs1186930 (C/T)–rs10046055 (A/T)) showed significant evidence of association to the phenotype of psychosis (global p value = 0.014), as shown in Table 1. This remains significant even after correcting for the fact that

Discussion

The results of our study confirm the earlier findings of Pimm et al. (2005) and Tang et al. (2006), that the Epsin 4 gene is associated with psychotic disorders. This confirms the role of this gene in schizophrenia spectrum disorders in a third distinct population sample and is also, to our knowledge, the first gene confirmed to be associated with psychotic disorders in a Mexican and Central American population. The current study is also the largest sample studied to date for evidence of

Contributors

Dr. Escamilla designed the study, wrote the protocol, participated in assessments and diagnoses of subjects, and was primary author of the manuscript. Dr. Walss-Bass and Dr. Lee assisted with genotyping and statistical analysis of the results. Drs. Ontiveros, Raventos, Medina, Nicolini, Mendoza, Jerez, and Munoz led the respective research sites which recruited and assessed the subjects in this paper. Dr. Figueroa assisted with statistical analysis of the data. Dr. Dassori oversaw the clinical

Conflict of interest

Drs. Escamilla, Walss-Bass, Ontiveros, Raventos, Medina, Nicolini, Mendoza, Jerez, Munoz, Canive, Lee, Dassori, Armas, Contreras and Ramirez have no conflicts of interest which would influence this manuscript.

Acknowledgments

The authors thank the many families who participated in this research project, as well as clinicians and hospitals throughout the Southwest United States, Mexico, Costa Rica and Guatemala. We thank Paulina Quezada (UTHSCSA) for assistance in genotyping for this paper and Drs. Rudy Guerra (Rice University) and Elizabeth Hare (UTHSCSA) for assistance in statistical analyses. We thank Erasmo Cano for his coordinating activities and Drs. Alec Miller and Douglas Levinson for their assistance as part

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