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BCL9 and C9orf5 Are Associated with Negative Symptoms in Schizophrenia: Meta-Analysis of Two Genome-Wide Association Studies

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BCL9 and C9orf5 Are Associated with Negative Symptoms in Schizophrenia: Meta-Analysis of Two Genome-Wide Association Studies University of Texas Rio Grande Valley ScholarWorks @ UTRGV Health and Biomedical Sciences Faculty Publications and Presentations College of Health Professions 2013 BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies Chun Xu The University of Texas Rio Grande Valley Nagesh Aragam Xia Li Erika Cynthia Villa Liang Wang See next page for additional authors Follow this and additional works at: https://scholarworks.utrgv.edu/hbs_fac Part of the Psychiatry and Psychology Commons Recommended Citation Xu, C., Aragam, N., Li, X., Villla, E. C., Wang, L., Briones, D., Petty, L., Posada, Y., Arana, T. B., Cruz, G., Mao, C., Camarillo, C., Su, B. B., Escamilla, M. A., & Wang, K. (2013). BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies. PloS one, 8(1), e51674. https://doi.org/10.1371/journal.pone.0051674 This Article is brought to you for free and open access by the College of Health Professions at ScholarWorks @ UTRGV. It has been accepted for inclusion in Health and Biomedical Sciences Faculty Publications and Presentations by an authorized administrator of ScholarWorks @ UTRGV. For more information, please contact [email protected], [email protected]. Authors Chun Xu, Nagesh Aragam, Xia Li, Erika Cynthia Villa, Liang Wang, David Briones, Brenda Bin Su, Michael A. Escamilla, and KeSheng Wang This article is available at ScholarWorks @ UTRGV: https://scholarworks.utrgv.edu/hbs_fac/85 BCL9 and C9orf5 Are Associated with Negative Symptoms in Schizophrenia: Meta-Analysis of Two Genome-Wide Association Studies Chun Xu1*, Nagesh Aragam2,3, Xia Li4, Erika Cynthia Villla5, Liang Wang2, David Briones1, Leonora Petty1, Yolanda Posada6, Tania Bedard Arana1, Grace Cruz1, ChunXiang Mao7, Cynthia Camarillo1, Brenda Bin Su7, Michael A. Escamilla1, KeSheng Wang2* 1 Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, Departments of Psychiatry/Neurology and the Center of Excellence in Neuroscience, El Paso, Texas, United States of America, 2 Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, Tennesee, United States of America, 3 Department of Microbiology and Immunology, Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 4 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, People’s Republic of China, 5 University of Texas at El Paso, El Paso, Texas, United States of America, 6 Walden University, Minneapolis, Minnesota, United States of America, 7 University of Toronto, Toronto, Canada Abstract Schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p,561025. Especially we detected five SNPs in the first 26 two genes/loci strongly associated with negative symptoms of schizophrenia (Pmeta-analysis,6.22610 ), which included 27 three SNPs in the BCL9 gene: rs583583 showed the strongest association at a Pmeta-analysis of 6.00610 and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 61026). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes. Citation: Xu C, Aragam N, Li X, Villla EC, Wang L, et al. (2013) BCL9 and C9orf5 Are Associated with Negative Symptoms in Schizophrenia: Meta-Analysis of Two Genome-Wide Association Studies. PLoS ONE 8(1): e51674. doi:10.1371/journal.pone.0051674 Editor: Monika Stoll, Leibniz-Institute for Arteriosclerosis Research at the University Muenster, Germany Received May 23, 2012; Accepted November 5, 2012; Published January 29, 2013 Copyright: ß 2013 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (CX); [email protected] (KW) Introduction geneity, using too broad phenotypes, or a lack of consideration of the effect of the disease-associated single nucleotide polymor- Schizophrenia (SCZ) is one of the most tragic psychiatric phisms (SNPs) on gene regulation. This highlights an urgent need disorders with a high degree of genetic and clinical heterogeneity for re-thinking strategic, complementary approaches to identify and a prevalence of approximately 1% worldwide. Given its true biomarkers for the disorder. Molecular genetics technology debilitation, morbidity, mortality and economic burden, SCZ development and the results from the recent genome-wide represents a major public health concern and an important topic association (GWA) meta-analyses suggest a number of genes/loci in health research. Schizophrenia is known to be a multifactorial to be associated with the broader SCZ spectrum of phenotypes; disorder with a demonstrated heritability of 80% in family studies however, with regard to the identified causative variants, it is likely and meta-analysis of multiple twin studies [1,2]. While the number that genetic variants with a more definitive effect on SCZ of genes potentially implicated in SCZ has been estimated to be phenotypes are still missing. over 1000, the progress in the identification of susceptibility genes It has been well documented that using intermediate pheno- has been slow. Previous functional studies have not been types may aid in the genetic dissection of neuropsychiatric diseases successfully replicated, which may be due, at least in part, to the like SCZ (see review in [3]). Intermediate phenotypes, in contrast inherent limitations associated with assessing phenotypic hetero- to broad phenotypes, appear to follow simple inheritance patterns PLOS ONE | www.plosone.org 1 January 2013 | Volume 8 | Issue 1 | e51674 Association with Schizophrenia-Negative Symptoms allowing for genetic linkage and association study of patients [4]. SCZ. In the present study we use two existing GWA-data sets Therefore, using an intermediate phenotype approach permits (729,454 markers) and large sample sizes (1774 cases with negative mapping of the effect of individual risk genes based on symptoms of SCZ and 2726 controls) to identify novel variants neurobiological parameters, known to be associated with causes associated with negative symptom-susceptibility. of SCZ rather than targeting the effects of the disorder, which are believed to be less genetically complex than those associated with Results the disorder itself [4]. A recent study with a focus on a number of SCZ-related intermediate phenotypes (e.g., neurophysiological Genotype Quality Control and Descriptive Statistics and neurocognitive data), examined 1536 SNPs and identified a We removed SNPs with HWE p,0.00001 or call rates ,95% number of genetic variants that were associated with 12 SCZ or minor allele frequency (MAF) ,1%. In total, 722,112 SNPs intermediate phenotypes. This finding supports the use of relevant were left for the GAIN sample and 711,137 SNPs were remained intermediate phenotypes and the bootstrap total significance test for the nonGAIN sample. The details about these subjects were for identifying genetic variation underlying the etiology of SCZ described elsewhere [18–20]. After merging SNP genotype data [5], and provides evidence that using SCZ-related intermediate with phenotype data and removing outlier individuals based on phenotypes will increase the chance of detecting genetic linkage the principal-component analysis, 950 cases with negative and association not feasible with the broader spectrum of SCZ symptoms and 1,378 controls (1,298 males and 1,040 females) [3,4]. Among the SCZ intermediate phenotypes, negative were left in the GAIN sample while 824 cases and 1,348 controls symptoms of SCZ are of particular interest. One feature of the (1,258 males and 924 females) were left in the nonGAIN sample
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