Prostate Cancer Related JAZF1 Gene is Associated with Schizophrenia

Research Article

J Schizophr Res. 2014;1(1): 6.

Prostate Cancer Related JAZF1 Gene is Associated with Schizophrenia

Ke-Sheng Wang1*, Lingjun Zuo2, Daniel Owusu1,Yue Pan3 and Xingguang Luo2

1Department of Biostatistics and Epidemiology, East Tennessee State University, USA

2Department of Psychiatry, Yale University School of Medicine, USA

3Department of Public Health Sciences, University of Miami, USA

*Corresponding author: Kesheng Wang, Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN 37614-1700, USA

Received: July 29, 2014; Accepted: August 08, 2014; Published: August 11, 2014


Background: Epidemiological studies have shown that there is a reduced risk of prostate cancer among persons diagnosed with Schizophrenia (SCZ). However, the mechanism of such relationship is not clear. The reduced incidence of cancer observed in SCZ patients may be related to differences in genetic background. Recently, the JAZF1 gene is found to be associated with prostate cancer and type 2 diabetes. However, no study has focused on the association of JAZF1 with the risk of SCZ.

Methods: We examined genetic associations of 118 Single-Nucleotide Polymorphisms (SNPs) within the JAZF1 gene with SCZ using one European American (EA) sample of 1,149 cases and 1,347 controls. Logistic regression analysis of SCZ as a binary trait was performed using PLINK software.

Results: The most significant association with SCZ was observed with rs10258132 (p = 0.0011); while the next best signal was rs17156259 (p = 0.0031). The third best associated SNP was rs7791865 (p = 0.00889). In addition, haplotype analyses revealed that the A-C haplotype from rs10244184 and rs10258132 was associated with SCZ (p = 0.00093); and the G-G haplotype from rs17156238 and rs17156259 was associated with SCZ (p = 0.00455).

Conclusion: These findings provide evidence of several genetic variants in JAZF1 gene influencing the risk of SCZ and will serve as a resource for replication in other populations.

Keywords: Schizophrenia; Prostate cancer; JAZF1; Single nucleotide polymorphism; Pleiotropy


BMI: Body Mass Index; CNS: Central Nervous System; GWAS: Genome-wide Association Study; JAZF1: Juxtaposed with another Zinc Finger Protein 1; JJAZ1: Joined to JAZF1 protein 1; MAF: Minor Allele Frequency; LD: Linkage Disequilibrium; PrCa: Prostate Cancer; SCZ: Schizophrenia; TIP27: TAK1-interacting protein 27; T2D: Type 2 Diabetes; ZNF802: Zinc Finger Protein 802


Schizophrenia (SCZ) is the most tragic psychiatric disorder with high degree of genetic and clinical heterogeneity. The prevalence of SCZ is approximately 1% worldwide and currently affects 1.1% of the Unites States (US) population over the age of 18 [1-3]. SCZ is known to be a multifactorial disorder with a demonstrated heritability of 80% in family studies and meta-analysis of multiple twin studies [4,5]. Prostate Cancer (PrCa) is the most common non-skin malignancy cancer in the developed world and the second leading cause of cancer death in men [6,7]. In the US, approximately 240, 890 new cases and 33, 720 deaths were expected in 2011 [8]. The established risk factors for PrCa are age, ethnicity and family history [9]. Twin studies suggest that about 42% of the disease risk may be attributed to heritable factors [10].

It has been reported that there is a reduced risk of some cancers among persons diagnosed with SCZ [11-13]. For example, the incidence of PrCa in individuals with SCZ is significantly lower than expected [14,15]. Cancer risks in schizophrenic patients were negatively associated with age in the general populations (e.g. stomach cancer, pancreatic cancer and PrCa) [16]. Furthermore, patients with SCZ showed higher co-occurrence of SCZ with breast cancer, yet lower co-occurrence of melanoma and PrCa with SCZ [17]. Additionally, Ibáñez et al [18] found inverse expression deregulations between Central Nervous System (CNS) disorders (Alzheimer's disease, Parkinson's disease, and SCZ) and three cancer types (lung, prostate, and colorectal cancers). However, other studies found no evidence that SCZ confers protection against cancer in general [19].

The reduced incidence of cancer observed in SCZ patients could potentially attributed to differences in genetic background [20]. For example, Catts and Catts [21] suggested that the reduced incidence of cancer observed in SCZ patients might be linked to differences in apoptosis, and proposed p53, a tumor suppressor gene, which is considered as a candidate gene for the susceptibility. Park et al [20] found that the p53 polymorphism specifically identified in Korean SCZ patients may be associated with reduced vulnerability to lung cancer.

The juxtaposed with another zinc finger protein 1 (JAZF1) also known as TAK1-interacting protein 27 (TIP27) or zinc finger protein 802 (ZNF802) gene is located at 7p15 [22] and is highly expressed in testis, followed by colon, ovary, prostate, and placenta, but lower expressed in pancreas, brain, and liver [23]. Li et al [24] stated that the first 3 exons of JAZF1 are joined to the last 15 exons of Joined to JAZF1 protein 1 gene (JJAZ1) in the JAZF1/JJAZ1 fusion transcript, and suggested that there is a genetic pathway for progression of a benign precursor to a sarcoma involving increased cell survival, followed by accelerated cellular proliferation upon allelic exclusion of the unrearranged copy of that gene. JAZF1 has been associated with somatic fusion proteins in endometrial tumors [22,25-27]. Using a large genome-wide association study (GWAS), Thomas et al [28] found that Single-Nucleotide Polymorphisms (SNP) rs10486567 within JAZF1 was associated PrCa. Later, this variant was found to be associated with PrCa in a multiethnic sample of 2,768 incident PrCa cases and 2,359 controls from a multiethnic cohort (African Americans, European Americans, Latinos, Japanese Americans, and Native Hawaiians) [29]. Eeles et al [30] confirmed the associaiton of this SNP with PrCa from the second stage of genotyped 43,671 SNPs among 3,650 PrCa cases and 3,940 controls. Another study established rs10486567 as a bona-fide marker for association with susceptibility to PrCa in individuals of European ancestry [31]. Recently, the association of rs10486567 was valided in a African American populaiton [32] and confirmed by a meta-analysis [33]. Other studies showed the JAZF1 locus was associated with height[34], and type 2 diabetes (T2D) [35,36].

Previous studies have shown that zinc finger protein genes such as Zinc Finger Protein 74 (ZNF74) and 804A (ZNF804A) are associated with SCZ [37-40]. However, no study has focused on the association of JAZF1 with the risk of SCZ. This study explored the association of 118 SNPs within JAZF1 gene with the risk of SCZ in a European American (EA) sample (1,149 cases and 1,437 controls) from the Molecular Genetics of Schizophrenia - non GAIN Sample.

Material and Methods


NonGAIN sample is part of the Molecular Genetics of Schizophrenia (MGS) genome wide association study of 3,972 cases and 3,629 controls after quality control (dbGaP Study Accession: phs000167.v1.p1). Unrelated adult cases with DSM-IIIR (SGI study) or DSM-IV (MGS1, MGS2 studies) SCZ or schizoaffective disorder were collected under institutional review board-approved protocols in three studies, Schizophrenia Genetics Initiative (SGI), Molecular Genetics of Schizophrenia Part 1 (MGS1), and MGS23. Cases selected met criteria for SCZ or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV). The details about these subjects were described elsewhere [41-43]. Genotyping data using the Affymetrix Genome-wide human SNP Array 6.0 (total 729,454 SNPs) were available for the sample. 1,179 European American (EA) patients with SCZ and 1,364 EA controls were selected from the nonGAIN Sample. We investigated the genetic associations of 118 SNPs within the JAZF1 gene with the risk of SCZ.

Statistical methods

For the initial Analysis, HelixTree Software (—Variation/HelixTree/index.html, Golden Helix, Bozeman, MT) was used to assess control genotype data for conformity with Hardy-Weinberg equilibrium (HWE). To deal with population stratification, the principal-component analysis approach with ten principal components [44] in HelixTree was used to identify outlier individuals. Then, logistic regression analysis of SCZ as a binary trait, adjusted for age and sex, was performed for the nonGAIN sample using PLINK v1.07 [45]. The asymptotic p values for this test were observed while the Odds Ratios (ORs) and standard errors of ORs were estimated. For logistic regression, the additive model was applied. In addition to obtaining nominal p values, empirical p-values were generated by 100,000 permutation tests using Max (T) permutation procedure implemented in PLINK. Minor Allele Frequency (MAF) was determined for each SNP and the Linkage Disequilibrium (LD) structure was constructed using Haploview software [46]. Haplotype analysis based on a slide-window was performed using PLINK.


Based on the analysis of the first ten principal components using HelixTree and other exclusion criteria, 1,149 cases and 1,347 controls were left for further analyses. Participant characteristics are presented in Table 1. The mean values of age are 42.9 and 49.8 years for cases and controls, respectively.