Neuroscience Letters 562 (2014) 24–27 Contents lists available at ScienceDirect Neuroscience Letters jo ur nal ho me p age: www.elsevier.com/locate/neulet Association analysis of a functional variant in ATXN2 with schizophrenia Fuquan Zhang a,b,c,1 , Guoqiang Wang a,1 , Yin Yao Shugart d,1 , Yong Xu e , Chenxing Liu b,c , Lifang Wang b,c , Tianlan Lu b,c , Hao Yan b,c , Yanyan Ruan b,c , Zaohuo Cheng a , Lin Tian a , Chunhui Jin a , Janmin Yuan a , Zhiqiang Wang a , Wei Zhu a , Leiming Cao a , Yansong Liu a , Weihua Yue b,c,∗ , Dai Zhang b,c,∗ a Wuxi Mental Health Center, Wuxi, Jiangsu Province, China b Institute of Mental Health, Peking University, Beijing, China c Key Laboratory of Mental Health, Ministry of Health, Beijing, China d Unit on Statistical Genomics, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States e Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China a r t i c l e i n f o Article history: Received 25 October 2013 Received in revised form 27 November 2013 Accepted 2 December 2013 Keywords: Schizophrenia ATXN2 rs7969300 a b s t r a c t Schizophrenia (SZ) is a severe mental disorder characterized by multiple neurodevelopmental dysfunc- tions including a breakdown of thinking process and a deficit of typical emotional responses. Ataxin-2 (ATXN2) plays vital roles in cell proliferation and growth, and functional mutations of ATXN2 cause neurodegenerative phenotypes, including spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). To explore the possible role of ATXN2 in SZ, we conducted a two-stage study to examine the association of ATXN2 polymorphisms with SZ in the Han Chinese population. Association analy- sis of seven SNPs in 768 patients and 1348 controls revealed two associated SNPs, including rs630511 (P = 1.76E-4) and rs7969300 (P = 5.08E-4). We examined these two SNPs in a validation sample of 1957 patients and 1509 controls, and observed an association of rs7969300 with SZ (P = 5.03E-3). The SNP rs7969300 is a non-synonymous SNP causing a Ser to Asn substitution, which is predicted to increase the protein stability of ATXN2. Our data suggest that the ATXN2 gene may confer vulnerability for SZ, adding further evidence for the genetic variants within the developmental pathway in the illness. © 2014 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Schizophrenia (SZ) is a severe mental disorder characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, percep- tion, affect, and sense of self. The onset of the illness is typically in late adolescence or early adulthood. The neurodevelopmental hypothesis has received much support from epidemiological, developmental and neuroimaging studies [24] and has been the dominant paradigm for SZ research over the past two decades [16]. This hypothesis posits that SZ has its origins in disturbed develop- ment of the nervous system, in which cerebral insults occur during early brain development, long before the full-blown of the illness. ∗ Corresponding authors at: Institute of Mental Health, Peking University, No. 51 Hua Yuan Bei Road, Beijing 100191, PR China. Tel.: +86 10 82801937; fax: +86 10 62078246. E-mail addresses: dyue@bjmu.edu.cn (W. Yue), daizhang@bjmu.edu.cn (D. Zhang). 1 These authors contributed equally to this work. It has been shown that ATXN2 protein plays a direct role in trans- lational regulation by associating with polyribosomes [21] and is mainly localized at the rough endoplasmic reticulum [23]. ATXN2 also participates in the formation of stress granules (SGs), where untranslated mRNAs are translationally inhibited during conditions of cell stress [15,19]. Animal studies showed that over-expression of ATXN2 potentiates toxicity from neurodegenerative disease pro- teins [2], while the deficiency of ATXN2 could cause mice to grow to excessive size and weight, through modulation of insulin signaling [11,12]. Thus, ATXN2 is a relevant regulator of general cell growth. A majority of human population carry a repeat size of 22–23 CAG triplets coding for glutamine in ATXN2 exon 1 [17], and only individuals having a polyQ-repeat of 32 CAGs or more may develop SCA2, with larger repeat sizes resulting in a more severe disease course and earlier manifestation [1], while triplets between 27 and 33 are viewed as intermediate size expansions which result in a higher risk for related neurodegenerative diseases such as ALS and progressive supranuclear palsy [4,8,20]. In addition, ATXN2 has been shown to be associated with longevity among human cen- tenarians [22], microcirculation [10] and blood pressure [6]. 0304-3940/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.12.001