31 October 2011. With the heritability of schizophrenia estimated at around 80 percent, much of it still unaccounted for, the search for underlying genes is a hotbed of research. Most recently, two independent genomewide association studies (GWAS) find three novel susceptibility loci of interest in the Han Chinese population, according to two papers published online October 30 in Nature Genetics.
Researchers led by Dai Zhang of Peking University in Beijing, China, and Wei Huang of Shanghai Jiao Tong University in Shanghai, China, performed a two-stage GWAS examining data from a total of 4,773 individuals with schizophrenia and 7,202 healthy individuals in two separate cohorts, and found that the chromosome locus 11p11.2 contained novel risk single nucleotide polymorphisms (SNPs). The second study comes from the laboratory of Lin He, at Shanghai Jiao Tong University in Shanghai, China. Utilizing a total of 8,133 schizophrenia and 11,007 healthy subjects, He's group also performed a two-part GWAS and identified novel SNPs associated with schizophrenia at chromosomes 1q24.2 and 8p12.
The majority of GWAS to date have been performed using individuals of European descent, and the current studies represent some of the largest GWAS undertakings in Asian populations. In addition to identifying novel risk variants associated with schizophrenia, studies such as these also aim to address the issue of whether genetic risk variants for schizophrenia are similar among people of different descents.
In the initial phase of the Peking University study, first authors Wei-Hua Yue and Liang-Dan Sun identified three SNPs within 11p11.2 that were later replicated in a second cohort. These three SNPs reached genomewide significance in the combined cohort that included subjects from both phases, and were all located adjacent to tetraspanin 18 (TSPAN18), a gene that encodes a protein of currently unknown function. Interestingly, TSPAN8, a gene encoding another tetraspanin in the same family, has been associated with bipolar disorder in a GWAS (Sklar et al., 2008).
In the second study, first authors Yongyong Shi, Zhiqiang Li, Qi Xu, and colleagues found three SNPs within 1q24.2 and two SNPs within 8p12 that were strongly associated with schizophrenia. When the data were combined with a second population sample, all five SNPs reached genomewide significance. Of note, one SNP within 1q24.2 is located near the gene encoding myelin protein zero-like 1 (MPZL1), which is upregulated in schizophrenia (Tkachev et al., 2003) and recently implicated in risk for the illness (He et al., 2006). Additionally, one SNP within 8p12 is located near the gene encoding fibroblast growth factor receptor 1 protein (FGFR1). Increased levels of FGFR1 mRNA expression have been found in the hippocampus of subjects with schizophrenia and depression (Gaughran et al., 2006), and a SNP near a related gene, FGFR2, has also been implicated as a risk allele in schizophrenia (O’Donovan et al., 2009).
In addition to the novel variants within 11p11.2, Yue, Sun, and colleagues also identified three genomewide significant SNPs in a region previously implicated in GWAS of schizophrenia: the immune-related major histocompatibility complex (MHC) region of 6p21-p22.1 (Shi et al., 2009; Stefansson et al., 2009; see also SRF related news story). Additionally, although none of the SNPs within the MHC region of the Yue study reached genomewide significance, 8 percent of all the nominally associated SNPs were located within this region, further implicating 6p21-p22.1 in schizophrenia.
The role of ancestry in genetic risk for schizophrenia remains unclear, as the results from the two studies point to both similarities and differences between risk variants in subjects of Chinese and European descent. By comparing their identified SNPs with data from the International HapMap project, Yue, Sun, and colleagues observed substantially different minor allele frequencies between the European and Chinese ancestry populations, suggesting that individuals of different ancestries may differ in their susceptibility variants. In contrast, when Shi, Li, Xu, and colleagues compared their identified SNPs to data from the SGENE-plus project, the two SNPs within 8p12 were nominally associated with schizophrenia in a European population, and the direction of both effects was consistent between the Chinese and European populations.—Allison A. Curley.
Yongyong Shi, Zhiqiang Li, Qi Xu, Ti Wang, Tao Li, Jiawei Shen, Fengyu Zhang, Jianhua Chen, Guoquan Zhou, Weidong Ji, Baojie Li, Yifeng Xu, Dengtang Liu, Peng Wang, Ping Yang, Benxiu Liu, Wensheng Sun, Chunling Wan, Shengying Qin, Guang He, Stacy Steinberg, Sven Cichon, Thomas Werge, Engilbert Sigurdsson, Sarah Tosato, Aarno Palotie, Markus M Nöthen, Marcella Rietschel, Roel A Ophoff, David A Collier, Dan Rujescu, David St Clair, Hreinn Stefansson, Kari Stefansson, Jue Ji, Qingzhong Wang, Wenjin Li, Linqing Zheng, Hairong Zhang, Guoyin Feng , Lin He. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nat Genet. 2011 Oct 30.
Wei-Hua Yue, Hai-Feng Wang, Liang-Dan Sun, Fu-Lei Tang, Zhong-Hua Liu, Hong-Xing Zhang, Wen-Qiang Li, Yan-Ling Zhang, Yang Zhang, Cui-Cui Ma, Bo Du, Li-Fang Wang, Yun-Qing Ren, Yong-Feng Yang, Xiao-Feng Hu, Yi Wang, Wei Deng, Li-Wen Tan, Yun-Long Tan, Qi Chen, Guang-Ming Xu, Gui-Gang Yang, Xian-bo Zuo, Hao Yan, Yan-Yan Ruan, Tian-Lan Lu, Xue Han, Xiao-Hong Ma, Yan Wang, Li-Wei Cai, Chao Jin, Hong-Yan Zhang, Jun Yan, Wei-Feng Mi, Xian-Yong Yin, Wen-Bin Ma, Qi Liu, Lan Kang, Wei Sun, Cheng-Ying Pan, Mei Shuang, Fu-De Yang, Chuan-Yue Wang, Jian-Li Yang, Ke-Qing Li, Xin Ma, Ling-Jiang Li, Xin Yu, Qi-Zhai Li, Xun Huang, Lu-Xian Lv, Tao Li, Guo-Ping Zhao, Wei Huang, Xue-Jun Zhang & Dai Zhang. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet. 2011 Oct 30.