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ARTICLE Received 28 Apr 2015 | Accepted 13 Aug 2015 | Published 22 Sep 2015 DOI: 10.1038/ncomms9355 OPEN Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls Zezhang Zhu1,2,*, Nelson Leung-Sang Tang2,3,4,5,*, Leilei Xu1,2,*, Xiaodong Qin1,2, Saihu Mao1, Yueming Song6, Limin Liu6, Fangcai Li7, Peng Liu8,LongYi9, Jiang Chang10, Long Jiang11, Bobby Kin-Wah Ng12, Benlong Shi1, Wen Zhang1, Jun Qiao1,2, Xu Sun1,2, Xusheng Qiu1,2, Zhou Wang1, Fei Wang1, Dingding Xie1, Ling Chen1, Zhonghui Chen1, Mengran Jin1, Xiao Han1, Zongshan Hu1, Zhen Zhang1, Zhen Liu1, Feng Zhu1, Bang-ping Qian1,2, Yang Yu1,2, Bing Wang1,2, K.M. Lee5, Wayne Y.W. Lee12, T.P. Lam12, Yong Qiu1,2,** & Jack Chun-Yiu Cheng2,5,12,** Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci À 9 at 1p36.32 near AJAP1 (rs241215, Pcombined ¼ 2.95  10 ), 2q36.1 between PAX3 and À 13 EPHA4 (rs13398147, Pcombined ¼ 7.59  10 ) and 18q21.33 near BCL-2 (rs4940576, À 12 Pcombined ¼ 2.22  10 ). In addition, we refine a previously reported region associated with À 37 AIS at 10q24.32 (rs678741, Pcombined ¼ 9.68  10 ), which suggests LBX1AS1, encoding an antisense transcript of LBX1, might be a functional variant of AIS. This is the first GWAS investigating genetic variants associated with AIS in Chinese population, and the findings provide new insight into the multiple aetiological mechanisms of AIS. 1 Department of Spine Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China. 2 Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing 210008, China. 3 Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 4 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 5 Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 6 Department of Orthopaedic, The West China Hospital, Sichuan University, Chengdu 610000, China. 7 Department of Orthopaedic, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China. 8 Department of Orthopaedic, China-Japan Union Hospital of Jilin University, Changchun 130022, China. 9 Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing 210008, China. 10 State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China. 11 Department of Orthopaedic, Yixing People Hospital, Wuxi 214200, China. 12 Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. * These authors contributed equally to this work. ** These authors jointly supervised this work. Correspondence and requests for materials should be addressed to Y.Q. (email: [email protected]) or to J.C.-Y.C. (email: [email protected]). NATURE COMMUNICATIONS | 6:8355 | DOI: 10.1038/ncomms9355 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms9355 dolescent idiopathic scoliosis (AIS) is a structural Results deformity of the spine that is estimated to affect millions Association analyses in the discovery and replication.We Aof children, with a prevalence of 2–4% (refs 1,2). performed a four-stage GWAS in cohorts of 4,317 patients and Commonly understood as a complex trait (polygenic disease), 6,016 controls, all of the Chinese Han population. In the the genetic aetiology of AIS has been widely investigated by discovery stage, 906,703 single nucleotide polymorphisms (SNPs) linkage analysis and candidate gene association analysis3–5. were genotyped in 1,001 patients presenting a main thoracic During the era of candidate study, several genes were reported curve (major curve located in thoracic region) and 1,500 healthy to be associated with AIS, such as ERa (ref. 6), MATN1 (ref. 7), controls. After quality control filtering of the genotyping data, MTNR1B (ref. 8) and TGFB1 (ref. 9). However, few of them have 516,220 autosomal SNPs in 960 cases and 1,499 controls were been successfully replicated in different ethnicities10–13. The first retained for the subsequent Cochran–Armitage trend test. genome-wide association study (GWAS) in a Caucasian Analysis of population stratification with principal-component population reported that rs1400180 of CHL1 was associated analysis (PCA) showed that all subjects of our study were with AIS14, which however could not be replicated in a Chinese clustered in Chinese population (Supplementary Fig. 1). The Han population15. Subsequently, a GWAS performed in a genomic inflation factor (l) as shown by the quantile–quantile Japanese population revealed that LBX1 and GPR126 could play plot was 1.031, indicating that there was only a minimal a role in the etiopathogenesis of AIS16,17. In a recent study that amount of population stratification (Supplementary Fig. 2). combined the GWAS data of AIS in Caucasian and Japanese As shown by the Manhattan plot (Fig. 1), 43 SNPs were observed populations, Sharma et al.18 reported an enhancer locus of PAX1 to surpass the threshold of suggestive whole-genome significance was associated with the susceptibility of female AIS. As estimated (Po1.0  10 À 5) (Supplementary Table 2 and 3). by Kou et al.17, variants of LBX1 and GPR126 can only explain From each putative haplotype block defined by linkage B1% of the trait variance in AIS. Herein additional genetic risk disequilibrium (r24 0.8), we chose one representative SNP with factors need to be discovered for a better understanding of the the lowest P value for replication. Sixteen representative SNPs genetic susceptibility of AIS. (Supplementary Table 2) were then included in replication stage To map novel risk loci for AIS, here we report the results of a 1, composed of 1,916 cases and 2,001 controls. Significant four-stage GWAS in a Chinese population. Overall, we identify associations were found in four SNPs, which were further three new susceptibility loci: 1p36.32 near AJAP1, encoding genotyped in 1,400 cases and 2,515 controls. Combining the adherens junction associated protein 1 (rs241215, Pcombined ¼ 2.95 results from the discovery stage and three replication stages, four  10 À 9); 2q36.1 between PAX3 and EPHA4, encoding paired SNPs were found to reach a genome-wide significance threshold box 3 and EPH receptor A4, respectively (rs13398147, of Po5  10 À 8, including rs241215 at 1p36, rs13398147 at 2q36, À 13 Pcombined ¼ 7.59  10 ); and 18q21.33 near BCL-2, encoding rs678741 at 10q24 and rs4940576 at 18p21 (Table 1). We À 12 B-cell CLL/lymphoma 2 (rs4940576, Pcombined ¼ 2.22  10 ). performed imputation analysis around the four significant In addition, we refine a previously reported region associated with regions, and the logistic regression model showed similar À 37 AIS at 10q24.32 (rs678741, Pcombined ¼ 9.68  10 ), which association with those of the discovery stage (Supplementary suggests LBX1AS1, encoding an antisense transcript of LBX1 Table 4). The strongest evidence of association was attained with À 37 (lady-bird like homeobox), might be the functional variant of AIS. rs678741 (Pcombined ¼ 9.68  10 , odds ratio (OR) ¼ 1.44, 95% This is the first GWAS to our knowledge investigating the genetic confidential interval (CI): 1.37–1.52, Phet ¼ 0.95) located in the variants associated with AIS in a Chinese population, and the intron of the LBX1AS1 (Table 1, Fig. 2a and Supplementary À 12 findings provide new insight into the multiple aetiological Fig. 3). SNP rs4940576 (Pcombined ¼ 2.22  10 ,OR¼ 1.23, mechanisms of AIS. 95% CI: 1.14–1.29, Phet ¼ 0.13) was located in the intronic region 15.0 14.5 14.0 13.5 13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 –Log10 (P) 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chr1 Chr2 Chr3 Chr4 Chr5 Chr6 Chr7 Chr8 Chr9 Chr10 Chr11 Chr12 Chr13 Chr14 Chr15 Chr16 Chr17 Chr18 Chr19 Chr20 Chr21 Chr22 Figure 1 | Genome-wide association results for AIS in Han Chinese girls. Here we present Manhattan plot of P values on the À log10 scale in the discovery stage (960 cases and 1,499 controls). The x axis shows Chromosomes as delineated by different colours. The y axis shows À log10 P values of each SNP. The red line represents P ¼ 5  10 À 8, and the blue dashed line represents P ¼ 1  10 À 5. 2 NATURE COMMUNICATIONS | 6:8355 | DOI: 10.1038/ncomms9355 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms9355 ARTICLE Table 1 | Association results for four SNPs in the GWAS, replication and combined samples. SNP Chr. Genes MA Stage MAF P value OR (95% CI) Phet Cases Control rs678741 10q24.32 LBX1AS1 A GWAS 0.532 0.444 1.79  10 À 9 1.42 (1.27–1.60) Replication 1 0.546 0.455 5.96  10 À 14 1.44 (1.32–1.58) Replication 2 0.549 0.452 3.83  10 À 12 1.48
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