1234 volume 41 | number 11 | november 2009 Nature GeNetics
l e t t e r s
We performed a genome-wide association study (GWAS)
of systemic lupus erythematosus (SLE) in a Chinese Han
population by genotyping 1,047 cases and 1,205 controls using
Illumina Human610-Quad BeadChips and replicating 78 SNPs
in two additional cohorts (3,152 cases and 7,050 controls). We
identified nine new susceptibility loci (ETS1, IKZF1, RASGRP3,
SLC15A4, TNIP1, 7q11.23, 10q11.22, 11q23.3 and 16p11.2;
1.77 × 10−25 ≤ Pcombined ≤ 2.77 × 10−8) and confirmed seven
previously reported loci (BLK, IRF5, STAT4, TNFAIP3, TNFSF4,
6q21 and 22q11.21; 5.17 × 10−42 ≤ Pcombined ≤ 5.18 × 10−12).
Comparison with previous GWAS findings highlighted the
genetic heterogeneity of SLE susceptibility between Chinese
Han and European populations. This study not only advances
our understanding of the genetic basis of SLE but also highlights
the value of performing GWAS in diverse ancestral populations.
Systemic lupus erythematosus (SLE) is a prototypic systemic
autoimmune disease that is characterized by a diverse array of
autoantibody production, complement activation, immune
complex deposition and tissue and organ damage1 and that is
influenced by both genetic and environmental factors2. SLE affects
predominantly women (prevalence ratio of women to men is 9:1),
particularly during the childbearing years. There are marked
disparities in SLE incidence and prevalence worldwide; SLE preva-
lence varies among different ethnic and geographical populations3.
The prevalence of SLE ranges from 31 to 70 cases per 100,000
persons among Chinese populations4 and from 7 to 71 cases per
100,000 persons in European populations5, and lupus nephritis is
more prevalent in Chinese populations than in European popula-
tions3. The ethnic and genetic heterogeneity of SLE may contribute
to the complexity of its clinical manifestation.
Over the past two decades, numerous studies have identified
multiple genetic factors related to SLE. In particular, four recent
genome-wide association studies (GWAS) of SLE in European popu-
lations have identified more than 20 robust susceptibility genes and/or
loci6–9. The genetic heterogeneity between ethnic populations has
Genome-wide association study in a Chinese Han
population identifies nine new susceptibility loci for
systemic lupus erythematosus
Jian-Wen Han1,2,18, Hou-Feng Zheng1,2,18, Yong Cui1,2,18, Liang-Dan Sun1,2, Dong-Qing Ye1,2, Zhi Hu1,2,
Jin-Hua Xu3, Zhi-Ming Cai4, Wei Huang5, Guo-Ping Zhao5, Hong-Fu Xie6, Hong Fang7, Qian-Jin Lu8,
Jian-Hua Xu9, Xiang-Pei Li10, Yun-Feng Pan11, Dan-Qi Deng12, Fan-Qin Zeng13, Zhi-Zhong Ye14,
Xiao-Yan Zhang15, Qing-Wen Wang4, Fei Hao16, Li Ma15, Xian-Bo Zuo1,2, Fu-Sheng Zhou1,2, Wen-Hui Du1,2,
Yi-Lin Cheng1,2, Jian-Qiang Yang1,2, Song-Ke Shen1,2, Jian Li1,2, Yu-Jun Sheng1,2, Xiao-Xia Zuo6, Wei-Fang Zhu7,
Fei Gao8, Pei-Lian Zhang12, Qing Guo13, Bo Li14, Min Gao1,2, Feng-Li Xiao1,2, Cheng Quan1,2, Chi Zhang1,2,
Zheng Zhang1,2, Kun-Ju Zhu1,2, Yang Li1,2, Da-Yan Hu1,2, Wen-Sheng Lu1,2, Jian-Lin Huang11, Sheng-Xiu Liu1,2,
Hui Li1,2, Yun-Qing Ren1,2, Zai-Xing Wang1,2, Chun-Jun Yang1,2, Pei-Guang Wang1,2, Wen-Ming Zhou1,2,
Yong-Mei Lv1,2, An-Ping Zhang1,2, Sheng-Quan Zhang1,2, Da Lin1,2, Yi Li17, Hui Qi Low17, Min Shen5,
Zhi-Fang Zhai16, Ying Wang5, Feng-Yu Zhang1,2, Sen Yang1,2, Jian-Jun Liu1,2 & Xue-Jun Zhang1–3
1Institute of Dermatology and Department of Dermatology at NO. 1 Hospital, Anhui Medical University, Hefei, Anhui, China. 2Key Laboratory of Dermatology,
Anhui Medical University, Ministry of Education, China, Hefei, Anhui, China. 3Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China.
4Department of Rheumatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China. 5Chinese National Human Genome Center at Shanghai, Shanghai,
China. 6Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China. 7Department of Dermatology, First Affiliated Hospital,
College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 8Department of Dermatology, Epigenetic Research Center, Second Xiangya Hospital, Central
South University, Changsha, Hunan, China. 9Department of Rheumatology at NO. 1 Hospital, Anhui Medical University, Hefei, Anhui, China. 10Department of
Rheumatology, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, China. 11Department of Rheumatology, The Third Affiliated Hospital of Sun
Yat-sen University, Guangzhou, Guangdong, China. 12Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan,
China. 13Department of Dermatology, The Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. 14Department of Rheumatology,
Shenzhen Fourth People’s Hospital, Shenzhen, Guangdong, China. 15Department of Dermatology, China-Japan Friendship Hospital, Beijing, China. 16Department
of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China. 17Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
18These authors contributed equally to this work. Correspondence should be addressed to X.-J.Z. (ayzxj@vip.sina.com), J.-J.L. (liuj3@gis.a-star.edu.sg)
or S.Y. (yangsen@medmail.com.cn).
Received 13 July; accepted 9 September; published online 18 October 2009; doi:10.1038/ng.472
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Nature GeNetics volume 41 | number 11 | november 2009 1235
l e t t e r s
been suggested to be important in SLE risk10, showing the need for
further GWAS in non-European populations.
We conducted a GWAS of SLE in a Chinese Han population by
analyzing 493,955 autosomal SNPs in 1,047 affected individuals
(cases) and 1,205 controls (Table 1). Principal component analysis
and genomic control (λgc = 1.045 for all 493,955 SNPs and 1.039 after
excluding 4,840 SNPs within the major histocompatibility complex
(MHC) region) indicated minimal inflation of the GWA results due
to population stratification (Supplementary Fig. 1).
The analysis revealed association at three loci—6p21 (MHC)6,7,9,
2q32.3 (STAT4)6,9 and 8p23.1 (BLK)6—with genome-wide significance
(P < 5 × 10−8) (Fig. 1a). Furthermore, a quantile-quantile plot of the
observed P values showed a clear deviation at the tail of the distribution
from the null distribution (the distribution expected if there were
no association) even after 4,840 SNPs were removed from the MHC
region. This suggests that the observed P values, particularly the ones
within the tail of the distribution, are smaller than those expected by
chance and probably reflect true genetic association (Fig. 1b).
In the MHC region, 13 SNPs, all located within the HLA class II
region, showed genome-wide significant association (P < 5 × 10−8); the
most significant association was identified at rs9271100 (P = 1.42 × 10−12,
odds ratio (OR) = 1.9, 95% CI = 1.59–2.27) (Supplementary
Fig. 2). Further conditional association analysis of the 13 SNPs con-
firmed that there were two independent associations within the HLA
class II region at rs9271100 near HLA-DRB1 and at rs3997854 near
HLA-DQA2. Our association results within the MHC region are
largely consistent with findings (including association at HLA-DRB1)
identified in previous GWAS of SLE in European populations6.
We performed a replication study by genotyping 78 non-MHC
SNPs (from 67 loci) in two additional cohorts of Chinese Han indi-
viduals (replication 1: 1,643 cases and 5,930 controls; replication 2:
1,509 cases and 1,120 controls; Table 1 and Supplementary Table 1).
In the replication study, the association analysis was performed in
the two individual replication samples separately as well as in the
combined GWAS and replication sample. Twenty-one SNPs within
16 loci were validated, with independent evidence supporting associa-
tion (P < 0.03) for the two replication samples and highly significant
evidence in the combined sample that surpassed genome-wide sig-
nificance (Pcombined < 5 × 10
−8). The 16 confirmed susceptibility loci
were located at 1q25.1, 2p22.3, 2q32.3, 5q33.1, 6q21, 6q23.3, 7p12.2,
7q11.23, 7q32.1, 8p23.1, 10q11.22, 11q23.3, 11q24.3, 12q24.32, 16p11.2
and 22q11.21 (5.17 × 10−42 ≤ Pcombined ≤ 2.77 × 10−8) (Table 2).
The associations at these 16 loci were independent of the associations
within the MHC region because the associations at these loci remained
similar even after controlling for the genetic effect of rs9271100 and
rs3997854 within the MHC region (Supplementary Table 2). Pairwise
interaction analysis was also performed among the top SNPs from the
16 non-MHC loci and the 2 MHC loci (rs9271100 and rs3997854),
but no interaction was identified (P > 0.05 after correction for mul-
tiple testing; data not shown).
The associations at 1q25.1, 2q32.3, 6q21, 6q23.3, 7q32.1, 8p23.1 and
22q11.21 were reported by previous GWAS in European populations,
table 1 summary of samples used in GWAs and replication studies
Cases Controls
Sample size Mean age (s.d.) Mean age of onset (s.d.) Male/female Female (%) Sample size Mean age (s.d.) Male/female Female (%)
GWASa 1,047 34.02 (11.53) 29.81 (10.08) 63/984 93.98 1,205 34.75 (12.97) 673/532 44.15
Replication 1b 1,643 35.36 (12.10) 30.89 (11.21) 136/1,507 91.72 5,930 29.64 (11.31) 2,729/3,201 53.98
Replication 2c 1,509 32.85 (11.16) 28.18 (10.42) 113/1,396 92.51 1,120 32.23 (14.48) 415/705 62.95
Total 4,199 34.12 (11.68) 29.65 (10.96) 312/3,887 92.57 8,255 30.74 (12.18) 3,817/4,438 53.76
aGWAS samples are from central China. bReplication 1 samples are from central China. cReplication 2 sample are from southern China.
12.0
12
10
8
6
4
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0 1 2 3 4 5 6
ba
+ with MHC
+ without MHC
11.5
11.0
10.5
10.0
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Chr. 1
Chr. 15 Chr. 16
Chr. 17 Chr. 18 Chr. 19 Chr. 20 Chr. 21 Chr. 22
Chr. 2 Chr. 3 Chr. 4 Chr. 5 Chr. 6 Chr. 7 Chr. 8
Chr. 9 Chr. 10 Chr. 11 Chr. 12 Chr. 13 Chr. 14
Figure 1 Summary of genome-wide association results for 1,047 cases and 1,205 controls. (a) The genome-wide P values (−log10 P) of the logistic
regression analysis adjusted for gender (493,955 SNPs) plotted against position on each chromosome. Each chromosome is depicted in a different
color. (b) Quantile-quantile plots of the observed P values versus the expected values from P value of association. The plot in blue was based on the
entire set of 493,955 SNPs, whereas the plot in red was obtained after removing 4,840 SNPs within MHC region (Chr. 6: 25–37 Mb).
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1236 volume 41 | number 11 | november 2009 Nature GeNetics
l e t t e r s
implicating TNFSF4 (ref. 11), STAT4 (refs. 6,9), PRDM1-ATG5 (ref. 7),
TNFAIP3 (ref. 9), IRF5 (refs. 6,7,9), BLK6 and HIC2-UBE2L3 (ref. 7)
as SLE susceptibility genes. The replication results of the remaining
57 SNPs are summarized in Supplementary Table 3.
To identify susceptibility genes underlying each of the nine newly
discovered associations, we investigated patterns of recombination
and linkage disequilibrium (LD) around the risk-associated SNPs
and the gene(s) located within each region harboring the associa-
tion (Supplementary Fig. 3). Only one gene was implicated by the
associations at 2p22.3 (RASGRP3), 7p12.2 (IKZF1), 11q24.3 (ETS1)
and 12q24.32 (SLC15A4), where a single gene was found within the
LD block harboring the association. At 5q33.1, two genes (TNIP1 and
GPX3) were found within this locus, but TNIP1 is more plausible
as a susceptibility gene due to its important role in modulating cell
activation, cytokine signaling and apoptosis12. For the associations
at 7q11.23, 10q11.22, 11q23.3 and 16p11.2, there were more than
one gene or transcript within the each region. Further fine mapping
analyses are required to determine the susceptibility genes underly-
ing these newly discovered SLE risk loci. Of note, the association at
16p11.2 is located close to the ITGAM-ITGAX susceptibility locus
identified in European populations6,7,13. However, the association
identified in our study is within an LD block that is distinct from the
one in which ITGAM and ITGAX are located. Furthermore, the minor
allele frequencies (MAFs) of five previously reported SNPs within
the ITGAM-ITGAX locus were very low (<0.01) in the Chinese Han
population (Supplementary Table 4a). Further studies will be needed
to confirm the susceptibility gene within this region.
To investigate how these loci might influence SLE susceptibility, we
further explored the biological function of the five newly discovered
susceptibility genes (RASGRP3, IKZF1, ETS1, SLC15A4 and TNIP1).
ETS1 encodes a member of the ETS family of transcription factors that
regulate the development, senescence and death of many immune cells
and that play a role both in innate and adaptive immune response14.
IKZF1 encodes a lymphoid-restricted zinc finger transcription factor
that regulates lymphocyte differentiation and proliferation15 as well
as self-tolerance through regulation of B-cell receptor signaling16.
RasGRP3 is responsible for Ras-ERK signaling mediated by B-cell
receptor ligation in B cells and might be involved in immunoglobulin
production and B-cell proliferation17. TNIP1 interacts with TNFAIP3
and could act as a negative regulator of the NF-κB pathway down-
stream of TNF-α, which has a key role in modulating cell activation,
cytokine signaling and apoptosis12. SLC15A4 is a transporter for Nod1
ligands in early endosomes and is involved in Nod1-dependent NF-κB
signaling, with potential participation in the antigen presentation
in immune response18. These newly discovered susceptibility genes
provide further supporting evidence for the three biological proc-
esses that were highlighted by findings from recent GWAS of SLE in
European populations19,20: immune complex processing (SLC15A4);
Toll-like receptor function and type I interferon production (TNIP1);
and immune signal transduction in lymphocytes (ETS1, RASGRP3
and IKZF1). It is worth pointing out that TNIP1 and TNFAIP3 are
also associated with psoriasis21, suggesting that the genetic basis of
SLE and psoriasis might be partially shared, possibly through regula-
tion of inflammation.
This first GWAS of SLE in a Chinese Han population allowed us to
perform a direct comparison with GWAS findings in European popula-
tions. We first investigated the association evidence from our study for
48 SLE-associated SNPs (from 22 loci) identified by previous GWAS in
European populations, including seven SNPs within the MHC region
(Supplementary Table 4a). In addition to the three SNPs within three
loci that were confirmed by our GWAS and replication studies, the ta
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