Top

Published in:

Open Access 01-12-2018 | Research article

Meta-analysis of GWAS on both Chinese and European populations identifies GPR173 as a novel X chromosome susceptibility gene for SLE

Authors: Huoru Zhang, Yan Zhang, Yong-Fei Wang, David Morris, Nattiya Hirankarn, Yujun Sheng, Jiangshan Shen, Hai-Feng Pan, Jing Yang, Sen Yang, Yong Cui, Dong-Qing Ye, Timothy J. Vyse, Xuejun Zhang, Yu Lung Lau, Wanling Yang

Published in: Arthritis Research & Therapy | Issue 1/2018

Abstract

Background

Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin.

Methods

This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total. Conditional analysis of the known associated loci on chromosome X was also performed to further explore independent signals.

Results

Single-nucleotide polymorphism rs13440883 in GPR173 was found to be significantly associated with SLE (P_meta = 7.53 × 10^− 9, OR_meta= 1.16), whereas conditional analysis provided evidence of a potential independent signal in the L1CAM-IRAK1-MECP2 region in Asian populations (rs5987175 [LCA10]).

Conclusions

We identified a novel SLE susceptibility locus on the X chromosome. This finding emphasizes the importance of the X chromosome in disease pathogenesis and highlights the role of sex chromosomes in the female bias of SLE.

Available only for authorised users

Huang JL, Hung JJ, Wu KC, Lee WI, Chan CK, Ou LS. Septic arthritis in patients with systemic lupus erythematosus: salmonella and nonsalmonella infections compared. Semin Arthritis Rheum. 2006;36(1):61–7.CrossRefPubMed

Boddaert J, Huong DL, Amoura Z, Wechsler B, Godeau P, Piette JC. Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine (Baltimore). 2004;83(6):348–59.CrossRef

Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, Reveille JD, Alarcon GS, Vila LM, Reid J, et al. Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58(8):2511–7.CrossRefPubMedPubMedCentral

Ohno S, Kaplan WD, Kinosita R. Formation of the sex chromatin by a single X-chromosome in liver cells of Rattus norvegicus. Exp Cell Res. 1959;18:415–8.CrossRefPubMed

Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, Aguirre M, Gauthier L, Fleharty M, Kirby A, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550(7675):244–8.CrossRefPubMedPubMedCentral

Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031):400–4.CrossRefPubMed

Hewagama A, Gorelik G, Patel D, Liyanarachchi P, McCune WJ, Somers E, Gonzalez-Rivera T, Michigan Lupus C, Strickland F, Richardson B. Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun. 2013;41:60–71.CrossRefPubMedPubMedCentral

Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, Wu YL, Yu CY, Tang Y, Chen JY, et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2010;107(36):15838–43.CrossRefPubMedPubMedCentral

Zhang Y, Zhang J, Yang J, Wang Y, Zhang L, Zuo X, Sun L, Pan HF, Hirankarn N, Wang T, et al. Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus. Hum Mol Genet. 2015;24(1):274–84.CrossRefPubMed

10.

Bentham J, Morris DL, Cunninghame Graham DS, Pinder CL, Tombleson P, Behrens TW, Martin J, Fairfax BP, Knight JC, Chen L, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–64.CrossRefPubMedPubMedCentral

11.

Zhu Z, Liang Z, Liany H, Yang C, Wen L, Lin Z, Sheng Y, Lin Y, Ye L, Cheng Y, et al. Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus. Arthritis Res Ther. 2015;17:349.CrossRefPubMedPubMedCentral

12.

Kaufman KM, Zhao J, Kelly JA, Hughes T, Adler A, Sanchez E, Ojwang JO, Langefeld CD, Ziegler JT, Williams AH, et al. Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis. 2013;72(3):437–44.CrossRefPubMed

13.

Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC, et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010;6(2):e1000841.CrossRefPubMedPubMedCentral

14.

Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1234–7.CrossRefPubMed

15.

O’Connell J, Gurdasani D, Delaneau O, Pirastu N, Ulivi S, Cocca M, Traglia M, Huang J, Huffman JE, Rudan I, et al. A general approach for haplotype phasing across the full spectrum of relatedness. PLoS Genet. 2014;10(4):e1004234.CrossRefPubMedPubMedCentral

16.

Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet. 2010;11(7):499–511.CrossRefPubMed

17.

Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26(17):2190–1.CrossRefPubMedPubMedCentral

18.

Hughes T, Adler A, Merrill JT, Kelly JA, Kaufman KM, Williams A, Langefeld CD, Gilkeson GS, Sanchez E, Martin J, et al. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann Rheum Dis. 2012;71(5):694–9.CrossRefPubMed

19.

Morris DL, Sheng Y, Zhang Y, Wang YF, Zhu Z, Tombleson P, Chen L, Cunninghame Graham DS, Bentham J, Roberts AL, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016;48(8):940–6.CrossRefPubMedPubMedCentral

20.

Cowper-Sal∙lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, Moore JH, Lupien M. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet. 2012;44(11):1191–8.CrossRef

21.

Consortium EP. A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 2011;9(4):e1001046.CrossRef

22.

Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26(18):2336–7.CrossRefPubMedPubMedCentral

23.

Duma D, Collins JB, Chou JW, Cidlowski JA. Sexually dimorphic actions of glucocorticoids provide a link to inflammatory diseases with gender differences in prevalence. Sci Signal. 2010;3(143):ra74. A published erratum appears in Sci Signal. 2010;3(145):er10CrossRefPubMedPubMedCentral

24.

Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337(6099):1190–5.CrossRefPubMedPubMedCentral

25.

Schaub MA, Boyle AP, Kundaje A, Batzoglou S, Snyder M. Linking disease associations with regulatory information in the human genome. Genome Res. 2012;22(9):1748–59.CrossRefPubMedPubMedCentral

26.

Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790–7.CrossRefPubMedPubMedCentral

27.

Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–52.CrossRefPubMedPubMedCentral

28.

Fischer A, Schmid B, Ellinghaus D, Nothnagel M, Gaede KI, Schurmann M, Lipinski S, Rosenstiel P, Zissel G, Hohne K, et al. A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1. Am J Respir Crit Care Med. 2012;186(9):877–85.CrossRefPubMed

29.

Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.CrossRefPubMedPubMedCentral

30.

Gourraud PA, Sdika M, Khankhanian P, Henry RG, Beheshtian A, Matthews PM, Hauser SL, Oksenberg JR, Pelletier D, Baranzini SE. A genome-wide association study of brain lesion distribution in multiple sclerosis. Brain. 2013;136(Pt 4):1012–24.CrossRefPubMedPubMedCentral

31.

Padyukov L, Seielstad M, Ong RT, Ding B, Ronnelid J, Seddighzadeh M, Alfredsson L, Klareskog L, Epidemiological Investigation of Rheumatoid Arthritis (EIRA) Study Group. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis. 2011;70(2):259–65.CrossRefPubMed

32.

Zhao SX, Xue LQ, Liu W, Gu ZH, Pan CM, Yang SY, Zhan M, Wang HN, Liang J, Gao GQ, et al. Robust evidence for five new Graves’ disease risk loci from a staged genome-wide association analysis. Hum Mol Genet. 2013;22(16):3347–62.CrossRefPubMed

Title: Meta-analysis of GWAS on both Chinese and European populations identifies GPR173 as a novel X chromosome susceptibility gene for SLE
Authors: Huoru Zhang
Yan Zhang
Yong-Fei Wang
David Morris
Nattiya Hirankarn
Yujun Sheng
Jiangshan Shen
Hai-Feng Pan
Jing Yang
Sen Yang
Yong Cui
Dong-Qing Ye
Timothy J. Vyse
Xuejun Zhang
Yu Lung Lau
Wanling Yang
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-018-1590-3

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Meta-analysis of GWAS on both Chinese and European populations identifies GPR173 as a novel X chromosome susceptibility gene for SLE

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Correction to: identification of multiple cancer-associated myositis-specific autoantibodies in idiopathic inflammatory myopathies: a large longitudinal cohort study

Secukinumab provides sustained PASDAS-defined remission in psoriatic arthritis and improves health-related quality of life in patients achieving remission: 2-year results from the phase III FUTURE 2 study

Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on rheumatoid arthritis synovial fibroblasts

Metabolomics approach by 1H NMR spectroscopy of serum reveals progression axes for asymptomatic hyperuricemia and gout

Intrauterine fetal deaths related to antiphospholipid syndrome: a descriptive study of 65 women

Polydatin effectively attenuates disease activity in lupus-prone mouse models by blocking ROS-mediated NET formation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page