Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2018 May 30;20(1):100.
doi: 10.1186/s13075-018-1604-1.

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus

Antonio Julià  1 , Francisco Javier López-Longo  2 , José J Pérez Venegas  3 , Silvia Bonàs-Guarch  4 , Àlex Olivé  5 , José Luís Andreu  6 , Mª Ángeles Aguirre-Zamorano  7 , Paloma Vela  8 , Joan M Nolla  9 , José Luís Marenco de la Fuente  10 , Antonio Zea  11 , José María Pego-Reigosa  12 , Mercedes Freire  13 , Elvira Díez  14 , Esther Rodríguez-Almaraz  15 , Patricia Carreira  15 , Ricardo Blanco  16 , Víctor Martínez Taboada  16 , María López-Lasanta  17 , Mireia López Corbeto  17 , Josep M Mercader  4 , David Torrents  4   18 , Devin Absher  19 , Sara Marsal  20 , Antonio Fernández-Nebro  21
Affiliations
Meta-Analysis

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus

Antonio Julià et al. Arthritis Res Ther. .

Abstract

Background: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE.

Methods: We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software.

Results: We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10- 8): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10- 6), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10- 5), interleukin-4 signaling (p = 3.97 × 10- 5) and cell surface interactions at the vascular wall (p = 4.63 × 10- 5).

Conclusions: Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.

Keywords: Biological pathway analysis; Genetic susceptibility; Genome-wide association study; Meta-analysis; Systemic lupus erythematosus.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

All the procedures were followed in compliance with the principles of the Declaration of Helsinki and informed consent was obtained from all participants. The study and the consent procedure were reviewed and approved by the local institutional review boards.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Manhattan plot of genome-wide association study meta-analysis results including the Spain cohort. Plot of the -log10 (p values) of association between the 7,110,321 markers after meta-analysis between the European and Spain cohorts. The dashed horizontal line represents the genome-wide significance threshold (p value = 5 × 10− 8). The known regions associated with systemic lupus erythematosus (SLE) risk and genome-wide significant are colored in red. The five new genomic regions associated with SLE risk in this study are colored in green, with the name of the corresponding gene above
Fig. 2
Fig. 2
Regional association plots from the meta-analysis of the two cohorts for all five genome-wide significant loci: -log10 (p values) for both directly genotyped and imputed single nucleotide polymorphisms (SNPs) are plotted as a function of genomic position (NCBI Build 37). The purple diamond indicates the lead SNP at each locus; the remaining markers are colored based on the LD (r [2]) in relation to the lead SNP. Underlying the image, the estimated recombination rate (cM/Mb) for the CEU panel from 1000 Genomes is depicted
See this image and copyright information in PMC

References

    1. Danchenko N, Satia J, Anthony M. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15(5):308–318. doi: 10.1191/0961203306lu2305xx. - DOI - PubMed
    1. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40(2):204–210. doi: 10.1038/ng.81. - DOI - PMC - PubMed
    1. Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1228–1233. doi: 10.1038/ng.468. - DOI - PMC - PubMed
    1. 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):1457–1464. doi: 10.1038/ng.3434. - DOI - PMC - PubMed
    1. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, Burtt NP, Guiducci C, Parkin M, Gates C. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008;40(9):1059–1061. doi: 10.1038/ng.200. - DOI - PMC - PubMed

Publication types

MeSH terms