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Arthritis Res Ther. 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.

Author information

1
Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain. toni.julia@vhir.org.
2
Department of Rheumatology, Hospital Universitario Gregorio Marañón, 28007, Madrid, Spain.
3
Department of Rheumatology, Hospital del SAS de Jerez de la Frontera, 11407, Cádiz, Spain.
4
Barcelona Supercomputing Center. Joint BSC-CRG-IRB Research Program in Computational Biology, 08034, Barcelona, Spain.
5
Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, 08916, Badalona, Spain.
6
Department of Rheumatology, Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain.
7
Department of Rheumatology, Hospital Universitario Reina Sofía, 14004, Córdoba, Spain.
8
Department of Rheumatology, Hospital General Universitario de Alicante, 03010, Alicante, Spain.
9
Department of Rheumatology, Hospital Universitari de Bellvitge, 08907, Barcelona, Spain.
10
Department of Rheumatology, Hospital de Valme, 41007, Sevilla, Spain.
11
Department of Rheumatology, Hospital Universitario Ramón y Cajal, 28034, Madrid, Spain.
12
Department of Rheumatology, Hospital do Meixoeiro, Grupo IRIDIS, Instituto de Investigación sanitaria Galicia Sur (IISGS), 36312, Vigo, Spain.
13
Department of Rheumatology, Hospital Universitario A Coruña, 15006, A Coruña, Spain.
14
Department of Rheumatology, Hospital Complejo Asistencial Universitario de León, 24071, León, Spain.
15
Department of Rheumatology, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain.
16
Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, 39008, Santander, Spain.
17
Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain.
18
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain.
19
HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
20
Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain. sara.marsal@vhir.org.
21
Department of Rheumatology, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga, 29011, Málaga, Spain.

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

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