Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with systemic lupus erythematosus in Thai population

Abstract

Background: Differences in the expression of variants across ethnic groups in the systemic lupus erythematosus (SLE) patients have been well documented. However, the genetic architecture in the Thai population has not been thoroughly examined. In this study, we carried out genome-wide association study (GWAS) in the Thai population.

Methods: Two GWAS cohorts were independently collected and genotyped: discovery dataset (487 SLE cases and 1606 healthy controls) and replication dataset (405 SLE cases and 1590 unrelated disease controls). Data were imputed to the density of the 1000 Genomes Project Phase 3. Association studies were performed based on different genetic models, and pathway enrichment analysis was further examined. In addition, the performance of disease risk estimation for individuals in Thai GWAS was assessed based on the polygenic risk score (PRS) model trained by other Asian populations.

Results: Previous findings on SLE susceptible alleles were well replicated in the two GWAS. The SNPs on HLA class II (rs9270970, A>G, OR = 1.82, p value = 3.61E-26), STAT4 (rs7582694, C>G, OR = 1.57, p value = 8.21E-16), GTF2I (rs73366469, A>G, OR = 1.73, p value = 2.42E-11), and FAM167A-BLK allele (rs13277113, A>G, OR = 0.68, p value = 1.58E-09) were significantly associated with SLE in Thai population. Meta-analysis of the two GWAS identified a novel locus at the FBN2 that was specifically associated with SLE in the Thai population (rs74989671, A>G, OR = 1.54, p value = 1.61E-08). Functional analysis showed that rs74989671 resided in a peak of H3K36me3 derived from CD14+ monocytes and H3K4me1 from T lymphocytes. In addition, we showed that the PRS model trained from the Chinese population could be applied in individuals of Thai ancestry, with the area under the receiver-operator curve (AUC) achieving 0.76 for this predictor.

Conclusions: We demonstrated the genetic architecture of SLE in the Thai population and identified a novel locus associated with SLE. Also, our study suggested a potential use of the PRS model from the Chinese population to estimate the disease risk for individuals of Thai ancestry.

Keywords: Genetic susceptibility; Genome-wide association study; Polygenic risk score; Single nucleotide polymorphisms; Systemic lupus erythematosus; Thai population.

Fig. 1

Quality control and dataset preparation flow diagram of both discovery and validation datasets. The flow diagram was modified from the PRISMA flow diagram [15] (a). Manhattan plot on the meta-analysis result of the two SLE GWAS datasets in the Thai population using R-Bioconductor package qqman (b)

Fig. 2

Regional plot of novel SLE susceptible variants on FBN2 locus with their relative variants around FBN2 locus (a). Haplotype block of significant variants on FBN2 locus with their correlation to show linkage disequilibrium between SNPs (b). The picture illustrated histone markers overlapped with FBN2 SNP site (c)

Fig. 3

Diagram plot showed enrichment pathway from functional annotation analysis of significant variants (p value < 5E−05) using SNPnexus

Fig. 4

The graph shows the polygenic risk score calculation and the mean difference between SLE and healthy controls (a). The circular plot showed loci which identified in this study at individual chromosomes using package Rcircos [33] (b)