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 1,606 healthy controls) and replication dataset (405 SLE cases and 1,590 unrelated-disease controls). Data were imputed to the density of the 1,000 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.

Identification of Shared and Asian‐Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi‐Ancestral Genome‐Wide Association Study

“…GWAS data on Chinese populations were retrieved from our previous studies derived from Hong Kong, Guangzhou, Central China, and Jining populations (7,15), comprising 4,734 cases and 9,425 controls (7,15). The Thai GWAS was obtained from a recent study (9) and was reanalyzed to be consistent with the processes of imputation and quality control for the European and Chinese GWAS (7), resulting in a total of 835 cases and 2,995 controls. Sample information for each cohort is summarized in Supplementary Table 1, on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42021.…”

“…We further demonstrated that the ancestral genetic differences affected transferability of polygenic risk scores (PRS) among different populations (7). Additionally, in a study focusing on a Thai SLE cohort, we have shown that the FBN2 locus was associated with SLE in the Thai population but not in either Chinese or European populations (9). Consistent with studies on other complex diseases (10–12), multi‐ancestral genome‐wide association studies (GWAS) in SLE have proven to be valuable in detecting genetic factors that underlie ancestral differences.…”

Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus

“…The GWAS summary statistics of the multi-ancestry and multi-trait SLE meta-analysis result have been deposited on the Shiny App [https:// liugroupstatgen.shinyapps.io/SLEv] for users to download and interactively explore research results. This meta-analysis result was derived via MTAG 30 and METAL 88 from the following datasets: SLE 11,[16][17][18][19][20][21][22][23]108 , ATD 22 , CD 109,110 , CEL 111,112 , MS [112][113][114] , PBC 115,116 , RA 22,117 , SJO 22,118 , SSC 119 , T1D 22,120 , and VIT 121 . We also obtained GWAS data from FinnGen Release 5 website [https://www.finngen.fi/en/access_results], Pan-UK Biobank website [https://pan.ukbb.broadinstitute.org], and BioBank Japan PheWeb [https://pheweb.jp] for traits available in these biobanks.…”

“…Previous SLE GWAS results were primarily from individuals of European ancestry [16][17][18][19] . Fortunately, several recent GWAS efforts have greatly increased the sample size of non-European ancestry including East Asians 11,[20][21][22][23] .…”