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Ten New Lupus-Linked Loci Uncovered Through GWAS Meta-Analysis

NEW YORK (GenomeWeb) – An international team of researchers has linked 10 new loci to systemic lupus erythematosus.

As they reported in Nature Genetics today, the researchers pulled together data from three genome-wide association studies that were conducted in Chinese and European populations. A meta-analysis of the combined data found that more than half the known lupus-associated loci are present in both populations, and uncovered a further 10 novel disease-linked loci. Many of the lupus risk loci could be traced to the same genomic regions, even within the two different populations, though a calculation of risk allele frequencies that hints at why lupus is more common among Asian individuals.

"The increased genetic risk load in Chinese individuals would help explain the continued increased prevalence of [lupus] in Asians after their migration to Western locations," King's College London's Timothy Vyse and his colleagues wrote in their paper.

He and his colleagues imputed data from three GWAS — a European study of 4,036 cases and 6,959 controls, a study from China's Anhui Province of 1,047 cases and 1,205 controls, and a Hong Kong study of 612 cases and 2,193 control — to 1000 Genomes Project data. When they compared their meta-analysis of these cohorts to published data, they found that many alleles linked to lupus in one ethnic population were also present in the other.

The meta-analysis also revealed three new associations, rs17603856, rs1887428, and rs669763, in novel loci as well as uncovered transancestral heterogeneity at the major histocompatibility complex and at the IRF locus on chromosome 7.

In a two-stage replication study, Vyse and his colleagues genotyped 66 SNPs at 56 loci — including those novel ones they uncovered — in an additional 3,043 cases and 5,074 controls from Anhui Province. In this stage, 18 SNPs were replicated, including two of the three novels ones. They then genotyped these SNPs in a further 2,643 cases and 9,032 controls of European ancestry. Of those 18 SNPs replicated in the first stage, 11 SNPs reached a genome-wide significance in the second stage. The strongest signal, the investigators noted, was for rs1887428.

For each of the 10 novel loci linked to lupus, the researchers tested their association with cis-acting gene expression in different types of immune and blood cells. From this, they found that lupus risk alleles were largely linked with reduced expression. This also enabled the researchers to home in on likely causal variants at some loci like IKBKE and JAK2 and on multiple candidates at other loci.

Through fine-mapping of published loci linked to lupus and the new ones reported in this study, Vyse and his colleagues determined the most likely causal variants for each population and where they overlapped. They noted, for instance, that STAT4 reflected a co-localization of signals from each ancestry, while IRF7 was only associated in Europeans and ELF1 only in Chinese.

Vyse and his colleagues further examined the amount of shared risk alleles between Chinese and European populations using a co-heritability analysis. On average, the risk allele frequencies in Chinese control subjects were higher than those in European controls, though the effect sizes weren't statistically different. This suggested to the researchers that the difference in the prevalence of lupus in Asians and Europeans likely has a genetic basis.

Similarly, when the researchers calculated genetic risk scores for lupus, it was significantly higher for East Asians as compared to Europeans in the 1000 Genomes data and in the GWAS controls. Together, this indicates an increased genetic risk load in East Asians for lupus, they said.

"A more detailed study of the increased prevalence of [lupus] in Asians, and in Africans, will require extensive comparisons of genetic and environmental data, including generation of DNA sequence data to exclude European bias in genotyping arrays," Vyse and his colleagues wrote.