SLE is a complex autoimmune disease with high genetic heretabilty. During my Ph.D. study, I have been involved in mutlitple SLE common variants GWAS analysis projects. I have identified 3 novel loci associated with SLE, and replicated known chrX SLE associated loci and higher trisomy X ratio in East Asian population. Currently, I am preparing a manuscript about a extra novel SLE associated loci by meta-analyze multiple SNP array and WGS cohorts (Manuscript preparing, not shown here). In addition, I am replicating known SLE associated loci using whole-genome sequencing (WGS) techonolgy, trying to boost depolying of WGS in complex trait analysis (Manuscript preparing, not shown here).

1. Identification of KLF2, STAB2, and DOTL1 loci in SLE.

My first GWAS study was analyzing a cohort of SLE SNP array data from the Northern Chinese population. It is a small cohort with 512 cases and 994 controls after quality control. At first, no signal passed the genome-wide significant threshold (5E-8). As shown in Fig 1, HLA region and GTF2I was identified with P value less than 5E-8. Some well known SLE associated loci, including STAT4, TNFSF4, and BLK, were identified passing suggestive significance threshold (1E-5).

In hypothesis testing, a non-significant P value means we don’t have enough evidence to say the correlation is significant. It does’t mean there is no extra novel locus associated with SLE, as it possible due to limited sample size (statistic power). In GWAS, the t test results from independent cohorts could be combined to increase the statistical power.

I performed a multiple SLE cohorts meta-analysis uisng 4 East Asian (EAS) cohorts and 4 European (EUR) cohorts. A comparison of EAS and EUR cohorts was also performed. Loci around STAB2 and DOTL1 were identified surpass P-value < 5E-8 in both EAS and EUR cohort. A locus around KLF2 was identified pass genome-wide significance in EAS cohort. The LocusZoom results of these 3 loci were shown in Fig 2.

Publication of this work is find here: Oxford Rheumatology.

2. X chromosome and SLE.

SLE is known for far more higher (9:1) onset prevalence in females. X chromosome is a capativating region for SLE genetic research. One of research in our team has reported GPR173 locus on X chromosome is associated with SLE, and showed a candidate idependent novel signal in L1CAM-IRAK1-MECP2 region in Asian population. Inspired by this work, I performed a chromosome X wide association study (XWAS) using Hong Kong and Thailand population’s SNP array data, and conducted meta-analysis.

As the Fig 3 shows, the known SLE associated loci TLR7 and TMEM187-IRKA2-MECP2 pass the genome-wide significant threshold (5E-8), and the PRPS2 locus pass the suggestive significant threshold (1E-5). Two extra candidate loci, CT83-KLHL13 and LOC38985-SOX3 were identified surpass the suggestive significant threshold (1E-5).

Previous studies have discovered there are higher ratio of trisomy X, a subject have 3 X chromosomes, in European SLE female patients. We also replicated this finding in East Asian population. In our dataset, we have 2,231 females with SLE (1,453 with Chinese ancestry and 778 with Thai ancestry) and 2,410 female controls (856 with Chinese ancestry and 1,554 with Thai ancestry).

The frequency of 47,XXX was approximately 0.22% (5/2231) in females with SLE in our datasets, with a higher frequency in the Chinese dataset (0.34%, 5/1453 females with SLE). In contrast, the frequency of trisomy X among female controls was around 0.08% (2/2410), which was very close to previous reports (1 in 1000 female births) in European population. Our data indicated that the frequency of trisomy X was significantly higher in females with SLE than controls (two-sided exact binomial test p=0.002).

Publication of this work is here: BMJ Lupus Science & Medicine.