Next generation sequencing analysis reveals complex genetic architecture of childhood-onset systemic lupus erythematosus

Abstract

Objectives: Our current understanding of the genetic architecture of childhood-onset SLE (cSLE) is limited by a dearth of comprehensive genomic studies in cSLE. We have quantified the number of known rare and common SLE risk variants in a diverse cSLE cohort. We characterised type I interferon (IFN) gene expression scores along with genomic data.

Methods: We performed whole genome sequencing on 83 patients with cSLE and 109 unaffected parents and analysed sequences for known common and rare SLE-associated risk variants. Type I IFN gene expression was quantified on a subset of patients. We investigated the relationship between clinical phenotype, genomic profile and type I IFN signatures in this cohort.

Results: Patients with cSLE were enriched for common SLE risk variants compared with unaffected parents and controls. We identified rare SLE risk variants in 11% of individuals with cSLE; those with rare variants had earlier disease onset (<12 years) than those without variants. Patients with cSLE had elevated type I IFN gene expression compared with unaffected parents and controls, even though most patients were treated with immunosuppressive therapy.

Conclusions: Patients with cSLE from this ancestrally and geographically diverse cohort are enriched for common cSLE risk variants compared with controls, and 11% carry a rare variant in known monogenic SLE risk genes. The relationship between rare and common risk variant burden is more complex than previously hypothesised. Our findings indicate that studying patients with cSLE is important for understanding genetic contributions to SLE pathogenesis.

Keywords: Interferon Type I; Lupus Erythematosus, Systemic; Polymorphism, Genetic.

Figure 1. Comparison of wPRS for 83 patients with cSLE and 109 unaffected parents. Wilcoxon rank-sum test, p<0.05. (A) wPRS for the non-HLA regions of patients with cSLE and unaffected parents. (B) wPRS for the HLA regions of patients with cSLE and unaffected parents. (C) Total (HLA and non-HLA) wPRS for patients with cSLE and unaffected parents. cSLE, childhood-onset SLE; HLA, human leucocyte antigen; wPRS, weighted polygenic risk score.

Figure 2. Comparison of wPRS for 83 patients with cSLE stratified by genetic ancestry, sex and age of SLE diagnosis. (A) wPRS in patients with cSLE stratified by genetic ancestry, non-HLA regions, HLA regions and total (HLA and non-HLA) wPRS; p values represent differences in wPRS between ancestries by Kruskal-Wallis test. (B) wPRS in patients with cSLE stratified by sex; n=65 F, n=18 M; p values represent differences in wPRS by chromosomal sex by Wilcoxon rank-sum test. (C) wPRS in patients with cSLE stratified by age of diagnosis; early onset defined as diagnosis <12 years of age, late onset defined as diagnosis >12 years of age; p values represent differences in wPRS by age of diagnosis. ADMX, Admixed; AFR, African; AMR, Amerindian; cSLE, childhood-onset SLE; EAS, East Asian; EUR, European; F, female; HLA, human leucocyte antigen; M, male; SAS, South Asian; wPRS, weighted polygenic risk score.

Figure 3. Linear regression analysis of weighted polygenic risk score (wPRS) as a function of age of SLE diagnosis (years) for 83 patients with childhood-onset SLE (cSLE) in all regions (HLA, non-HLA and total), p<0.05. (A) Association of wPRS with age of diagnosis for non-HLA wPRS. (B) Association of wPRS with age of diagnosis for HLA wPRS. (C) Association of wPRS with age of diagnosis for total wPRS. Age denotes age of SLE diagnosis (years); R denotes Pearson’s correlation coefficient; p denotes p value. HLA, human leucocyte antigen.

Figure 4. Genetic architecture of rare and common SLE variants in childhood-onset SLE (cSLE). (A) Distribution of weighted polygenic risk score (wPRS) for patients with cSLE who harbour rare variants in the coding regions of monogenic SLE risk genes (red) and those without (black) in 83 patients with cSLE. (B) Distribution of rare variants in monogenic SLE risk genes (red) found in a subset of 83 patients with cSLE by genetic ancestry. (C) Distribution of rare variants in monogenic SLE risk genes (red) found in 83 patients with cSLE categorised by age of onset (years) at SLE diagnosis. (D) Distribution of rare variants in monogenic SLE risk genes (red) in 83 patients with cSLE categorised by biological sex: male (n=18), female (n=65). ADMX, Admixed; AFR, African; AMR, Amerindian; EAS, East Asian; EUR, European; SAS, South Asian.

Figure 5. Type I IFN gene expression levels in patients with cSLE compared with parents and healthy controls. Type I IFN score expression levels between 36 patients with cSLE, 18 unaffected parents, 8 adult healthy controls (Adult HC) and 5 paediatric healthy controls (Child HC), measuring 28 IFN regulated genes shared between all cohorts, Wilcoxon rank-sum pairwise comparison. cSLE, childhood-onset SLE; IFN, interferon.