Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus

• Published in: Genes and immunity Vol. 24; no. 4; pp. 200 - 206
• Main Authors: Vazzana, Kathleen M., Musolf, Anthony M., Bailey-Wilson, Joan E., Hiraki, Linda T., Silverman, Earl D., Scott, Christiaan, Dalgard, Clifton L., Hasni, Sarfaraz, Deng, Zuoming, Kaplan, Mariana J., Lewandowski, Laura B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2023; Nature Publishing Group
• Subjects: 45/23; 631/208/212; 631/250/38; Adolescent; Age; Age of Onset; Association analysis; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Childhood; Children; Ciliary movement; DNA nucleotidylexotransferase; DNA repair; Female; Gene Expression; Genes; Genetic analysis; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomes; Human Genetics; Humans; Immunology; Linkage Disequilibrium; Lupus; Lupus Erythematosus, Systemic - genetics; Male; Movement protein; Population genetics; Systemic lupus erythematosus; Whole genome sequencing
• ISSN: 1476-5470; 1466-4879; 1476-5470
• DOI: 10.1038/s41435-023-00214-x

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10 −8 ) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2 , a DNA repair protein, and DNAH11 , a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.