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

Kathleen M. Vazzana, Anthony M. Musolf, Joan E. Bailey-Wilson, Linda T. Hiraki, Earl D. Silverman, Christiaan Scott, Clifton L. Dalgard, Sarfaraz Hasni, Zuoming Deng, Mariana J. Kaplan, Laura B. Lewandowski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)200-206
Number of pages7
JournalGenes and Immunity
Issue number4
StatePublished - Aug 2023
Externally publishedYes


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