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

Abstract

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.

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The data from this paper are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank all the cSLE patients and their families for participation in this study. We are grateful to Michael Ombrello for his thoughtful review of this manuscript, and Yolanda L. Jones, National Institutes of Health Library, for manuscript review and editing. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

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LBL, SH, and MK designed the clinical protocol. CD performed the sequencing protocol. LBL, KV, AM, and JEBW designed the research methodology. ZD, LBL and AM performed the data analysis. LBL, KV, and AM wrote the manuscript. KV, LH, CS, AB, ZD, CD, JEBW, AM, SH, MK and LBL reviewed and revised the full manuscript.

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Correspondence to Laura B. Lewandowski.

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The authors have no conflicts of interest to declare. KV, LBL, SH, ZD, CD, and MK were funded by the National Institute of Arthritis Musculoskeletal and Skin Diseases Intramural research program. AMM and JEBW were funded by the National Human Genome Research Institute Intramural research program of the National Institutes of Health. LH was funded by US Department of Defense Idea Award and a Canada Research Chair Tier 2 Award.

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Vazzana, K.M., Musolf, A.M., Bailey-Wilson, J.E. et al. Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus. Genes Immun 24, 200–206 (2023). https://doi.org/10.1038/s41435-023-00214-x

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