Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 23, Uppsala, Sweden.
Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden.
Eur J Hum Genet. 2021 Jan;29(1):184-193. doi: 10.1038/s41431-020-0698-5. Epub 2020 Jul 28.
By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.
通过对 71 个瑞典亲子三胞胎进行全基因组测序，我们研究了新生变异在系统性红斑狼疮（SLE，OMIM 152700）患者发病风险中的作用。在所研究的患者中，与健康对照相比，SLE 患者的新生单核苷酸变异（SNV）在基因启动子中显著富集，每个患者的新生启动子 SNV 比预期多 26 个。我们在先前与 SLE 相关或与 SLE 相关功能相关的基因启动子区域中鉴定出 12 个新生 SNV。此外，我们还检测到三个错义新生 SNV、五个新生插入缺失和三个具有潜在影响与 SLE 相关基因表达的新生结构变异。基于富集分析，预计三分之一的 SLE 患者会出现与疾病相关的新生 SNV。本研究表明，启动子中的新生变异通常会导致 SLE 的遗传风险增加。SLE 中的新生 SNV 富集到启动子区域这一事实突出了使用全基因组测序来识别新生变异的重要性。
