Department of Medical Genomics, GENYO, Center for Genomics and Oncological Research Pfizer, University of Granada, Granada, Spain.
Unit of Chronic Inflammation, Institute for Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
Front Immunol. 2019 Feb 26;10:258. doi: 10.3389/fimmu.2019.00258. eCollection 2019.
The importance of low frequency and rare variation in complex disease genetics is difficult to estimate in patient populations. Genome-wide association studies are therefore, underpowered to detect rare variation. We have used a combined approach of genome-wide-based imputation with a highly stringent sequence kernel association (SKAT) test and a case-control burden test. We identified 98 candidate genes containing rare variation that in aggregate show association with SLE many of which have recognized immunological function, but also function and expression related to relevant tissues such as the joints, skin, blood or central nervous system. In addition we also find that there is a significant enrichment of genes annotated for disease-causing mutations in the OMIM database, suggesting that in complex diseases such as SLE, such mutations may be involved in subtle or combined phenotypes or could accelerate specific organ abnormalities found in the disease. We here provide an important resource of candidate genes for SLE.
低频和罕见变异在复杂疾病遗传学中的重要性在患者群体中难以估计。因此，全基因组关联研究无法检测到罕见变异。我们采用了全基因组基于 imputation 的方法，结合高度严格的序列核关联（SKAT）测试和病例对照负担测试。我们确定了 98 个候选基因，其中包含与 SLE 相关的罕见变异，这些基因中有许多具有公认的免疫学功能，但也与关节、皮肤、血液或中枢神经系统等相关组织的功能和表达有关。此外，我们还发现，在 OMIM 数据库中注释为致病突变的基因存在显著富集，这表明在 SLE 等复杂疾病中，这些突变可能参与了微妙或综合表型，或者可能加速了疾病中发现的特定器官异常。我们在此为 SLE 提供了一个重要的候选基因资源。
