Saeed Mohammad
Department of Genomics, Arkana Laboratories, 10810 Executive Center Drive, Suite 100, Little Rock, AR, 72211, USA.
Immunogenetics. 2017 May;69(5):295-302. doi: 10.1007/s00251-017-0976-8. Epub 2017 Feb 28.
Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes.
系统性红斑狼疮（SLE）是一种复杂的疾病。复杂疾病的基因关联研究存在以下三个主要问题：表型异质性、假阳性（I型错误）和假阴性（II型错误）结果。因此，在标准分析中会遗漏低至中等效应的基因，尤其是在进行统计校正之后。OASIS是一种新型的连锁不平衡聚类算法，它有可能解决复杂疾病（如SLE）的全基因组关联研究（GWAS）中的假阳性和假阴性问题。OASIS被应用于两个SLE dbGAP GWAS数据集（6077名受试者；约75万个单核苷酸多态性）。OASIS鉴定出三个已知的SLE基因，即IFIH1、TNIP1和CD44，这些基因此前未在这些GWAS数据集中被报道过。此外，还鉴定出22个SLE的新基因座，并验证了此前使用这些数据集报道过的5个SLE基因。使用单变量复制和基于基因的GATES分析对OASIS方法进行了验证。这使得60%的OASIS基因座得到了验证。OASIS鉴定并进一步验证的新SLE基因包括TNFAIP6、DNAJB3、TTF1、GRIN2B、MON2、LATS2、SNX6、RBFOX1、NCOA3和CHAF1B。本研究介绍了OASIS算法、软件，以及对两个公开可用的SLE GWAS数据集的荟萃分析和新的SLE基因。因此，OASIS是一种新型的连锁不平衡聚类方法，可普遍应用于现有GWAS数据集以鉴定新基因。
