Identifying causal genes in alopecia areata using integrative analysis of differential expression and Mendelian randomization

Background Compared with sporadic patients with Alopecia areata (AA), the familial cases have a poorer prognosis. At present, the genetic basis of AA still needs further study to improve treatment and prognosis. The aim of this study is to identify the causal genes related to AA. Methods We first used bioinformatics analysis to screen the differentially expressed genes (DEGs) related to AA, and then analyzed large-scale eQTL data and AA GWAS summary data using Mendelian randomization (MR). The enrichment analysis of causal gene functions and pathways as well as immune cell infiltration analysis were also performed, and finally the screened causal genes were analyzed and validated in the experimental group of AA and the normal control group. Results Differential expressed gene (DEG) analysis identified 429 up-regulated and 423 down-regulated genes. Among DEGs, MR screened out four intersecting genes, GIMAP6 and AA (IVW OR: 1.868; 95% CI: 1.175–2.970, p = 0.008), ALOX15 and AA (IVW OR: 1.616; 95% CI: 1.167–2.239, p = 0.004), GALNT6 and AA (IVW OR: 0.710; 95% CI: 0.533–0.945, p = 0.019), HEG1 and AA (IVW OR: 0.648; 95% CI: 0.431–0.975, p = 0.037). Indicating that all four intersecting genes have a causal relationship with AA, they are the four causal genes most related to AA. Among them, genes GIMAP6 and ALOX15 are risk factors for AA, while genes GALNT6 and HEG1 are protective factors for AA. Finally, validation analysis was conducted on the four causal genes between the AA experimental group and the normal control group, and significant differences were found in the GALNT6 and HEG1 genes in the validation group. Conclusion In this study, we identified four causal genes for AA and found that genes GIMAP6 and ALOX15 are risk factors for AA and genes GALNT6 and HEG1 are protective factors for AA. Our data analysis showed significant differences between the GALNT6 and HEG1 genes in the validation group. This study will provide new research directions for the pathogenesis and clinical diagnosis and treatment of AA.