Ran Gao, Wenting Su, Jiahui Deng, Bing Zhai, Gaizhi Zhu, Jinming Qiu, Ziqing Bian, He Xiao, Guoming Luan, Renxi Wang
OBJECTIVES: Our aim was to gain deeper insight into the genetic susceptibility of iron deficiency anemia (IDA). METHODS: We performed the first multi-ancestry meta-analysis of genome-wide association study (GWAS), which included 113 055 IDA cases and 1 783 936 healthy controls. RESULTS: Through multi-ancestry meta-analysis, 31 risk loci were identified, alongside 703 candidate genes indicated and 47 genes prioritized for IDA. Heritability analyses demonstrated that the liability scale heritability was 3.1% ± 0.2%, whereas an estimated 43.92 million effective sample size would be required to explain 90% of the phenotypic variance. Gene enrichment analysis, gene-set analyses, and genetic correlation studies revealed that IDA-related genes were enriched in whole blood, influenced the role of HFE (hemochromatosis gene) in regulating systemic iron homeostasis, and showed positive correlations with inflammatory diseases, psychological diseases, and cardiovascular diseases. Finally, gene-based prioritized analysis and gene-drug interaction analysis identified some potential targets (e.g., BLK), while drug repurposing approaches highlighted exploratory drug candidates (e.g., folic acid) for IDA. CONCLUSION: We identified 31 novel risk loci for IDA and further characterized its genetic architecture.