A Trace Element–Ulcer Map: Decoding Micronutrient–Ulcer Relationships Through Genetic Architecture and Pleiotropy‐Aware Inference

The contribution of circulating micronutrients to ulcer susceptibility remains poorly defined across anatomical sites. In this study, we constructed a systematic trace element-ulcer map by integrating genetic-instrumented inference, pleiotropy-aware modeling, and heterogeneity-sensitive clustering. Summary-level data were obtained from large-scale genome-wide association studies (GWAS) encompassing 10 circulating micronutrients (calcium, iron, zinc, copper, magnesium, selenium, carotene, vitamin B12, vitamin C, and vitamin D) and nine ulcer phenotypes (corneal ulcer, recurrent oral aphthae, esophageal ulcer, gastric ulcer, duodenal ulcer, vaginal/vulvar ulcer, decubitus ulcer, lower limb ulcer, and chronic skin ulcer), covering more than 3 million individuals of European ancestry. Our two-sample Mendelian randomization (MR) analysis identified genetically elevated zinc levels as a risk factor for gastric (OR: 1.141, 95% CI: 1.060-1.228, <i>p</i> = 4.57 × 10^-4) and esophageal ulcers, but inversely associated with vaginal/vulvar ulcer risk. Protective effects were observed for iron with gastric ulcers and calcium with duodenal ulcers. Carotene and magnesium were nominally associated with increased risk of oral aphthae and vaginal ulcers, respectively. To refine these associations, we applied Causal Analysis Using Summary Effect estimates (CAUSE) and MR-Clust. While CAUSE did not confirm robust putative causal relationships in most pairs, MR-Clust uncovered three distinct SNP clusters in the vitamin C-corneal ulcer pair, indicating potential mechanistic heterogeneity. These pleiotropy-aware and cluster-based approaches enhanced the interpretability of borderline signals and revealed genetic heterogeneity beyond mean-effect estimates. Collectively, this study offers a panoramic view of trace element-ulcer relationships and prioritizes zinc as a key candidate for further mechanistic exploration in gastric ulcer pathogenesis. Our integrative framework may serve as a foundation for future etiological and nutritional intervention studies.