Forward Mendelian randomization analysis did not suggest a causal effect of adiponectin on systemic sclerosis risk (odds ratio = 1.21, p = 0.57), whereas reverse Mendelian randomization provided evidence for a causal effect of genetic liability to systemic sclerosis on lowering circulating adiponectin levels (ß = −0.027, p = 6.8E-06). This evidence concerns the gene ADIPOQ and systemic sclerosis.