The SHBG-lowering allele C rs10454142 PPP1R21 has a risk value for BC in obese women (allelic model: CvsT, OR = 1.52, 95%CI = 1.10–2.11, and pperm = 0.013; additive model: CCvsTCvsTT, OR = 1.71, 95%CI = 1.15–2.62, and pperm = 0.011; dominant model: CC + TCvsTT, OR = 1.95, 95%CI = 1.13–3.37, and pperm = 0.017) and is not associated with the disease in women without obesity. Here, SHBG is linked to obesity due to melanocortin 4 receptor deficiency.