Significance Statement Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy. Although variability in serum levels of galactose-deficient IgA1 has a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly determined. The authors performed a genome-wide association study of serum galactose-deficient IgA1 levels among 1127 patients with IgA nephropathy in a Chinese population, identifying two genome-wide significant loci, of which one is novel. They also observed potential associations between galactose-deficient IgA1 loci and susceptibility to IgA nephropathy. In addition, they found genetic interactions between the two loci associated with both serum levels of galactose-deficient IgA1 and susceptibility to developing IgA nephropathy. This study provides novel insights into the genetic link between galactose-deficient IgA1 and IgA nephropathy. Background Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. Methods To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. Results We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P=1.20×10−9); the locus we identified at GALNT12 (rs7856182; β=0.73, P=2.38×10−9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10−2) and disease risk (P=6.55×10−3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. Conclusions Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.