Genetic Evaluation of the Role of Galactose-Deficient IgA1 in IgA Nephropathy: Evidence from Association Testing and Mendelian Randomization

Elevated galactose deficient IgA1 (Gd-IgA1) is known to be associated with IgA nephropathy (IgAN) and is often regarded as the first of four steps in the "four hit" hypothesis to explain disease pathogenesis. However, while the proposed downstream hits have support from unbiased genetic association studies, similar genetic evidence to support a causal role for Gd-IgA1 in the disease is lacking. Multiple previous genome-wide association studies have shown that common variation in the gene C1GALT1 is strongly associated with Gd-IgA1 levels. We used this established relationship first to calculate power to detect an association of C1GALT1 alleles with IgAN risk and second to conduct association and Mendelian randomisation analyses to detect and quantify evidence for a causal role of Gd-IgA1 in IgA nephropathy. Despite adequate power, we did not observe significant genetic evidence for a causal role of Gd-IgA1 in IgAN that would explain the well-established observational association, and infer that this may not be explained by causation. This raises the possibility that Gd-IgA1 might better be regarded as a biomarker than a cause of IgA nephropathy and suggests that caution is needed when inferring clinical efficacy of treatments based on their effects on Gd-IgA1 levels. Lay SummaryImmunoglobulin A (IgA) nephropathy is a kidney disease in which IgA builds up in the kidneys, causing inflammation there. People with the condition often have higher levels of a form of IgA that lacks a sugar called galactose (galactose-deficient IgA1, or Gd-IgA1) but it has been unclear whether this abnormal IgA actually causes the disease, or whether it is simply a marker of it. To address this, we used two genetic experiments: first, we tested whether people who inherit genetic variants that increase Gd-IgA1 levels are more likely to develop IgA nephropathy; and second, we used Mendelian randomization methods that compare the genetic effects on Gd-IgA1 levels with their effects on disease risk. Despite adequate power, neither approach showed that Gd-IgA1 causes IgA nephropathy, suggesting the raised levels seen in patients might be a consequence of other processes. This means treatments should not be judged solely on whether they lower Gd-IgA1.