Impact of atopy on risk of glioma: a Mendelian randomisation study

Linden Disney-Hogg, Alex J. Cornish, Amit Sud, Philip J. Law, Ben Kinnersley, Daniel I. Jacobs, Quinn T. Ostrom, Karim Labreche, Jeanette E. Eckel-Passow, Georgina N. Armstrong, Elizabeth B. Claus, Dora Il’yasova, Joellen Schildkraut, Jill S. Barnholtz-Sloan, Sara H. Olson, Jonine L. Bernstein, Rose K. Lai, Minouk J. Schoemaker, Matthias Simon, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Stephen Chanock, Preetha Rajaraman, Christoffer Johansen, Robert B. Jenkins, Beatrice S. Melin, Margaret R. Wrensch, Marc Sanson, Melissa L. Bondy, Richard S. Houlston

An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis. Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194). Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.