A response to Yurko et al: H-MAGMA, inheriting a shaky statistical foundation, yields excess false positives

Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA) was initially developed to advance MAGMA by assigning non-coding SNPs to their cognate genes based on threedimensional chromatin architecture. Yurko and colleagues raised concerns that the SNP-wise mean gene-analysis model of MAGMA may allow inflation in type I errors. Accordingly, we updated MAGMA and found that the updated version (MAGMA v.1.08) effectively controls for error rate inflation. Intrigued by this result, H-MAGMA was also updated by implementing MAGMA v.1.08. As expected, H-MAGMA v.1.08 detected a smaller set of risk genes than its original version (v.1.07), but the overall statistical architecture remained largely unchanged between v.1.07 and v.1.08. H-MAGMA v.1.08 was then applied to genome-wide association studies (GWAS) of five psychiatric disorders, from which we recapitulated our previous findings that psychiatric disorder risk genes display neuronal and prenatal enrichment. Therefore, issues raised by Yurko and colleagues can be overcome by using (H-)MAGMA v.1.08.