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BACKGROUND AND AIMS: Microscopic colitis (MC) is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis (CC) and lymphocytic colitis (LC). Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiology.METHODS: We conducted a GWAS meta-analysis in 1,498 CC and 373 LC patients and 13,487 controls from Europe and US, combined with publicly available MC GWAS data from UK Biobank and FinnGen (2,599 MC cases and 552,343 controls in total). HLA alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied.RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77 and R74 as key to this association (best P=1.4×10 -23, OR=1.96). Nominally significant genetic correlations were detected between CC and Pneumonia (rg=0.77; P=0.048) and oesophageal diseases (rg=0.45, P=0.023). An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 (rs35099084, P=2.0×10 -8, OR=1.31). No significant association was detected for LC.CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.