Multi-ancestry GWAS of diarrhea during acute SARS-CoV2 infection identifies multiple novel loci and contrasting etiological roles of irritable bowel syndrome subtypes

A substantial proportion of acute SARS-CoV2 infection cases exhibit gastrointestinal symptoms, yet the genetic determinants of these extrapulmonary manifestations are poorly understood. Using survey data from 239,866 individuals who tested positively for SARS-CoV2, we conducted a multi-ancestry GWAS of 80,289 cases of diarrhea occurring during acute COVID-19 infection (33.5%). Six loci (CYP7A1, LZFTL1- -CCR9, TEME182, NALCN, LFNG, GCKR) met genome-wide significance in a trans-ancestral analysis. The top significant GWAS hit mapped to the CYP7A1 locus, which plays an etiologic role in bile acid metabolism and is in high LD (r2= 0.93) with the SDCBP gene, which was previously implicated in antigen processing and presentation in the COVID-19 context. Another association was observed with variants in the LZTFL1-CCR9 region, which is a known locus for COVID-19 susceptibility and severity. PheWAS showed a shared association across three of the six SNPs with irritable bowel syndrome (IBS) and its subtypes. Mendelian randomization showed that genetic liability to IBS-diarrhea increased (OR=1.40,95%,CI[1.33-1.47]), and liability to IBS-constipation decreased (OR=0.86, 95%CI[0.79-0.94]) the relative odds of experiencing COVID-19+ diarrhea. Our genetic findings provide etiological insights into the extrapulmonary manifestations of acute SARS-CoV2 infection.