The genetic basis of dermatophytosis skin infection susceptibility

Dermatophytosis is an infection caused by fungi that utilize keratinized tissues, such as skin, nails, and hair, as their energy source. This infection commonly presents as red, itchy and ring-like patches on the skin, nail thickening, or hair loss. With ever-increasing case numbers, it has become a significant public health concern estimated to affect 20 % of the worlds population. Despite the high prevalence, the genetic risk factors for dermatophytosis are poorly understood. Our goal was to elucidate the biological mechanisms underlying individual susceptibility to dermatophytosis and to explore its genetic associations with other diseases and traits. We performed a large-scale genome-wide association meta-analysis of dermatophytosis infections with over 250,000 cases and 1,370,000 controls using data from FinnGen, Estonian Biobank, UK Biobank and Million Veterans Program. We identified 30 genome-wide significant loci including seven missense variants and two variants in high linkage disequilibrium with missense variants. The strongest associations were with variants within or closest to ZNF646 (p = 6.60x10-79, beta = 0.07), HLA-DQB1 (p = 1.42x10-36, beta = 0.05), FLG (p = 1.96x10-27, beta = -0.22), FTO (p = 5.75x10-26, beta = -0.04), SLURP2 (p = 3.33x10-24, beta = 0.04) and KRT77 (p = 1.28x10-15, beta = 0.03) genes. Overall, our findings implicate keratin lifecycle and skin integrity, immune defense, and obesity as risk factors for dermatophytosis. Our findings highlight the clinical comorbidities with other skin diseases and with high BMI and identify novel genetic variants some of which are novel candidates for managing dermatophytosis infection.