Genetic insights into the therapeutic potential of hydrogen sulfide

Hydrogen sulfide (H₂S) is a chalcogen-hydrogen gas that can be endogenously synthesized and is the third known bioactive gaseous signalling molecule (gasotransmitter). H₂S has diverse physiological roles, such as with cell division, neurotransmission and inflammation. Its involvement with a variety of disease-related processes has spurred growing interest in its therapeutic potential. We propose that variants in genes implicit in regulating cellular H₂S availability could help prioritise conditions for exploration of H₂S as a therapeutic target. Here, we present the first systematic genetic investigation of H₂S biology across thousands of human disease endpoints and clinical measures, leveraging common frequency genetic variants associated with gene expression and rare predicted loss-of-function variants. These analyses revealed a broad phenotypic spectrum of association signals with H₂S related variants, in line with the complexity and pleiotropy of genes involved in this system. Notably, genetically predicted expression of SUOX (sulfite oxidase) showed strong associations with several diseases, including type 1 diabetes and other autoimmune diseases. Polygenic enrichment of common variant signals provided some evidence of a link between H₂S biology and cerebrovascular disease. Our findings reveal new insights into genetic influences on H₂S signalling and its relevance to human disease, highlighting genetic variation as a tool to prioritise indications for H₂S-targeted therapies.