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pH sensing by GPR65 regulates various inflammatory conditions, but its role in skin remains unknown. In this study, we performed a phenome-wide association study and report that the T allele of GPR65-intronic single-nucleotide polymorphism rs8005161, which reduces GPR65 signaling, showed a significant association with atopic dermatitis, in addition to inflammatory bowel diseases and asthma, as previously reported. Consistent with this genetic association in humans, we show that deficiency of GPR65 in mice resulted in markedly exacerbated disease in the MC903 experimental model of atopic dermatitis. Deficiency of GPR65 also increased neutrophil migration in vitro. Moreover, GPR65 deficiency in mice resulted in higher expression of the inflammatory cytokine TNF-α by T cells. In humans, CD4+ T cells from rs8005161 heterozygous individuals expressed higher levels of TNF-α after PMA/ionomycin stimulation, particularly under pH 6 conditions. pH sensing by GPR65 appears to be important for regulating the pathogenesis of atopic dermatitis.

Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10-75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.

Rheumatoid arthritis (RA) is an area of active drug development, with over 100 candidates in clinical trials. However, most of those drugs act on a small number of immunomodulatory targets. Drug candidates that act through new targets or mechanisms could expand treatment options for RA. We applied an integrative biomedical-informatics-based approach and in vivo testing to identify new drug candidates and therapeutic targets that could form the basis for future drug development in RA. A computational model of RA was constructed by integrating patient gene expression data, molecular interactions, and clinical drug-disease associations. Drug candidates were scored based on their predicted efficacy across these data types. FDA-approved treatments for RA were significantly enriched among the top-ranked candidates (p = 1.7x10-15). Ten high-scoring novel candidates were subsequently screened in the collagen-induced arthritis model of RA in rats. Treatment with three candidates, exenatide, olopatadine, and TXR-112, significantly reduced ankle size, alleviated limb inflammation, improved joint histopathology, and improved mobility as observed using a novel digital motion endpoint. These three drug candidates do not act on common RA therapeutic targets; however, links between known candidate pharmacology and pathological processes in RA suggest hypothetical mechanisms that could contribute to the observed efficacy. Future studies will help elucidate druggable targets, pathways, and mechanisms that could contribute to each candidate9s efficacy in RA. The candidates may be modified and optimized to increase efficacy. Targets identified in these studies could also be the basis of new drug discovery initiatives.