Identification of therapeutic targets for 18 clinical diseases by integrating human plasma proteome with genome

Abstract The proteome is an abundant source of potential therapeutic targets, and a comprehensive evaluation of proteins as therapeutic targets for a wide range of diseases is required. By screening 4,907 plasma proteins, we conducted a systematically two-sample proteome-wide Mendelian randomisation (MR) study to uncover potential therapeutic targets for 18 clinical diseases. Following MR analysis and stringent process filtering, a total of 146 causative plasma proteins (false discovery rate<0.05) were discovered. Colocalization analysis (Posterior Probability H4>0.8) further supported the causality of three proteins (MAP2K1, GFRA1, and THBS3) in gastroesophageal reflux disease; LYPLAL1 in keratoconus; three proteins (PCSK9, ANGPTL4, and GCKR) in familial hyperlipidemia; CRAT in atopic eczema; three proteins (IRF3, CA12, and TNFRSF1B) in hypothyroidism; AIF1 in age-related hearing impairment; SCARF2 in male pattern baldness; IRF3 in basal cell carcinoma; and four proteins (RPS6KA1, ULK3, MPPED2, and BTN3A1) in prostate cancer. Interestingly, having a genetically higher circulating CA12 level is associated with a lower risk of hypothyroidism (OR=0.47, p -value=1.68e-05, Posterior Probability H4=0.82). Single-cell RNA sequencing analysis showed that CA12 was mainly expressed in fibroblasts and epithelial cells in patient thyroid tissue and that its expression increased in older adults. Furthermore, with a proportion of 3.8%, hypothyroidism appears to mediate the effect of IRF3 on idiopathic pulmonary fibrosis, according to mediation analysis. Overall, our research could provide new insights into the etiology of clinical diseases as well as intriguing targets for the development of screening biomarkers and therapeutic treatments.