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Adiposity is an established risk factor for multiple diseases, but the causal relationships of different adiposity types with circulating protein biomarkers have not been systematically investigated. We examine the causal associations of general and central adiposity with 2923 plasma proteins among 3977 Chinese adults (mean BMI = 23.9 kg/m²). Genetically-predicted body mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-to-hip ratio (WHR) are significantly (FDR < 0.05) associated with 399, 239, 436, and 283 proteins, respectively, with 80 proteins associated with all four and 275 with only one adiposity trait. WHR is associated with the most proteins (n = 90) after adjusting for other adiposity traits. These associations are largely replicated in Europeans (mean BMI = 27.4 kg/m²). Two-sample Mendelian randomisation (MR) analyses in East Asians using cis-protein quantitative trait locus (cis-pQTLs) identified in GWAS find 30/2 proteins significantly affect levels of BMI/WC, respectively, with 10 showing evidence of colocalisation, and seven (inter-alpha-trypsin inhibitor heavy chain H3, complement factor B, EGF-containing fibulin-like extracellular matrix protein 1, thioredoxin domain-containing protein 15, alpha-2-antiplasmin, fibronectin, mimecan) are replicated in separate MR using different cis-pQTLs identified in Europeans. These findings identified potential novel mechanisms and targets, to our knowledge, for improved treatment and prevention of obesity and associated diseases., (© 2024. The Author(s).)

Adiposity is associated with multiple diseases and traits, but little is known about the causal relevance and mechanisms underlying these associations. Large-scale proteomic profiling, especially when integrated with genetic data, can clarify mechanisms linking adiposity with disease outcomes. We examined the associations of adiposity with plasma levels of 1463 proteins in 3977 Chinese adults, using measured and genetically-instrumented BMI. We further used two-sample bi-directional MR analyses to assess if certain proteins influenced adiposity, along with other (e.g. enrichment) analyses to clarify possible mechanisms underlying the observed associations. Overall, the mean (SD) baseline BMI was 23.9 (3.3) kg/m 2 , with only 6% being obese (i.e. BMI ≥ 30 kg/m 2 ). Measured and genetically-instrumented BMI was significantly associated at FDR < 0.05 with levels of 1096 (positive/inverse: 826/270) and 307 (positive/inverse: 270/37) proteins, respectively, with FABP4, LEP, IL1RN, LSP1, GOLM2, TNFRSF6B, and ADAMTS15 showing the strongest positive and PON3, NCAN, LEPR, IGFBP2 and MOG showing the strongest inverse genetic associations. These associations were largely linear, in adiposity-to-protein direction, and replicated (> 90%) in Europeans of UKB (mean BMI 27.4 kg/m 2 ). Enrichment analyses of the top > 50 BMI-associated proteins demonstrated their involvement in atherosclerosis, lipid metabolism, tumour progression and inflammation. Two-sample bi-directional MR analyses using cis-pQTLs identified in CKB GWAS found eight proteins (ITIH3, LRP11, SCAMP3, NUDT5, OGN, EFEMP1, TXNDC15, PRDX6) significantly affect levels of BMI, with NUDT5 also showing bi-directional association. The findings among relatively lean Chinese adults identified novel pathways by which adiposity may increase disease risks and novel potential targets for treatment of obesity and obesity-related diseases., (© 2023. The Author(s).)