Elucidating the proteomic pathways linking childhood body mass index with type 2 diabetes: a Mendelian randomization and recall-by-genotype study.

BACKGROUND: Increased childhood adiposity contributes to higher type 2 diabetes (T2D) risk, but the underlying mechanisms remain unclear. Furthermore, whether these mechanistic pathways are shared across ethnic groups has not been explored. METHODS: We conducted a two-step Mendelian randomization (MR) using European-based summary statistics from genome-wide association studies of childhood body mass index (BMI) (n = 61 111), adulthood proteomics (n = 35 559), and later life T2D (cases: 242 283; controls: 1 569 734). We also conducted a recall-by-genotype (RbG) study in a Chinese birth cohort (n = 250) to assess whether childhood BMI was associated with the identified proteomic signals in an East Asian population. Analyses included multi-instrument MR methods (inverse variance weighted and MR-Egger) and, for single-instrument proteins, cis-MR using the Wald ratio, with colocalization validation. Multiple testing was adjusted using false discovery rate (FDR). RESULTS: Higher genetically predicted childhood BMI was associated with 1299 proteins (FDR-adjusted P < .05), of which 36 proteins were associated with higher T2D risk. Six proteins were supported by colocalization (PPH4 > 80%). Genetically predicted higher childhood BMI was positively associated with GCKR, RBP1, ENTPD6, and GST A1-1, and inversely associated with PRSS27 and SHBG. The proportion of the BMI-T2D effect mediated by these proteins ranged from 1.87% to 12.92%. However, only SHBG was replicated in Asians in the RbG study. CONCLUSIONS: Our study identified putative actionable proteins that could reduce the elevated T2D risk attributable to childhood adiposity in Europeans, but their relevance in Asian populations requires further investigation.