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

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. 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). 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. 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.