Abstract 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.
Siyu Chen, Yiwen Liang, Shan Luo et al.· International Journal of Epi...· 0 citations
Parental smoking has been linked to several adverse offspring cardiometabolic outcomes; however, evidence is conflicting regarding the causal and long-term nature of these associations.
We investigated the effects of maternal and paternal smoking, capturing exposure before, during, and after pregnancy, on eleven offspring cardiometabolic risk factors related to body composition, blood pressure, glucose, and lipid levels in adulthood. We applied a multi-method intergenerational Mendelian randomization (MR) framework, combining two-sample MR (outcome GWAS, n = up to 564,160) and one-sample MR analyses (n = up to 17,484 genotyped mother-father-offspring trios with offspring cardiometabolic risk factors) from the HUNT cohort, Norway, and the UK Biobank and ALSPAC cohorts in the United Kingdom. Smoking behaviour was instrumented using genome-wide significant variants for smoking initiation and heaviness from large genome-wide association studies (2019 and 2022), with additional analyses of the
CHRNA5
variant rs16969968.
Using the two-sample MR approach, we found an average change in adult offspring waist-hip ratio (WHR) per one standard deviation (SD) increase in maternal cigarettes smoked per day of 0.25 SD (95% CI: 0.13, 0.38; 2019 GWAS), 0.19 SD (95% CI: 0.08, 0.31; 2022 GWAS) and 0.27 SD (95% CI: 0.07, 0.47;
CHRNA5
rs16969968). We also found tentative evidence of comparable effects on offspring body mass index and C-reactive protein. One-sample MR analyses using
CHRNA5
rs16969968, restricted to maternal ever-smokers, provided supporting evidence consistent with the primary findings for maternal smoking heaviness on offspring WHR. We found little evidence that maternal smoking initiation affected WHR, and little evidence that maternal smoking heaviness affected the remaining cardiometabolic risk factors; paternal smoking showed no clear effect on any outcome. Results from sensitivity analyses were consistent with these main findings.
Adult offspring of mothers with a propensity to heavier smoking exhibited greater central adiposity, a phenotype associated with increased cardiometabolic risk. These findings are consistent with a causal influence of maternal smoking heaviness across the preconception, perinatal, and postnatal periods on later-life offspring body fat distribution. Further triangulation using alternative causal approaches is warranted.
G. Power, T. Bond, L. Bhatta et al.· BMC Medicine· 0 citations