Leveraging family history data to disentangle time-varying effects on disease risk using lifecourse mendelian randomization

Abstract

Lifecourse Mendelian randomization is a causal inference technique which harnesses genetic variants with time-varying effects to develop insight into the influence of age-dependent lifestyle factors on disease risk. Here, we apply this approach to evaluate whether childhood body size has a direct consequence on 8 major disease endpoints by analysing parental history data from the UK Biobank study.Our findings suggest that, whilst childhood body size increases later risk of outcomes such as heart disease (odds ratio (OR) = 1.15, 95% CI = 1.07 to 1.23, P = 7.8 × 10^{- 5}) and diabetes (OR = 1.43, 95% CI = 1.31 to 1.56, P = 9.4 × 10^{- 15}) based on parental history data, these findings are likely attributed to a sustained influence of being overweight for many years over the lifecourse. Likewise, we found evidence that remaining overweight throughout the lifecourse increases risk of lung cancer, which was partially mediated by lifetime smoking index. In contrast, using parental history data provided evidence that being overweight in childhood may have a protective effect on risk of breast cancer (OR = 0.87, 95% CI = 0.78 to 0.97, P = 0.01), corroborating findings from observational studies and large-scale genetic consortia.Large-scale family disease history data can provide a complementary source of evidence for epidemiological studies to exploit, particularly given that they are likely more robust to sources of selection bias (e.g. survival bias) compared to conventional case control studies. Leveraging these data using approaches such as lifecourse Mendelian randomization can help elucidate additional layers of evidence to dissect age-dependent effects on disease risk.

Keywords: Childhood body size; Family disease history; Lifecourse epidemiology; Mendelian randomization; UK Biobank.

Fig. 1

Schematic representation of applying (A) Univariable Mendelian randomization to estimate the ‘total effect’ of childhood body size on disease risk and and multivariable Mendelian randomization to separately estimates the (B) ‘direct effect’ and (C) ‘indirect effect’ of childhood body size on disease risk whilst accounting for the effect of adulthood body size (known as ‘lifecourse Mendelian randomization’). For example, previous applications of this approach have suggested that childhood body size has a direct effect (B) on risk of type 1 diabetes [6], but an indirect effect (C) on risk of type 2 diabetes [7]. These findings can be interpreted as indicating that being overweight in childhood exerts an effect in early life on risk of type 1 diabetes, whereas its influence on risk of type 2 diabetes is likely attributed to a sustained effect of remaining overweight at later stages of the lifecourse. The red arrows represent thee causal pathway being evaluated in each scenario

Fig. 2

Univariable and multivariable Mendelian randomization estimates for childhood (yellow) and adult (purple) body size on risk of 8 major disease endpoints using parental history as proxy outcomes in the UK Biobank study