Analytical approaches which disentangle heterogeneous effects on trait susceptibility provide important insight on the relationship between complex traits and disease. Lifecourse Mendelian randomization (MR) is a novel statistical approach which has been developed to address lifecourse specific effects on disease susceptibility (1, 2, 3). Additionally, stratifying instrumental variables based on tissue derived gene expression data provides further molecular context to interpret the effect (4, 5).

Evaluation of the relationship between lifecourse and tissue dependent effects on biomarkers measured in early life provides important insight on key etiological and susceptibility windows of disease. The results of a recent analysis have provided evidence of a direct effect for the brain-mediated component of body-size on the adipose tissue secreted hormone leptin measured at age 10 in the lifecourse (Richardson et al, in revision). Through the integration of tissue-specific data, this approach highlights the etiological importance of appetite regulation in the links between adiposity and leptin levels in early life.

Additionally, this study also showed evidence for an effect of adult body-size on circulating leptin measured in childhood (when accounting for the effect of early life body size), which is directionally implausible. This raises the possibility that the adult derived exposure may be a strong predictor for traits in early life which have an effect on childhood leptin levels. In this project we will further characterize the relationship between adult body size and early life adiposity measures and a range of childhood biomarkers to refine the interpretation of this causal relationship.

References:

1. Richardson TG, Sanderson E, Elsworth B, Tilling K, Davey Smith G. Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomisation study. BMJ. 2020;369:m1203.
2. Richardson TG, Power GM, Davey Smith G. Adiposity may confound the association between vitamin D and disease risk - a lifecourse Mendelian randomization study. Elife. 2022;11.
3. Sanderson E, Richardson TG, Morris TT, Tilling K, Davey Smith G. Estimation of causal effects of a time-varying exposure at multiple time points through multivariable mendelian randomization. PLoS Genet. 2022;18(7):e1010290.
4. Leyden GM, Shapland CY, Davey Smith G, Sanderson E, Greenwood MP, Murphy D, et al. Harnessing tissue-specific genetic variation to dissect putative causal pathways between body mass index and cardiometabolic phenotypes. Am J Hum Genet. 2022.
5. Leyden GM, Greenwood MP, Gaborieau V, Han Y, Amos CI, Brennan P, et al. Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation. Br J Cancer. 2022.