Parent-of-origin effects in the life-course evolution of cardiometabolic traits

Cardiometabolic traits are heritable, and some display parent-of-origin effects, which indicates preferential inheritance from one parent or parental bias. Most studies of these phenomena have focused on adult populations. We aimed to investigate the heritability and parent-of-origin effects on cardiometabolic traits in a birth cohort with serial measurements to determine whether these patterns emerged early in life.

The Pune Maternal Nutrition Study comprises a birth cohort in which offspring and parents were studied from birth and followed up for 24 years. We investigated parent-of-origin effects on cardiometabolic traits cross-sectionally at available timepoints using linear regression, and longitudinally across the life course using mixed-effect regression. Maternal and paternal effects on offspring phenotype were modelled after adjusting for age, sex and BMI. Parent-of-origin effects were calculated based on the difference between maternal and paternal effects. We also investigated these effects in another birth cohort, that of the Pune Children's Study. Genetic parent-of-origin effects were assessed using generalised estimating equations after taking the parental origin of the alleles into account.

Birthweight showed a maternal parent-of-origin effect. At 24 years, maternal bias was seen for some obesity-related traits for daughters, while paternal bias was seen for WHR in sons. A shift from paternal bias at 6 years to maternal bias at 24 years for the skinfold thickness was observed in daughters. Fasting glucose and lipids showed maternal bias at 6, 12 and 24 years. For fasting insulin and HOMA2-S, a negative maternal effect at 6 years transitioned to a positive one at 12 years. For HOMA2-B, a paternal effect at 6 years transitioned to a maternal one at 12 years, and this remained so at 24 years. Some of these findings were also observed in the cohort from the Pune Children's Study. Longitudinal modelling revealed stronger paternal effects over time for fasting insulin and HOMA indices but maternal effects for glucose and lipids, reflecting their cumulative effect over time. Genetic variants at the KCNQ1 locus showed a maternal parent-of-origin effect on birthweight, on HOMA2-B at 12 years, and on lipids at 6 and 12 years.

Our study provides proof of concept of the existence of parent-of-origin effects on cardiometabolic traits from birth, through childhood and puberty, until adult age. Our results indicate a predominantly maternal influence on intrauterine, pubertal and reproductive-age metabolism in the offspring. While the longitudinal analysis indicated a maternal bias for the macronutrients (glucose and lipids), and a paternal bias for glucose-insulin metabolism, the cross-sectional analysis revealed a transition between parental influence across physiological stages. This dynamic relationship may have its origins in the life-history theory of evolution, and could inform strategies for primordial prevention aimed at curbing the rising burden of cardiometabolic disease. Further studies are needed to determine the mechanisms underlying such effects.