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. 2025 Jun;68(6):1298-1314.
doi: 10.1007/s00125-025-06396-5. Epub 2025 Apr 2.

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

Rucha Wagh  1   2 , Gad Hatem  3 , Jonas Andersson  3 , Pooja Kunte  1 , Souvik Bandyopadhyay  4 , Chittaranjan S Yajnik #  1 , Rashmi B Prasad #  5   6
Affiliations

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

Rucha Wagh et al. Diabetologia. 2025 Jun.

Abstract

Aims/hypothesis: 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.

Methods: 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.

Results: 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.

Conclusions/interpretation: 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.

Keywords: Genetics; Life-course programming; Macronutrients; Parent-of-origin; Sex-specific parental effects; Type 2 diabetes.

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Conflict of interest statement

Acknowledgements: We are grateful to all study participants and their family members for their cooperation over many years. We thank C. Fall, B. Coyaji, V. N. Rao (all KEM Hospital Research Centre, India) and the late D. J. P. Barker (Southampton General Hospital, UK) for their support in establishing the PMNS. We also thank the staff of the Diabetes Unit at the King Edward Memorial Hospital Research Centre for their help in conducting the study over a 30 year period. We are grateful to the Indian Council of Medical Research, the Department of Biotechnology of the Government of India, the Wellcome Trust and the Medical Research Council, UK for their funding support. We thank J. Postma for grant management, I. Artner and N. Wierup for critical reading of the manuscript, M. Marziaz for statistical advice and Leif Groop for critical insights and advice on the parent-of-origin concepts (all Lund University, Sweden). Some of the data formed part of GH’s PhD thesis. In addition, some of the data were presented as an abstract at the 60th EASD Annual Meeting in 2024. Data availability: The data that support the findings of this study are not openly available for reasons of sensitivity, and are available from the corresponding author upon reasonable request. Data are stored in controlled-access data storage at the King Edward Memorial Hospital, Pune, India, and Lund University, Malmö, Sweden. Funding: Open access funding provided by Lund University. This study was supported by Network grant for Indo-Swedish collaboration from the Swedish Research Council (2015-06722) and the Department of Science and Technology of the Government of India (DST/INT/SWD/VR/P-04/2016) to RBP and CSY. The PMNS and PCS cohorts were funded by the Wellcome Trust, UK (grants 038128/Z/93, 059609/Z/99, 079877/Z/06/Z, 098575/B/12/Z and 083460/Z/07/Z), the Medical Research Council, UK (grant MR/J000094/1) and the Department of Biotechnology, Government of India (grant BT/PR-6870/PID/20/268/2005). The PMNS cohort was also funded intramurally by the King Edward Memorial Hospital Research Centre. RBP was supported by the Crafoord Foundation (grant number 20200891), the Åke Wibergs Stiftelse (grant number M20-0214), the Swedish Heart Lung Foundation (grant number 20180522), the Hjelt Foundation, the Swedish Research Council (2021-02623), VINNOVA (2023-04234), the Direktör Albert Påhlssons Stiftelse, the EFSD and the Lilly European Diabetes Research Programme. CSY was a visiting professor at the Danish Diabetes Academy (supported by Novo Nordisk Foundation) and the Southern University of Denmark during 2016-2019. Authors’ relationships and activities: SB is employed at Cytel Inc. All authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: RW, GH, JA and RBP analysed the data. RBP developed the study concept and design. RW and RBP wrote the manuscript. All authors took part in interpretation of the results, reviewed the manuscript critically for important intellectual content, and gave final approval of the version to be published. RBP and CSY are the guarantors of this work, and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Figures

Fig. 1
Fig. 1
Study design for the PMNS. DEXA, dual-energy x-ray absorptiometry
Fig. 2
Fig. 2
Circular heatmaps for (a) anthropometric traits and (b) metabolic traits, representing the phenotype associations between maternal traits or paternal traits and the offspring traits at the various timepoints. The outer circle represents the β coefficients for mother–offspring associations and father–offspring associations. The inner circle represents the parent-of-origin effects expressed as Z values. The black dots indicate a significant p value (p<0.05). Wt, weight; Ht, height; Chol, cholesterol; FPG, fasting plasma glucose; FPI, fasting plasma insulin; H2-S, HOMA2-S; H2-B, HOMA2-B; HDL-c and HDL, HDL-cholesterol; LDL-c and LCL, LDL-cholesterol; TG, triglycerides; Mat, maternal; Pat, paternal; POE, parent-of-origin effects
Fig. 3
Fig. 3
Individual Sankey diagrams representing the parent-of-origin effects (expressed as Z values) separately for each phenotype at each available timepoint: (a–d) anthropometric traits; (e–h) glycaemic traits; (i–l) lipids. A significant maternal bias is indicated in red, and a significant paternal bias is indicated in blue. Insignificant parent-of-origin effects are represented in grey. HDL-c, HDL-cholesterol; LDL-c, LDL-cholesterol
See this image and copyright information in PMC

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