Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood
Open accessAbstract
Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.
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High genetic risk for obesity can be attenuated by healthy lifestyle factors.
“Recent work on polygenic risk scores improved individual prediction of obesity susceptibility, revealing that high genetic risk can be attenuated by healthy lifestyle factors [24].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [24]
The Summary (p. 3) reports an improved polygenic predictor of obesity susceptibility. The Discussion (p. 10) cites prior studies linking lifestyle factors to BMI more strongly in genetically predisposed people and suggests targeted prevention, but it does not show that healthy lifestyle factors attenuated high genetic risk in this study. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe failure to identify a qualitative or monogenic inheritance pattern and the findings from GWAS, Mendelian randomization, familial and twin studies suggest that the heritability of PCOS is likely due to the combination of multiple genes with small effect size.
“The failure to identify a qualitative or monogenic inheritance pattern and the findings from GWAS, MR, familial and twin studies, suggests that the heritability of PCOS is likely to be due to the combination of multiple genes with small effect size, as has been found with obesity and type 2 diabetes [79,80,94,95,96].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [96]
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References 75 · Cited by 789
- Authors
- Khera, A. V., Chaffin, M., Wade, K. H., Zahid, S., Brancale, J., Xia, R., Distefano, M., Senol-Cosar, O., Haas, M. E., Bick, A., Aragam, K. G., Lander, E. S., Smith, G. D., Mason-Suares, H., Fornage, M., Lebo, M., Timpson, N. J., Kaplan, L. M., & Kathiresan, S.
- Affiliations
- Broad Institute (US)
- University of Bristol (GB)
- Harvard University (US)
- The University of Texas Health Science Center at Houston (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Khera, Amit V.
- Kathiresan, Sekar
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 177
- Issue
- 3
- Pages
- 587-596.e9
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6661115
- OpenAlex
- W2936480486
- Cited by
- 789
- References
- 75
- Citations by year
- 2026: 79 · 2025: 101 · 2024: 122 · 2023: 117 · 2022: 104 · 2021: 117 · 2020: 103 · 2019: 44
- FWCI
- 55.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by-nc-nd)
- Explore Bristol Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (DK088661, DK090956, DK040561)
- Massachusetts General Hospital (HG008895)
- Harvard University
- Virginia Marine Resources Commission
- Neos Therapeutics
- Merck
- University of Bristol (20190017119)
- Wellcome Trust (202802/Z/16/Z)
- National Heart, Lung, and Blood Institute (HL127564)
- National Lipid Association
- Sage Therapeutics
- Broad Institute
- Medical Research Council (102215/2/13/2, MC_UU_12013/3)
- National Institute on Aging (AG0005)
- National Human Genome Research Institute (U01-HG04424, U01-HG004446, HG008895, 1K08HG010155)
- Ethicon Endo-Surgery (HHSN268201300027C, HHSN268201300028C, HHSN268201300026C, HHSN268201300029C)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- polygenic risk score, obesity, body weight trajectories, heritability of obesity, common genetic variants, birth weight, child weight gain, longitudinal birth cohort, obesity prevention
- MeSH terms
- Adolescent, Body Weight, Child, Female, Humans, Infant, Newborn, Longitudinal Studies, Male, Middle Aged, Obesity, Risk Factors, Severity of Illness Index, Body Mass Index, Databases, Factual, Multifactorial Inheritance, Genome-Wide Association Study
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