Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood

Amit V Khera; Mark Chaffin; Kaitlin H Wade; Sohail Zahid; Joseph Brancale; Rui Xia; Marina Distefano; Ozlem Senol-Cosar; Mary E Haas; Alexander Bick; Krishna G Aragam; Eric S Lander; George Davey Smith; Heather Mason-Suares; Myriam Fornage; Matthew Lebo; Nicholas J Timpson; Lee M Kaplan; Sekar Kathiresan

doi:10.1016/j.cell.2019.03.028

Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood

Cell. 2019 Apr 18;177(3):587-596.e9. doi: 10.1016/j.cell.2019.03.028.

Authors

Amit V Khera¹, Mark Chaffin², Kaitlin H Wade³, Sohail Zahid⁴, Joseph Brancale⁵, Rui Xia⁶, Marina Distefano⁷, Ozlem Senol-Cosar⁷, Mary E Haas², Alexander Bick⁸, Krishna G Aragam⁹, Eric S Lander¹⁰, George Davey Smith¹¹, Heather Mason-Suares⁷, Myriam Fornage⁶, Matthew Lebo⁷, Nicholas J Timpson³, Lee M Kaplan⁵, Sekar Kathiresan¹²

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: avkhera@mgh.harvard.edu.
² Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1TH, UK; Population Health Science, Bristol Medical School, Bristol, Bristol BS8 1TH, UK; Avon Longitudinal Study of Parents and Children, Bristol BS8 1TH, UK.
⁴ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁵ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Obesity, Metabolism, and Nutrition Institute, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁷ Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Harvard Medical School, Cambridge, MA 02115, USA.
⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Program in Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
¹¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1TH, UK; Population Health Science, Bristol Medical School, Bristol, Bristol BS8 1TH, UK.
¹² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: skathiresan1@mgh.harvard.edu.

Abstract

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.

Keywords: UK Biobank; body mass index; genetic risk prediction; genomic medicine; human genetics; melanocortin 4 receptor; polygenic score; severe obesity; weight.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Body Mass Index
Body Weight*
Child
Databases, Factual
Female
Genome-Wide Association Study
Humans
Infant, Newborn
Longitudinal Studies
Male
Middle Aged
Multifactorial Inheritance / genetics*
Obesity / genetics
Obesity / pathology*
Risk Factors
Severity of Illness Index

Abstract

Publication types

MeSH terms

Grants and funding