title: Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome.
abstract: Obesity is an escalating health problem worldwide, and hence the causes underlying its development are of primary importance to public health. There is growing evidence that suboptimal intrauterine environment can perturb the metabolic programing of the growing fetus, thereby increasing the risk of developing obesity in later life. However, the link between early exposures in the womb, genetic susceptibility, and perturbed epigenome on metabolic health is not well understood. In this study, we shed more light on this aspect by performing a comprehensive analysis on the effects of variation in prenatal environment, neonatal methylome, and genotype on birth weight and adiposity in early childhood.
  
  
  
  In a prospective mother-offspring cohort (N = 987), we interrogated the effects of 30 variables that influence the prenatal environment, umbilical cord DNA methylation, and genotype on offspring weight and adiposity, over the period from birth to 48 months. This is an interim analysis on an ongoing cohort study.
  
  
  
  Eleven of 30 prenatal environments, including maternal adiposity, smoking, blood glucose and plasma unsaturated fatty acid levels, were associated with birth weight. Polygenic risk scores derived from genetic association studies on adult adiposity were also associated with birth weight and child adiposity, indicating an overlap between the genetic pathways influencing metabolic health in early and later life. Neonatal methylation markers from seven gene loci (ANK3, CDKN2B, CACNA1G, IGDCC4, P4HA3, ZNF423 and MIRLET7BHG) were significantly associated with birth weight, with a subset of these in genes previously implicated in metabolic pathways in humans and in animal models. Methylation levels at three of seven birth weight-linked loci showed significant association with prenatal environment, but none were affected by polygenic risk score. Six of these birth weight-linked loci continued to show a longitudinal association with offspring size and/or adiposity in early childhood.
  
  
  
  This study provides further evidence that developmental pathways to adiposity begin before birth and are influenced by environmental, genetic and epigenetic factors. These pathways can have a lasting effect on offspring size, adiposity and future metabolic outcomes, and offer new opportunities for risk stratification and prevention of obesity.
  
  
  
  This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875 .
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.|Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
authors.forename: Ives Yubin
authors.initials: IY
authors.lastname: Lim
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
authors.forename: Ai Ling
authors.initials: AL
authors.lastname: Teh
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
authors.forename: Izzuddin M
authors.initials: IM
authors.lastname: Aris
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.|Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
authors.forename: Shu E
authors.initials: SE
authors.lastname: Soh
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.|Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
authors.forename: Mya Thway
authors.initials: MT
authors.lastname: Tint
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Julia L
authors.initials: JL
authors.lastname: MacIsaac
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Morin
authors.affiliation: KK Women's and Children's Hospital, Singapore, 229899, Singapore.
authors.forename: Fabian
authors.initials: F
authors.lastname: Yap
authors.affiliation: KK Women's and Children's Hospital, Singapore, 229899, Singapore.
authors.forename: Kok Hian
authors.initials: KH
authors.lastname: Tan
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117597, Singapore.|Singapore Eye Research Institute, Singapore, 169856, Singapore.|Duke NUS Medical School, Singapore, 169857, Singapore.
authors.forename: Seang Mei
authors.initials: SM
authors.lastname: Saw
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.|Ludmer Centre for Neuroinformatics and Mental Health, Douglas University Mental Health Institute, McGill University, Montreal, Quebec, H4H 1R3, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Meaney
authors.affiliation: MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Godfrey
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.|Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
authors.forename: Yap Seng
authors.initials: YS
authors.lastname: Chong
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Holbrook
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.|Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.|Division of Paediatric Endocrinology and Diabetes, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, 119228, Singapore.
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.|Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland, Auckland, 1142, New Zealand.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.affiliation: Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore. neerja_karnani@sics.a-star.edu.sg.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore. neerja_karnani@sics.a-star.edu.sg.
authors.forename: Neerja
authors.initials: N
authors.lastname: Karnani
mesh_terms: D050154:Adiposity / Q000235:genetics*; D001724:Birth Weight; D019175:DNA Methylation; D004777:Environment; D057890:Epigenomics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D009765:Obesity / Q000150:complications / Q000235:genetics*; D011446:Prospective Studies
keywords: Birth weight; DNA methylation; Epigenome-wide association study; Offspring adiposity; Prenatal environment