title: Low birthweight and risk of type 2 diabetes: a Mendelian randomisation study.
abstract: Low birthweight has been associated with a high risk of type 2 diabetes mellitus in observational studies. However, it remains unclear whether this relation is causal.
  
  
  
  The present study included 3627 individuals with type 2 diabetes and 12,974 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-Up Study. A genetic risk score (GRS) was calculated based on five low-birthweight-related single nucleotide polymorphisms (SNPs). We assessed the evidence for causality first by examining the association of the GRS and the individual SNPs with type 2 diabetes, and second by performing a Mendelian randomisation analysis to estimate the potentially causal effect size of low birthweight on type 2 diabetes.
  
  
  
  In a meta-analysis of the two studies, each 1 point increment in the GRS was associated with a 6% (95% CI 3%, 9%) higher risk of type 2 diabetes. CCNL1 rs900400 and 5q11.2 rs4432842 showed dose-response associations with risk of type 2 diabetes; the corresponding ORs and 95% CIs were 1.09 (1.03, 1.16) and 1.09 (1.02, 1.16), respectively. Furthermore, we observed an overall Mendelian randomisation OR of 2.94 (95% CI 1.70, 5.16; p < 0.001) for type 2 diabetes per 1 SD lower genetically determined birthweight.
  
  
  
  A genetically lowered birthweight was associated with increased susceptibility to type 2 diabetes. Our findings support a potential causal relation between birthweight and risk of type 2 diabetes, providing new evidence to support the role of intrauterine exposures in the pathogenesis of type 2 diabetes.
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Tiange
authors.identifier: 0000-0002-3691-4643
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA. lqi1@tulane.edu.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. lqi1@tulane.edu.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. lqi1@tulane.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D000328:Adult; D000368:Aged; D001724:Birth Weight / Q000235:genetics / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007230:Infant, Low Birth Weight; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012984:Software; D044465:White People; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: D012359:tRNA Methyltransferases; C525110:CDKAL1 protein, human; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: Birthweight; Mendelian randomisation; Type 2 diabetes