title: How Can Genetic Studies Help Us to Understand Links Between Birth Weight and Type 2 Diabetes?
abstract: In observational epidemiology, both low and high birth weights are associated with later type 2 diabetes. The mechanisms underlying the associations are poorly understood. We review evidence for the roles of genetic and non-genetic factors linking both sides of the birth weight distribution to risk of type 2 diabetes, focusing on contributions made by the most recent genome-wide association studies (GWAS) of birth weight.
  
  
  
  There are now nine genetic loci robustly implicated in both fetal growth and type 2 diabetes. At many of these, the same alleles are associated both with a higher risk of type 2 diabetes and a lower birth weight. This supports the Fetal Insulin Hypothesis and reflects a general pattern for type 2 diabetes susceptibility alleles: genome-wide, there is an inverse genetic correlation with birth weight, and initial estimates suggest genetic factors explain a large part of the covariance between the two traits. However, the associations at individual loci show heterogeneity; some fetal risk alleles are associated with higher birth weight. For most of these, the association reflects their correlation with the maternal risk allele which raises maternal glucose, thus increasing fetal insulin-mediated growth. GWAS have improved our understanding of the mechanisms underlying associations between type 2 diabetes and birth weight but questions remain about the relative importance of genetic versus non-genetic factors and of maternal versus fetal genotypes. To answer these questions, future work will require well-powered analyses of parents and offspring.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, RILD Building, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Robin N
authors.initials: RN
authors.lastname: Beaumont
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Dr., Oxford, OX3 7BN, UK.|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Momoko
authors.initials: M
authors.lastname: Horikoshi
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Dr., Oxford, OX3 7BN, UK.|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford, OX3 7IL, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, RILD Building, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK. r.freathy@exeter.ac.uk.|Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK. r.freathy@exeter.ac.uk.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
mesh_terms: D001724:Birth Weight; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics*; D047109:Fetal Development; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans
keywords: Birth weight; Fetal; Genetics; Genome-wide association study; Maternal; Type 2 diabetes