Genome-wide associations for birth weight and correlations with adult disease

Research output: Contribution to journalLetterResearchpeer-review

Momoko Horikoshi, Robin N Beaumont, Felix R Day, Nicole M Warrington, Marjolein N Kooijman, Juan Fernandez-Tajes, Bjarke Feenstra, Natalie R van Zuydam, Kyle J Gaulton, Niels Grarup, Jonathan P Bradfield, David P Strachan, Ruifang Li-Gao, Tarun Veer Singh Ahluwalia, Eskil Kreiner, Rico Rueedi, Leo-Pekka Lyytikäinen, Diana L Cousminer, Ying Wu, Elisabeth Thiering & 31 others Carol A Wang, Christian T Have, Jouke-Jan Hottenga, Natalia Vilor-Tejedor, Peter K Joshi, Eileen Tai Hui Boh, Ioanna Ntalla, Niina Pitkänen, Anubha Mahajan, Elisabeth M van Leeuwen, Raimo Joro, Vasiliki Lagou, Michael Nodzenski, Louise A Diver, Krina T Zondervan, Mariona Bustamante, Pedro Marques-Vidal, Josep M Mercader, Emil V. R. Appel, Johannes Waage, Thorkild I A Sørensen, Mads Melbye, Haja N Kadarmideen, Jens-Christian Holm, Torben Hansen, Klaus Bønnelykke, Hans Bisgaard, Charlotta Pisinger, Oluf Pedersen, Allan A Vaag, CHARGE Consortium Hematology Working Group

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10(-8)). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10(-13)), T2D (Rg = -0.27, P = 1.1 × 10(-6)) and coronary artery disease (Rg = -0.30, P = 6.5 × 10(-9)). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10(-4)). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Original languageEnglish
JournalNature
Volume538
Pages (from-to)248-252
Number of pages5
ISSN0028-0836
DOIs
Publication statusPublished - 28 Sep 2016

ID: 166503608