TY - JOUR
T1 - Genome-wide associations for birth weight and correlations with adult disease
AU - Horikoshi, Momoko
AU - Beaumont, Robin N
AU - Day, Felix R
AU - Warrington, Nicole M
AU - Kooijman, Marjolein N
AU - Fernandez-Tajes, Juan
AU - Feenstra, Bjarke
AU - van Zuydam, Natalie R
AU - Gaulton, Kyle J
AU - Grarup, Niels
AU - Bradfield, Jonathan P
AU - Strachan, David P
AU - Li-Gao, Ruifang
AU - Ahluwalia, Tarun Veer Singh
AU - Kreiner, Eskil
AU - Rueedi, Rico
AU - Lyytikäinen, Leo-Pekka
AU - Cousminer, Diana L
AU - Wu, Ying
AU - Thiering, Elisabeth
AU - Wang, Carol A
AU - Have, Christian T
AU - Hottenga, Jouke-Jan
AU - Vilor-Tejedor, Natalia
AU - Joshi, Peter K
AU - Boh, Eileen Tai Hui
AU - Ntalla, Ioanna
AU - Pitkänen, Niina
AU - Mahajan, Anubha
AU - van Leeuwen, Elisabeth M
AU - Joro, Raimo
AU - Lagou, Vasiliki
AU - Nodzenski, Michael
AU - Diver, Louise A
AU - Zondervan, Krina T
AU - Bustamante, Mariona
AU - Marques-Vidal, Pedro
AU - Mercader, Josep M
AU - Appel, Emil V. R.
AU - Waage, Johannes
AU - Sørensen, Thorkild I A
AU - Melbye, Mads
AU - Kadarmideen, Haja N
AU - Holm, Jens-Christian
AU - Hansen, Torben
AU - Bønnelykke, Klaus
AU - Bisgaard, Hans
AU - Pisinger, Charlotta
AU - Pedersen, Oluf
AU - Vaag, Allan A
AU - CHARGE Consortium Hematology Working Group
PY - 2016/9/28
Y1 - 2016/9/28
N2 - 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.
AB - 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.
U2 - 10.1038/nature19806
DO - 10.1038/nature19806
M3 - Letter
C2 - 27680694
VL - 538
SP - 248
EP - 252
JO - Nature
JF - Nature
SN - 0028-0836
ER -