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 -