Genome-wide associations for birth weight and correlations with adult disease.
Horikoshi M., Beaumont RN., Day FR., Warrington NM., Kooijman MN., Fernandez-Tajes J., Feenstra B., van Zuydam NR., Gaulton KJ., Grarup N., Bradfield JP., Strachan DP., Li-Gao R., Ahluwalia TS., Kreiner E., Rueedi R., Lyytikäinen L-P., Cousminer DL., Wu Y., Thiering E., Wang CA., Have CT., Hottenga J-J., Vilor-Tejedor N., Joshi PK., Boh ETH., Ntalla I., Pitkänen N., Mahajan A., van Leeuwen EM., Joro R., Lagou V., Nodzenski M., Diver LA., Zondervan KT., Bustamante M., Marques-Vidal P., Mercader JM., Bennett AJ., Rahmioglu N., Nyholt DR., Ma RCW., Tam CHT., Tam WH., CHARGE Consortium Hematology Working Group None., Ganesh SK., van Rooij FJ., Jones SE., Loh P-R., Ruth KS., Tuke MA., Tyrrell J., Wood AR., Yaghootkar H., Scholtens DM., Paternoster L., Prokopenko I., Kovacs P., Atalay M., Willems SM., Panoutsopoulou K., Wang X., Carstensen L., Geller F., Schraut KE., Murcia M., van Beijsterveldt CE., Willemsen G., Appel EVR., Fonvig CE., Trier C., Tiesler CM., Standl M., Kutalik Z., Bonas-Guarch S., Hougaard DM., Sánchez F., Torrents D., Waage J., Hollegaard MV., de Haan HG., Rosendaal FR., Medina-Gomez C., Ring SM., Hemani G., McMahon G., Robertson NR., Groves CJ., Langenberg C., Luan J., Scott RA., Zhao JH., Mentch FD., MacKenzie SM., Reynolds RM., Early Growth Genetics (EGG) Consortium None., Lowe WL., Tönjes A., Stumvoll M., Lindi V., Lakka TA., van Duijn CM., Kiess W., Körner A., Sørensen TI., Niinikoski H., Pahkala K., Raitakari OT., Zeggini E., Dedoussis GV., Teo Y-Y., Saw S-M., Melbye M., Campbell H., Wilson JF., Vrijheid M., de Geus EJ., Boomsma DI., Kadarmideen HN., Kadarmideen HN., Holm J-C., Hansen T., Sebert S., Hattersley AT., Beilin LJ., Newnham JP., Newnham JP., Pennell CE., Heinrich J., Adair LS., Borja JB., Mohlke KL., Eriksson JG., Widén EE., Kähönen M., Viikari JS., Lehtimäki T., Vollenweider P., Bønnelykke K., Bisgaard H., Mook-Kanamori DO., Hofman A., Rivadeneira F., Uitterlinden AG., Pisinger C., Pedersen O., Power C., Hyppönen E., Wareham NJ., Hakonarson H., Davies E., Walker BR., Jaddoe VW., Jarvelin M-R., Grant SF., Vaag AA., Lawlor DA., Frayling TM., Frayling TM., Davey Smith G., Morris AP., Ong KK., Felix JF., Timpson NJ., Perry JR., Evans DM., McCarthy MI., McCarthy MI., Freathy RM.
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.