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

Horikoshi, M. et al. (2016) Genome-wide associations for birth weight and correlations with adult disease. Nature, 538(7624), pp. 248-252. (doi: 10.1038/nature19806) (PMID:27680694) (PMCID:PMC5164934)

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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 disease1. 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.

Item Type:Articles (Letter)
Glasgow Author(s) Enlighten ID:Diver, Miss Louise and Davies, Professor Eleanor and MacKenzie, Dr Scott
Authors: Horikoshi, M., Beaumont, R. N., Day, F. R., Warrington, N. M., Kooijman, M. N., Fernandez-Tajes, J., Feenstra, B., van Zuydam, N. R., Gaulton, K. J., Grarup, N., Bradfield, J. P., Strachan, D. P., Li-Gao, R., Ahluwalia, T. S., Kreiner, E., Rueedi, R., Lyytikäinen, L.-P., Cousminer, D. L., Wu, Y., Thiering, E., Wang, C. A., Have, C. T., Hottenga, J.-J., Vilor-Tejedor, N., Joshi, P. K., Boh, E. T. H., Ntalla, I., Pitkänen, N., Mahajan, A., van Leeuwen, E. M., Joro, R., Lagou, V., Nodzenski, M., Diver, L. A., Zondervan, K. T., Bustamante, M., Marques-Vidal, P., Mercader, J. M., Bennett, A. J., Rahmioglu, N., Nyholt, D. R., Ma, R. C. W., Tam, C. H. T., Tam, W. H., Ganesh, S. K., van Rooij, F. J. A., Jones, S. E., Loh, P.-R., Ruth, K. S., Tuke, M. A., Tyrrell, J., Wood, A. R., Yaghootkar, H., Scholtens, D. M., Paternoster, L., Prokopenko, I., Kovacs, P., Atalay, M., Willems, S. M., Panoutsopoulou, K., Wang, X., Carstensen, L., Geller, F., Schraut, K. E., Murcia, M., van Beijsterveldt, C. E. M., Willemsen, G., Appel, E. V. R., Fonvig, C. E., Trier, C., Tiesler, C. M. T., Standl, M., Kutalik, Z., Bonàs-Guarch, S., Hougaard, D. M., Sánchez, F., Torrents, D., Waage, J., Hollegaard, M. V., de Haan, H. G., Rosendaal, F. R., Medina-Gomez, C., Ring, S. M., Hemani, G., McMahon, G., Robertson, N. R., Groves, C. J., Langenberg, C., Luan, J.’a., Scott, R. A., Zhao, J. H., Mentch, F. D., MacKenzie, S. M., Reynolds, R. M., Lowe, W. L., Tönjes, A., Stumvoll, M., Lindi, V., Lakka, T. A., van Duijn, C. M., Kiess, W., Körner, A., Sørensen, T. I. A., Niinikoski, H., Pahkala, K., Raitakari, O. T., Zeggini, E., Dedoussis, G. V., Teo, Y.-Y., Saw, S.-M., Melbye, M., Campbell, H., Wilson, J. F., Vrijheid, M., de Geus, E. J. C. N., Boomsma, D. I., Kadarmideen, H. N., Holm, J.-C., Hansen, T., Sebert, S., Hattersley, A. T., Beilin, L. J., Newnham, J. P., Pennell, C. E., Heinrich, J., Adair, L. S., Borja, J. B., Mohlke, K. L., Eriksson, J. G., Widén, E., Kähönen, M., Viikari, J. S., Lehtimäki, T., Vollenweider, P., Bønnelykke, K., Bisgaard, H., Mook-Kanamori, D. O., Hofman, A., Rivadeneira, F., Uitterlinden, A. G., Pisinger, C., Pedersen, O., Power, C., Hyppönen, E., Wareham, N. J., Hakonarson, H., Davies, E., Walker, B. R., Jaddoe, V. W. V., Järvelin, M.-R., Grant, S. F. A., Vaag, A. A., Lawlor, D. A., Frayling, T. M., Smith, G. D., Morris, A. P., Ong, K. K., Felix, J. F., Timpson, N. J., Perry, J. R. B., Evans, D. M., McCarthy, M. I., and Freathy, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN (Online):1476-4687
Published Online:28 September 2016
Copyright Holders:Copyright © 2016 Macmillan Publishers
First Published:First published in Nature 538(7624):248-252
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
518771Doctoral Training Grant 2009-13Mary GoodmanMedical Research Council (MRC)G0900185-1/1VICE PRINCIPAL RESEARCH & ENTERPRISE