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

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, Tarunveer S. Ahluwalia, Eskil Kreiner, Rico Rueedi, Leo Pekka Lyytikaïnen, Diana L. Cousminer, Ying Wu, Elisabeth ThieringCarol 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, Amanda J. Bennett, Nilufer Rahmioglu, Dale R. Nyholt, Ronald C.W. Ma, Claudia H.T. Tam, Wing Hung Tam, Santhi K. Ganesh, Frank J.A. Van Rooij, Samuel E. Jones, Po Ru Loh, Katherine S. Ruth, Marcus A. Tuke, Jessica Tyrrell, Andrew R. Wood, Hanieh Yaghootkar, Denise M Scholtens, Lavinia Paternoster, Inga Prokopenko, Peter Kovacs, Mustafa Atalay, Sara M. Willems, Kalliope Panoutsopoulou, Xu Wang, Lisbeth Carstensen, Frank Geller, Katharina E. Schraut, Mario Murcia, Catharina E.M. Van Beijsterveldt, Gonneke Willemsen, Emil V.R. Appel, Cilius E. Fonvig, Caecilie Trier, Carla M.T. Tiesler, Marie Standl, Zoltán Kutalik, Sílvia Bonàs-Guarch, David M. Hougaard, Friman Sánchez, David Torrents, Johannes Waage, Mads V. Hollegaard, Hugoline G. De Haan, Frits R. Rosendaal, Carolina Medina-Gomez, Susan M. Ring, Gibran Hemani, George McMahon, Neil R. Robertson, Christopher J. Groves, Claudia Langenberg, Jian'An Luan, Robert A. Scott, Jing Hua Zhao, Frank D. Mentch, Scott M. MacKenzie, Rebecca M. Reynolds, William L Lowe Jr, Anke Tönjes, Michael Stumvoll, Virpi Lindi, Timo A. Lakka, Cornelia M. Van Duijn, Wieland Kiess, Antje Körner, Thorkild I.A. Sørensen, Harri Niinikoski, Katja Pahkala, Olli T. Raitakari, Eleftheria Zeggini, George V. Dedoussis, Yik Ying Teo, Seang Mei Saw, Mads Melbye, Harry Campbell, James F. Wilson, Martine Vrijheid, Eco J.C.N. De Geus, Dorret I. Boomsma, Haja N. Kadarmideen, Jens Christian Holm, Torben Hansen, Sylvain Sebert, Andrew T. Hattersley, Lawrence J. Beilin, John P. Newnham, Craig E. Pennell, Joachim Heinrich, Linda S. Adair, Judith B. Borja, Karen L. Mohlke, Johan G. Eriksson, Elisabeth Widén, Mika Kähönen, Jorma S. Viikari, Terho Lehtimäki, Peter Vollenweider, Klaus Bønnelykke, Hans Bisgaard, Dennis O. Mook-Kanamori, Albert Hofman, Fernando Rivadeneira, André G. Uitterlinden, Charlotta Pisinger, Oluf Pedersen, Christine Power, Elina Hyppönen, Nicholas J. Wareham, Hakon Hakonarson, Eleanor Davies, Brian R. Walker, Vincent W.V. Jaddoe, Marjo Riitta Järvelin, Struan F.A. Grant, Allan A. Vaag, Debbie A. Lawlor, Timothy M. Frayling, George Davey Smith, Andrew P. Morris, Ken K. Ong, Janine F. Felix, Nicholas J. Timpson, John R.B. Perry, David M. Evans, Mark I. McCarthy*, Rachel M. Freathy

*Corresponding author for this work

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

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 lifecourse 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 (US)
Pages (from-to)248-252
Number of pages5
JournalNature
Volume538
Issue number7624
DOIs
StatePublished - Jan 1 2016

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Birth Weight
Genome
Type 2 Diabetes Mellitus
Blood Pressure
Chromatin Assembly and Disassembly
Genome-Wide Association Study
Metabolic Diseases
Glycogen
Observational Studies
Meta-Analysis
Coronary Artery Disease
Homeostasis
Genotype
Mothers
Insulin
Phenotype
Glucose
Growth
Proteins

ASJC Scopus subject areas

  • General

Cite this

Horikoshi, M., Beaumont, R. N., Day, F. R., Warrington, N. M., Kooijman, M. N., Fernandez-Tajes, J., ... Freathy, R. M. (2016). Genome-wide associations for birth weight and correlations with adult disease. Nature, 538(7624), 248-252. https://doi.org/10.1038/nature19806
Horikoshi, Momoko ; Beaumont, Robin N. ; Day, Felix R. ; Warrington, Nicole M. ; Kooijman, Marjolein N. ; Fernandez-Tajes, Juan ; Feenstra, Bjarke ; Van Zuydam, Natalie R. ; Gaulton, Kyle J. ; Grarup, Niels ; Bradfield, Jonathan P. ; Strachan, David P. ; Li-Gao, Ruifang ; Ahluwalia, Tarunveer S. ; Kreiner, Eskil ; Rueedi, Rico ; Lyytikaïnen, Leo Pekka ; Cousminer, Diana L. ; Wu, Ying ; Thiering, Elisabeth ; Wang, Carol A. ; Have, Christian T. ; Hottenga, Jouke Jan ; Vilor-Tejedor, Natalia ; Joshi, Peter K. ; Boh, Eileen Tai Hui ; Ntalla, Ioanna ; Pitkänen, Niina ; Mahajan, Anubha ; Van Leeuwen, Elisabeth M. ; Joro, Raimo ; Lagou, Vasiliki ; Nodzenski, Michael ; Diver, Louise A. ; Zondervan, Krina T. ; Bustamante, Mariona ; Marques-Vidal, Pedro ; Mercader, Josep M. ; Bennett, Amanda J. ; Rahmioglu, Nilufer ; Nyholt, Dale R. ; Ma, Ronald C.W. ; Tam, Claudia H.T. ; Tam, Wing Hung ; Ganesh, Santhi K. ; Van Rooij, Frank J.A. ; Jones, Samuel E. ; Loh, Po Ru ; Ruth, Katherine S. ; Tuke, Marcus A. ; Tyrrell, Jessica ; Wood, Andrew R. ; Yaghootkar, Hanieh ; Scholtens, Denise M ; Paternoster, Lavinia ; Prokopenko, Inga ; Kovacs, Peter ; Atalay, Mustafa ; Willems, Sara M. ; Panoutsopoulou, Kalliope ; Wang, Xu ; Carstensen, Lisbeth ; Geller, Frank ; Schraut, Katharina E. ; Murcia, Mario ; Van Beijsterveldt, Catharina E.M. ; Willemsen, Gonneke ; Appel, Emil V.R. ; Fonvig, Cilius E. ; Trier, Caecilie ; Tiesler, Carla M.T. ; Standl, Marie ; Kutalik, Zoltán ; Bonàs-Guarch, Sílvia ; Hougaard, David M. ; Sánchez, Friman ; Torrents, David ; Waage, Johannes ; Hollegaard, Mads V. ; De Haan, Hugoline G. ; Rosendaal, Frits R. ; Medina-Gomez, Carolina ; Ring, Susan M. ; Hemani, Gibran ; McMahon, George ; Robertson, Neil R. ; Groves, Christopher J. ; Langenberg, Claudia ; Luan, Jian'An ; Scott, Robert A. ; Zhao, Jing Hua ; Mentch, Frank D. ; MacKenzie, Scott M. ; Reynolds, Rebecca M. ; Lowe Jr, William L ; Tönjes, Anke ; Stumvoll, Michael ; Lindi, Virpi ; Lakka, Timo A. ; Van Duijn, Cornelia M. ; Kiess, Wieland ; Körner, Antje ; Sørensen, Thorkild I.A. ; Niinikoski, Harri ; Pahkala, Katja ; Raitakari, Olli T. ; Zeggini, Eleftheria ; Dedoussis, George V. ; Teo, Yik Ying ; Saw, Seang Mei ; Melbye, Mads ; Campbell, Harry ; Wilson, James F. ; Vrijheid, Martine ; De Geus, Eco J.C.N. ; Boomsma, Dorret I. ; Kadarmideen, Haja N. ; Holm, Jens Christian ; Hansen, Torben ; Sebert, Sylvain ; Hattersley, Andrew T. ; Beilin, Lawrence J. ; Newnham, John P. ; Pennell, Craig E. ; Heinrich, Joachim ; Adair, Linda S. ; Borja, Judith B. ; Mohlke, Karen L. ; Eriksson, Johan G. ; Widén, Elisabeth ; Kähönen, Mika ; Viikari, Jorma S. ; Lehtimäki, Terho ; Vollenweider, Peter ; Bønnelykke, Klaus ; Bisgaard, Hans ; Mook-Kanamori, Dennis O. ; Hofman, Albert ; Rivadeneira, Fernando ; Uitterlinden, André G. ; Pisinger, Charlotta ; Pedersen, Oluf ; Power, Christine ; Hyppönen, Elina ; Wareham, Nicholas J. ; Hakonarson, Hakon ; Davies, Eleanor ; Walker, Brian R. ; Jaddoe, Vincent W.V. ; Järvelin, Marjo Riitta ; Grant, Struan F.A. ; Vaag, Allan A. ; Lawlor, Debbie A. ; Frayling, Timothy M. ; Smith, George Davey ; Morris, Andrew P. ; Ong, Ken K. ; Felix, Janine F. ; Timpson, Nicholas J. ; Perry, John R.B. ; Evans, David M. ; McCarthy, Mark I. ; Freathy, Rachel M. / Genome-wide associations for birth weight and correlations with adult disease. In: Nature. 2016 ; Vol. 538, No. 7624. pp. 248-252.
@article{2b00061025a04deb9800b3f9d2636115,
title = "Genome-wide associations for birth weight and correlations with adult disease",
abstract = "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 lifecourse 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.",
author = "Momoko Horikoshi and Beaumont, {Robin N.} and Day, {Felix R.} and Warrington, {Nicole M.} and Kooijman, {Marjolein N.} and Juan Fernandez-Tajes and Bjarke Feenstra and {Van Zuydam}, {Natalie R.} and Gaulton, {Kyle J.} and Niels Grarup and Bradfield, {Jonathan P.} and Strachan, {David P.} and Ruifang Li-Gao and Ahluwalia, {Tarunveer S.} and Eskil Kreiner and Rico Rueedi and Lyytika{\"i}nen, {Leo Pekka} and Cousminer, {Diana L.} and Ying Wu and Elisabeth Thiering and Wang, {Carol A.} and Have, {Christian T.} and Hottenga, {Jouke Jan} and Natalia Vilor-Tejedor and Joshi, {Peter K.} and Boh, {Eileen Tai Hui} and Ioanna Ntalla and Niina Pitk{\"a}nen and Anubha Mahajan and {Van Leeuwen}, {Elisabeth M.} and Raimo Joro and Vasiliki Lagou and Michael Nodzenski and Diver, {Louise A.} and Zondervan, {Krina T.} and Mariona Bustamante and Pedro Marques-Vidal and Mercader, {Josep M.} and Bennett, {Amanda J.} and Nilufer Rahmioglu and Nyholt, {Dale R.} and Ma, {Ronald C.W.} and Tam, {Claudia H.T.} and Tam, {Wing Hung} and Ganesh, {Santhi K.} and {Van Rooij}, {Frank J.A.} and Jones, {Samuel E.} and Loh, {Po Ru} and Ruth, {Katherine S.} and Tuke, {Marcus A.} and Jessica Tyrrell and Wood, {Andrew R.} and Hanieh Yaghootkar and Scholtens, {Denise M} and Lavinia Paternoster and Inga Prokopenko and Peter Kovacs and Mustafa Atalay and Willems, {Sara M.} and Kalliope Panoutsopoulou and Xu Wang and Lisbeth Carstensen and Frank Geller and Schraut, {Katharina E.} and Mario Murcia and {Van Beijsterveldt}, {Catharina E.M.} and Gonneke Willemsen and Appel, {Emil V.R.} and Fonvig, {Cilius E.} and Caecilie Trier and Tiesler, {Carla M.T.} and Marie Standl and Zolt{\'a}n Kutalik and S{\'i}lvia Bon{\`a}s-Guarch and Hougaard, {David M.} and Friman S{\'a}nchez and David Torrents and Johannes Waage and Hollegaard, {Mads V.} and {De Haan}, {Hugoline G.} and Rosendaal, {Frits R.} and Carolina Medina-Gomez and Ring, {Susan M.} and Gibran Hemani and George McMahon and Robertson, {Neil R.} and Groves, {Christopher J.} and Claudia Langenberg and Jian'An Luan and Scott, {Robert A.} and Zhao, {Jing Hua} and Mentch, {Frank D.} and MacKenzie, {Scott M.} and Reynolds, {Rebecca M.} and {Lowe Jr}, {William L} and Anke T{\"o}njes and Michael Stumvoll and Virpi Lindi and Lakka, {Timo A.} and {Van Duijn}, {Cornelia M.} and Wieland Kiess and Antje K{\"o}rner and S{\o}rensen, {Thorkild I.A.} and Harri Niinikoski and Katja Pahkala and Raitakari, {Olli T.} and Eleftheria Zeggini and Dedoussis, {George V.} and Teo, {Yik Ying} and Saw, {Seang Mei} and Mads Melbye and Harry Campbell and Wilson, {James F.} and Martine Vrijheid and {De Geus}, {Eco J.C.N.} and Boomsma, {Dorret I.} and Kadarmideen, {Haja N.} and Holm, {Jens Christian} and Torben Hansen and Sylvain Sebert and Hattersley, {Andrew T.} and Beilin, {Lawrence J.} and Newnham, {John P.} and Pennell, {Craig E.} and Joachim Heinrich and Adair, {Linda S.} and Borja, {Judith B.} and Mohlke, {Karen L.} and Eriksson, {Johan G.} and Elisabeth Wid{\'e}n and Mika K{\"a}h{\"o}nen and Viikari, {Jorma S.} and Terho Lehtim{\"a}ki and Peter Vollenweider and Klaus B{\o}nnelykke and Hans Bisgaard and Mook-Kanamori, {Dennis O.} and Albert Hofman and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G.} and Charlotta Pisinger and Oluf Pedersen and Christine Power and Elina Hypp{\"o}nen and Wareham, {Nicholas J.} and Hakon Hakonarson and Eleanor Davies and Walker, {Brian R.} and Jaddoe, {Vincent W.V.} and J{\"a}rvelin, {Marjo Riitta} and Grant, {Struan F.A.} and Vaag, {Allan A.} and Lawlor, {Debbie A.} and Frayling, {Timothy M.} and Smith, {George Davey} and Morris, {Andrew P.} and Ong, {Ken K.} and Felix, {Janine F.} and Timpson, {Nicholas J.} and Perry, {John R.B.} and Evans, {David M.} and McCarthy, {Mark I.} and Freathy, {Rachel M.}",
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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, Lyytikaïnen, LP, Cousminer, DL, Wu, Y, Thiering, E, Wang, CA, Have, CT, Hottenga, JJ, 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, Ganesh, SK, Van Rooij, FJA, Jones, SE, Loh, PR, 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, CEM, Willemsen, G, Appel, EVR, Fonvig, CE, Trier, C, Tiesler, CMT, Standl, M, Kutalik, Z, Bonàs-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, JA, Scott, RA, Zhao, JH, Mentch, FD, MacKenzie, SM, Reynolds, RM, Lowe Jr, WL, Tönjes, A, Stumvoll, M, Lindi, V, Lakka, TA, Van Duijn, CM, Kiess, W, Körner, A, Sørensen, TIA, Niinikoski, H, Pahkala, K, Raitakari, OT, Zeggini, E, Dedoussis, GV, Teo, YY, Saw, SM, Melbye, M, Campbell, H, Wilson, JF, Vrijheid, M, De Geus, EJCN, Boomsma, DI, Kadarmideen, HN, Holm, JC, Hansen, T, Sebert, S, Hattersley, AT, Beilin, LJ, Newnham, JP, Pennell, CE, Heinrich, J, Adair, LS, Borja, JB, Mohlke, KL, Eriksson, JG, Widén, E, 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, VWV, Järvelin, MR, Grant, SFA, Vaag, AA, Lawlor, DA, Frayling, TM, Smith, GD, Morris, AP, Ong, KK, Felix, JF, Timpson, NJ, Perry, JRB, Evans, DM, McCarthy, MI & Freathy, RM 2016, 'Genome-wide associations for birth weight and correlations with adult disease', Nature, vol. 538, no. 7624, pp. 248-252. https://doi.org/10.1038/nature19806

Genome-wide associations for birth weight and correlations with adult disease. / Horikoshi, Momoko; Beaumont, Robin N.; Day, Felix R.; Warrington, Nicole M.; Kooijman, Marjolein N.; Fernandez-Tajes, Juan; Feenstra, Bjarke; Van Zuydam, Natalie R.; Gaulton, Kyle J.; Grarup, Niels; Bradfield, Jonathan P.; Strachan, David P.; Li-Gao, Ruifang; Ahluwalia, Tarunveer S.; Kreiner, Eskil; Rueedi, Rico; Lyytikaïnen, Leo Pekka; Cousminer, Diana L.; Wu, Ying; Thiering, Elisabeth; Wang, Carol A.; Have, Christian T.; Hottenga, Jouke Jan; Vilor-Tejedor, Natalia; Joshi, Peter K.; Boh, Eileen Tai Hui; Ntalla, Ioanna; Pitkänen, Niina; Mahajan, Anubha; Van Leeuwen, Elisabeth M.; Joro, Raimo; Lagou, Vasiliki; Nodzenski, Michael; Diver, Louise A.; Zondervan, Krina T.; Bustamante, Mariona; Marques-Vidal, Pedro; Mercader, Josep M.; Bennett, Amanda J.; Rahmioglu, Nilufer; Nyholt, Dale R.; Ma, Ronald C.W.; Tam, Claudia H.T.; Tam, Wing Hung; Ganesh, Santhi K.; Van Rooij, Frank J.A.; Jones, Samuel E.; Loh, Po Ru; Ruth, Katherine S.; Tuke, Marcus A.; Tyrrell, Jessica; Wood, Andrew R.; Yaghootkar, Hanieh; Scholtens, Denise M; Paternoster, Lavinia; Prokopenko, Inga; Kovacs, Peter; Atalay, Mustafa; Willems, Sara M.; Panoutsopoulou, Kalliope; Wang, Xu; Carstensen, Lisbeth; Geller, Frank; Schraut, Katharina E.; Murcia, Mario; Van Beijsterveldt, Catharina E.M.; Willemsen, Gonneke; Appel, Emil V.R.; Fonvig, Cilius E.; Trier, Caecilie; Tiesler, Carla M.T.; Standl, Marie; Kutalik, Zoltán; Bonàs-Guarch, Sílvia; Hougaard, David M.; Sánchez, Friman; Torrents, David; Waage, Johannes; Hollegaard, Mads V.; De Haan, Hugoline G.; Rosendaal, Frits R.; Medina-Gomez, Carolina; Ring, Susan M.; Hemani, Gibran; McMahon, George; Robertson, Neil R.; Groves, Christopher J.; Langenberg, Claudia; Luan, Jian'An; Scott, Robert A.; Zhao, Jing Hua; Mentch, Frank D.; MacKenzie, Scott M.; Reynolds, Rebecca M.; Lowe Jr, William L; Tönjes, Anke; Stumvoll, Michael; Lindi, Virpi; Lakka, Timo A.; Van Duijn, Cornelia M.; Kiess, Wieland; Körner, Antje; Sørensen, Thorkild I.A.; Niinikoski, Harri; Pahkala, Katja; Raitakari, Olli T.; Zeggini, Eleftheria; Dedoussis, George V.; Teo, Yik Ying; Saw, Seang Mei; Melbye, Mads; Campbell, Harry; Wilson, James F.; Vrijheid, Martine; De Geus, Eco J.C.N.; Boomsma, Dorret I.; Kadarmideen, Haja N.; Holm, Jens Christian; Hansen, Torben; Sebert, Sylvain; Hattersley, Andrew T.; Beilin, Lawrence J.; Newnham, John P.; Pennell, Craig E.; Heinrich, Joachim; Adair, Linda S.; Borja, Judith B.; Mohlke, Karen L.; Eriksson, Johan G.; Widén, Elisabeth; Kähönen, Mika; Viikari, Jorma S.; Lehtimäki, Terho; Vollenweider, Peter; Bønnelykke, Klaus; Bisgaard, Hans; Mook-Kanamori, Dennis O.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G.; Pisinger, Charlotta; Pedersen, Oluf; Power, Christine; Hyppönen, Elina; Wareham, Nicholas J.; Hakonarson, Hakon; Davies, Eleanor; Walker, Brian R.; Jaddoe, Vincent W.V.; Järvelin, Marjo Riitta; Grant, Struan F.A.; Vaag, Allan A.; Lawlor, Debbie A.; Frayling, Timothy M.; Smith, George Davey; Morris, Andrew P.; Ong, Ken K.; Felix, Janine F.; Timpson, Nicholas J.; Perry, John R.B.; Evans, David M.; McCarthy, Mark I.; Freathy, Rachel M.

In: Nature, Vol. 538, No. 7624, 01.01.2016, p. 248-252.

Research output: Contribution to journalArticle

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, Tarunveer S.

AU - Kreiner, Eskil

AU - Rueedi, Rico

AU - Lyytikaïnen, 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 - Bennett, Amanda J.

AU - Rahmioglu, Nilufer

AU - Nyholt, Dale R.

AU - Ma, Ronald C.W.

AU - Tam, Claudia H.T.

AU - Tam, Wing Hung

AU - Ganesh, Santhi K.

AU - Van Rooij, Frank J.A.

AU - Jones, Samuel E.

AU - Loh, Po Ru

AU - Ruth, Katherine S.

AU - Tuke, Marcus A.

AU - Tyrrell, Jessica

AU - Wood, Andrew R.

AU - Yaghootkar, Hanieh

AU - Scholtens, Denise M

AU - Paternoster, Lavinia

AU - Prokopenko, Inga

AU - Kovacs, Peter

AU - Atalay, Mustafa

AU - Willems, Sara M.

AU - Panoutsopoulou, Kalliope

AU - Wang, Xu

AU - Carstensen, Lisbeth

AU - Geller, Frank

AU - Schraut, Katharina E.

AU - Murcia, Mario

AU - Van Beijsterveldt, Catharina E.M.

AU - Willemsen, Gonneke

AU - Appel, Emil V.R.

AU - Fonvig, Cilius E.

AU - Trier, Caecilie

AU - Tiesler, Carla M.T.

AU - Standl, Marie

AU - Kutalik, Zoltán

AU - Bonàs-Guarch, Sílvia

AU - Hougaard, David M.

AU - Sánchez, Friman

AU - Torrents, David

AU - Waage, Johannes

AU - Hollegaard, Mads V.

AU - De Haan, Hugoline G.

AU - Rosendaal, Frits R.

AU - Medina-Gomez, Carolina

AU - Ring, Susan M.

AU - Hemani, Gibran

AU - McMahon, George

AU - Robertson, Neil R.

AU - Groves, Christopher J.

AU - Langenberg, Claudia

AU - Luan, Jian'An

AU - Scott, Robert A.

AU - Zhao, Jing Hua

AU - Mentch, Frank D.

AU - MacKenzie, Scott M.

AU - Reynolds, Rebecca M.

AU - Lowe Jr, William L

AU - Tönjes, Anke

AU - Stumvoll, Michael

AU - Lindi, Virpi

AU - Lakka, Timo A.

AU - Van Duijn, Cornelia M.

AU - Kiess, Wieland

AU - Körner, Antje

AU - Sørensen, Thorkild I.A.

AU - Niinikoski, Harri

AU - Pahkala, Katja

AU - Raitakari, Olli T.

AU - Zeggini, Eleftheria

AU - Dedoussis, George V.

AU - Teo, Yik Ying

AU - Saw, Seang Mei

AU - Melbye, Mads

AU - Campbell, Harry

AU - Wilson, James F.

AU - Vrijheid, Martine

AU - De Geus, Eco J.C.N.

AU - Boomsma, Dorret I.

AU - Kadarmideen, Haja N.

AU - Holm, Jens Christian

AU - Hansen, Torben

AU - Sebert, Sylvain

AU - Hattersley, Andrew T.

AU - Beilin, Lawrence J.

AU - Newnham, John P.

AU - Pennell, Craig E.

AU - Heinrich, Joachim

AU - Adair, Linda S.

AU - Borja, Judith B.

AU - Mohlke, Karen L.

AU - Eriksson, Johan G.

AU - Widén, Elisabeth

AU - Kähönen, Mika

AU - Viikari, Jorma S.

AU - Lehtimäki, Terho

AU - Vollenweider, Peter

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Mook-Kanamori, Dennis O.

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Pisinger, Charlotta

AU - Pedersen, Oluf

AU - Power, Christine

AU - Hyppönen, Elina

AU - Wareham, Nicholas J.

AU - Hakonarson, Hakon

AU - Davies, Eleanor

AU - Walker, Brian R.

AU - Jaddoe, Vincent W.V.

AU - Järvelin, Marjo Riitta

AU - Grant, Struan F.A.

AU - Vaag, Allan A.

AU - Lawlor, Debbie A.

AU - Frayling, Timothy M.

AU - Smith, George Davey

AU - Morris, Andrew P.

AU - Ong, Ken K.

AU - Felix, Janine F.

AU - Timpson, Nicholas J.

AU - Perry, John R.B.

AU - Evans, David M.

AU - McCarthy, Mark I.

AU - Freathy, Rachel M.

PY - 2016/1/1

Y1 - 2016/1/1

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 disease1. These lifecourse 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 disease1. These lifecourse 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.

UR - http://www.scopus.com/inward/record.url?scp=84991665514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991665514&partnerID=8YFLogxK

U2 - 10.1038/nature19806

DO - 10.1038/nature19806

M3 - Article

C2 - 27680694

AN - SCOPUS:84991665514

VL - 538

SP - 248

EP - 252

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7624

ER -

Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J et al. Genome-wide associations for birth weight and correlations with adult disease. Nature. 2016 Jan 1;538(7624):248-252. https://doi.org/10.1038/nature19806