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; Tarun Veer Singh Ahluwalia; Eskil Kreiner; Rico Rueedi; Leo-Pekka Lyytikäinen; Diana L Cousminer; Ying Wu; Elisabeth Thiering; Carol 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; Emil V. R. Appel; Johannes Waage; Thorkild I A Sørensen; Mads Melbye; Haja N Kadarmideen; Jens-Christian Holm; Torben Hansen; Klaus Bønnelykke; Hans Bisgaard; Charlotta Pisinger; Oluf Pedersen; Allan A Vaag; CHARGE Consortium Hematology Working Group

doi:10.1038/nature19806

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, Tarun Veer Singh Ahluwalia, Eskil Kreiner, Rico Rueedi, Leo-Pekka Lyytikäinen, 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, Emil V. R. Appel, Johannes Waage, Thorkild I A Sørensen, Mads Melbye, Haja N Kadarmideen, Jens-Christian Holm, Torben Hansen, Klaus Bønnelykke, Hans Bisgaard, Charlotta Pisinger, Oluf Pedersen, Allan A Vaag, CHARGE Consortium Hematology Working Group

194 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 (R_g =-0.22, P = 5.5 × 10^-13), T2D (R_g =-0.27, P = 1.1 × 10^-6) and coronary artery disease (R_g =-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 language	English
Journal	Nature
Volume	538
Pages (from-to)	248-252
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature19806
Publication status	Published - 28 Sept 2016

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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. V. S., Kreiner, E., Rueedi, R., Lyytikäinen, L-P., Cousminer, D. L., Wu, Y., ... CHARGE Consortium Hematology Working Group (2016). Genome-wide associations for birth weight and correlations with adult disease. Nature, 538, 248-252. https://doi.org/10.1038/nature19806

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, TVS, 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, Appel, EVR, Waage, J, Sørensen, TIA , Melbye, M , Kadarmideen, HN , Holm, J-C , Hansen, T , Bønnelykke, K, Bisgaard, H, Pisinger, C, Pedersen, O , Vaag, AA & CHARGE Consortium Hematology Working Group 2016, 'Genome-wide associations for birth weight and correlations with adult disease', Nature, vol. 538, pp. 248-252. https://doi.org/10.1038/nature19806

@article{42769b1e80e0434486c7eb8f68bfd04e,

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, {Tarun Veer Singh} and Eskil Kreiner and Rico Rueedi and Leo-Pekka Lyytik{\"a}inen and Cousminer, {Diana L} and Ying Wu and Elisabeth Thiering and Wang, {Carol A} and Have, {Christian T} and Jouke-Jan Hottenga 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 Appel, {Emil V. R.} and Johannes Waage and S{\o}rensen, {Thorkild I A} and Mads Melbye and Kadarmideen, {Haja N} and Jens-Christian Holm and Torben Hansen and Klaus B{\o}nnelykke and Hans Bisgaard and Charlotta Pisinger and Oluf Pedersen and Vaag, {Allan A} and {CHARGE Consortium Hematology Working Group}",

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doi = "10.1038/nature19806",

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volume = "538",

pages = "248--252",

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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 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.

U2 - 10.1038/nature19806

DO - 10.1038/nature19806

M3 - Letter

C2 - 27680694

SN - 0028-0836

VL - 538

SP - 248

EP - 252

JO - Nature

JF - Nature

ER -

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

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