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

Momoko Horikoshi; Robin Beaumont; Felix Day; Nicole  Warrington; Marjolein Kooijman; et. al., on behalf of the Early Growth Genetics (ECG) Consortium; Susan M Ring; Gibran Hemani; George McMahon; Thorkild Sorensen; Debbie A Lawlor; George Davey Smith; Nicholas John Timpson; David Evans; Rachel M Freathy; Lavinia Paternoster

doi:10.1038/nature19806

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

Momoko Horikoshi, Robin Beaumont, Felix Day, Nicole Warrington, Marjolein Kooijman, et. al., on behalf of the Early Growth Genetics (ECG) Consortium, Susan M Ring, Gibran Hemani, George McMahon, Thorkild Sorensen, Debbie A Lawlor, George Davey Smith, Nicholas John Timpson, David Evans, Rachel M Freathy, Lavinia Paternoster

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Abstract

Birth weight (BW) is influenced by both foetal 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 lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P<5x10^-8). Overall, ~15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (r_g=-0.22, P=5.5x10^-13), T2D (r_g=-0.27, P=1.1x10^-6) and coronary artery disease (r_g=-0.30, P=6.5x10^-9) and, in large cohort data sets, 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=1.9x10^-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.

Original language	English
Pages (from-to)	248-252
Number of pages	5
Journal	Nature
Volume	538
Issue number	7624
Early online date	28 Sept 2016
DOIs	https://doi.org/10.1038/nature19806
Publication status	Published - 13 Oct 2016

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MRC UoB UNITE Unit - programme 3
Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
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MRC UoB UNITE Unit - Programme 5
Lawlor, D. A. (Principal Investigator) & Lawlor, D. A. (Principal Investigator)
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Project: Research

Professor Gibran Hemani
- g.hemanibristol.acuk
- Bristol Medical School (PHS) - Professor in Statistical Genetics
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
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Professor Nicholas John Timpson
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- Bristol Medical School (PHS) - Professor of Genetic Epidemiology
- Bristol Population Health Science Institute
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Horikoshi, M., Beaumont, R., Day, F., Warrington, N., Kooijman, M., et. al., on behalf of the Early Growth Genetics (ECG) Consortium, Ring, S. M., Hemani, G., McMahon, G., Sorensen, T., Lawlor, D. A., Davey Smith, G., Timpson, N. J., Evans, D., Freathy, R. M., & Paternoster, L. (2016). Genome-wide associations for birth weight and correlations with adult disease. Nature, 538(7624), 248-252. https://doi.org/10.1038/nature19806

@article{ff1013e790d14cfc9a57a70ea9b8cbdd,

title = "Genome-wide associations for birth weight and correlations with adult disease",

abstract = "Birth weight (BW) is influenced by both foetal 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 lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P<5x10-8). Overall, ~15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P=5.5x10-13), T2D (rg=-0.27, P=1.1x10-6) and coronary artery disease (rg=-0.30, P=6.5x10-9) and, in large cohort data sets, 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=1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.",

author = "Momoko Horikoshi and Robin Beaumont and Felix Day and Nicole Warrington and Marjolein Kooijman and {et. al., on behalf of the Early Growth Genetics (ECG) Consortium} and Ring, {Susan M} and Gibran Hemani and George McMahon and Thorkild Sorensen and Lawlor, {Debbie A} and {Davey Smith}, George and Timpson, {Nicholas John} and David Evans and Freathy, {Rachel M} and Lavinia Paternoster",

year = "2016",

month = oct,

day = "13",

doi = "10.1038/nature19806",

language = "English",

volume = "538",

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journal = "Nature",

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Horikoshi, M, Beaumont, R, Day, F, Warrington, N, Kooijman, M, et. al., on behalf of the Early Growth Genetics (ECG) Consortium, Ring, SM , Hemani, G, McMahon, G, Sorensen, T, Lawlor, DA , Davey Smith, G , Timpson, NJ, Evans, D, Freathy, RM & Paternoster, L 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

TY - JOUR

T1 - Genome-wide associations for birth weight and correlations with adult disease

AU - Horikoshi, Momoko

AU - Beaumont, Robin

AU - Day, Felix

AU - Warrington, Nicole

AU - Kooijman, Marjolein

AU - et. al., on behalf of the Early Growth Genetics (ECG) Consortium

AU - Ring, Susan M

AU - Hemani, Gibran

AU - McMahon, George

AU - Sorensen, Thorkild

AU - Lawlor, Debbie A

AU - Davey Smith, George

AU - Timpson, Nicholas John

AU - Evans, David

AU - Freathy, Rachel M

AU - Paternoster, Lavinia

PY - 2016/10/13

Y1 - 2016/10/13

N2 - Birth weight (BW) is influenced by both foetal 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 lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P<5x10-8). Overall, ~15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P=5.5x10-13), T2D (rg=-0.27, P=1.1x10-6) and coronary artery disease (rg=-0.30, P=6.5x10-9) and, in large cohort data sets, 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=1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.

AB - Birth weight (BW) is influenced by both foetal 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 lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P<5x10-8). Overall, ~15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P=5.5x10-13), T2D (rg=-0.27, P=1.1x10-6) and coronary artery disease (rg=-0.30, P=6.5x10-9) and, in large cohort data sets, 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=1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.

U2 - 10.1038/nature19806

DO - 10.1038/nature19806

M3 - Article (Academic Journal)

C2 - 27680694

SN - 0028-0836

VL - 538

SP - 248

EP - 252

JO - Nature

JF - Nature

IS - 7624

ER -

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

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MRC UoB UNITE Unit - programme 3

MRC UoB UNITE Unit - Programme 1

MRC UoB UNITE Unit - Programme 5

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Professor Gibran Hemani

Professor Nicholas John Timpson

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