Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight

William D Thompson; Robin N Beaumont; Alan Kuang; Nicole M Warrington; Yingjie Ji; Jessica Tyrrell; Andrew R Wood; Denise M Scholtens; Bridget A Knight; David M Evans; William L Lowe Jr; Gillian Santorelli; Raq Azad; Dan Mason; Andrew T Hattersley; Timothy M Frayling; Hanieh Yaghootkar; Maria Carolina Borges; Deborah A Lawlor; Rachel M Freathy

doi:10.1093/hmg/ddab356

Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight

William D Thompson
, Robin N Beaumont
, Alan Kuang
, Nicole M Warrington
, Yingjie Ji
, Jessica Tyrrell
, Andrew R Wood
, Denise M Scholtens
, Bridget A Knight
, David M Evans
, William L Lowe Jr
, Gillian Santorelli
, Raq Azad
, Dan Mason
, Andrew T Hattersley
, Timothy M Frayling
, Hanieh Yaghootkar
, Maria Carolina Borges
, Deborah A Lawlor
, Rachel M Freathy^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

6 Citations (Scopus)

Abstract

Background
Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown.

Aim
We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI.

Methods
We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association.

Results
Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1–5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0–1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = −0.0019, P = 0.602).

Conclusions
Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

Original language	English
Pages (from-to)	1762-1775
Number of pages	14
Journal	Human Molecular Genetics
Volume	31
Issue number	11
Early online date	13 Dec 2021
DOIs	https://doi.org/10.1093/hmg/ddab356
Publication status	Published - 1 Jun 2022

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Thompson, W. D., Beaumont, R. N., Kuang, A., Warrington, N. M., Ji, Y., Tyrrell, J., Wood, A. R., Scholtens, D. M., Knight, B. A., Evans, D. M., Jr, W. L. L., Santorelli, G., Azad, R., Mason, D., Hattersley, A. T., Frayling, T. M., Yaghootkar, H., Borges, M. C., Lawlor, D. A., & Freathy, R. M. (2022). Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight. Human Molecular Genetics, 31(11), 1762-1775. https://doi.org/10.1093/hmg/ddab356

@article{3aec46f445604688959977523ff231b8,

title = "Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight",

abstract = "Background Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. Aim We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. Methods We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. Results Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95\% CI: 1{\textendash}5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95\% CI: 0{\textendash}1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = −0.0019, P = 0.602). Conclusions Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.",

author = "Thompson, \{William D\} and Beaumont, \{Robin N\} and Alan Kuang and Warrington, \{Nicole M\} and Yingjie Ji and Jessica Tyrrell and Wood, \{Andrew R\} and Scholtens, \{Denise M\} and Knight, \{Bridget A\} and Evans, \{David M\} and Jr, \{William L Lowe\} and Gillian Santorelli and Raq Azad and Dan Mason and Hattersley, \{Andrew T\} and Frayling, \{Timothy M\} and Hanieh Yaghootkar and Borges, \{Maria Carolina\} and Lawlor, \{Deborah A\} and Freathy, \{Rachel M\}",

year = "2022",

month = jun,

day = "1",

doi = "10.1093/hmg/ddab356",

language = "English",

volume = "31",

pages = "1762--1775",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "11",

}

Thompson, WD, Beaumont, RN, Kuang, A, Warrington, NM, Ji, Y, Tyrrell, J, Wood, AR, Scholtens, DM, Knight, BA, Evans, DM, Jr, WLL, Santorelli, G, Azad, R, Mason, D, Hattersley, AT, Frayling, TM, Yaghootkar, H, Borges, MC , Lawlor, DA & Freathy, RM 2022, 'Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight', Human Molecular Genetics, vol. 31, no. 11, pp. 1762-1775. https://doi.org/10.1093/hmg/ddab356

TY - JOUR

T1 - Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight

AU - Thompson, William D

AU - Beaumont, Robin N

AU - Kuang, Alan

AU - Warrington, Nicole M

AU - Ji, Yingjie

AU - Tyrrell, Jessica

AU - Wood, Andrew R

AU - Scholtens, Denise M

AU - Knight, Bridget A

AU - Evans, David M

AU - Jr, William L Lowe

AU - Santorelli, Gillian

AU - Azad, Raq

AU - Mason, Dan

AU - Hattersley, Andrew T

AU - Frayling, Timothy M

AU - Yaghootkar, Hanieh

AU - Borges, Maria Carolina

AU - Lawlor, Deborah A

AU - Freathy, Rachel M

PY - 2022/6/1

Y1 - 2022/6/1

N2 - Background Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. Aim We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. Methods We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. Results Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1–5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0–1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = −0.0019, P = 0.602). Conclusions Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

AB - Background Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. Aim We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. Methods We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. Results Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1–5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0–1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = −0.0019, P = 0.602). Conclusions Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

UR - https://doi.org/10.1093/hmg/ddab356

U2 - 10.1093/hmg/ddab356

DO - 10.1093/hmg/ddab356

M3 - Article (Academic Journal)

C2 - 34897462

SN - 0964-6906

VL - 31

SP - 1762

EP - 1775

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 11

ER -

Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight

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