Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores.
BMI
Child
DOHaD
Maternal
Mendelian randomisation
Obesity
Offspring
Pregnancy
Journal
BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723
Informations de publication
Date de publication:
01 02 2022
01 02 2022
Historique:
received:
02
08
2021
accepted:
13
12
2021
entrez:
1
2
2022
pubmed:
2
2
2022
medline:
24
3
2022
Statut:
epublish
Résumé
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (P Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Sections du résumé
BACKGROUND
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal.
METHODS
We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs).
RESULTS
MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (P
CONCLUSIONS
Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Identifiants
pubmed: 35101027
doi: 10.1186/s12916-021-02216-w
pii: 10.1186/s12916-021-02216-w
pmc: PMC8805234
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
34Subventions
Organisme : Medical Research Council
ID : MC_UU_00011/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_21038
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_19009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S03658X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N024397/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K501281/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15018
Pays : United Kingdom
Organisme : NIH HHS
ID : R01 DK10324
Pays : United States
Organisme : Medical Research Council
ID : MR/M013138/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : 102215/2/13/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P014054/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G9815508
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/F/20/90003
Pays : United Kingdom
Organisme : British Heart Foundation
ID : AA/18/7/34219
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600705
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102215/2/13/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT101597MA
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12013/4
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S019669/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT088806
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M013138/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CS/16/4/32482
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Epidemiology. 2014 Nov;25(6):877-85
pubmed: 25166881
Ann Hum Biol. 2011 Jan;38(1):7-11
pubmed: 21175302
Lancet. 2018 May 5;391(10132):1842-1852
pubmed: 29673874
Epidemiology. 2013 May;24(3):370-4
pubmed: 23549180
Am J Epidemiol. 2011 Nov 15;174(10):1159-65
pubmed: 21984656
JAMA. 2016 Mar 15;315(11):1129-40
pubmed: 26978208
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
PLoS Med. 2015 Aug 18;12(8):e1001865
pubmed: 26284790
Aust N Z J Public Health. 2016 Dec;40(6):572-578
pubmed: 27624991
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
PLoS Med. 2020 Aug 25;17(8):e1003305
pubmed: 32841251
PLoS Med. 2008 Mar 11;5(3):e33
pubmed: 18336062
Nutrients. 2018 Dec 12;10(12):
pubmed: 30545102
Science. 2007 May 11;316(5826):889-94
pubmed: 17434869
Science. 2018 Jan 26;359(6374):424-428
pubmed: 29371463
Gigascience. 2019 Jul 1;8(7):
pubmed: 31307061
Best Pract Res Clin Endocrinol Metab. 2012 Oct;26(5):627-39
pubmed: 22980045
Hum Genet. 2020 Jan;139(1):121-136
pubmed: 31134333
Bioinformatics. 2015 May 1;31(9):1466-8
pubmed: 25550326
Hum Mol Genet. 2018 Oct 15;27(20):3641-3649
pubmed: 30124842
Int J Epidemiol. 2003 Feb;32(1):1-22
pubmed: 12689998
Circulation. 2011 Jan 25;123(3):258-65
pubmed: 21220735
Diabetes. 2018 Nov;67(11):2137-2151
pubmed: 30348820
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Nat Genet. 2010 Nov;42(11):937-48
pubmed: 20935630
Int J Epidemiol. 2016 Dec 1;45(6):1866-1886
pubmed: 28108528
Nat Genet. 2018 Jul;50(7):906-908
pubmed: 29892013
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
BMJ. 2010 Nov 25;341:c6224
pubmed: 21109577
Bioinformatics. 2016 Jan 15;32(2):283-5
pubmed: 26395773
JAMA. 2021 Oct 26;326(16):1614-1621
pubmed: 34698778
PLoS Genet. 2013 Oct;9(10):e1003919
pubmed: 24204319
PLoS Genet. 2013 Mar;9(3):e1003348
pubmed: 23555274
Int J Epidemiol. 2013 Oct;42(5):1497-501
pubmed: 24159078
Genome Biol. 2017 May 16;18(1):86
pubmed: 28506277
Nat Rev Endocrinol. 2019 Aug;15(8):456-478
pubmed: 31270440
Nat Genet. 2014 Feb;46(2):100-6
pubmed: 24473328
Stat Methods Med Res. 2017 Oct;26(5):2333-2355
pubmed: 26282889
Int J Epidemiol. 2013 Feb;42(1):111-27
pubmed: 22507743
BMJ. 2013 Aug 13;347:f4539
pubmed: 23943697
Wellcome Open Res. 2017 Feb 14;2:11
pubmed: 28405635
Genet Epidemiol. 2020 Jun;44(4):395-399
pubmed: 32220115
Int J Epidemiol. 2015 Aug;44(4):1288-304
pubmed: 25855720
Surg Obes Relat Dis. 2012 Jul-Aug;8(4):387-91
pubmed: 22093379
Pediatrics. 2006 Dec;118(6):e1644-9
pubmed: 17142494
PLoS Med. 2017 Aug 22;14(8):e1002376
pubmed: 28829768
Int J Epidemiol. 2020 Feb 1;49(1):233-243
pubmed: 31074781
PLoS Genet. 2014 Apr 17;10(4):e1004234
pubmed: 24743097
Sci Rep. 2020 Mar 16;10(1):4806
pubmed: 32179833
Int J Epidemiol. 2011 Jun;40(3):755-64
pubmed: 21414999
Int J Epidemiol. 2015 Apr;44(2):512-25
pubmed: 26050253
PLoS Med. 2019 Feb 11;16(2):e1002744
pubmed: 30742624
Am J Hum Genet. 2011 Jan 7;88(1):76-82
pubmed: 21167468
Lancet Diabetes Endocrinol. 2017 Jan;5(1):53-64
pubmed: 27743978
Int J Epidemiol. 2013 Feb;42(1):97-110
pubmed: 22507742
J Clin Endocrinol Metab. 2009 Nov;94(11):4275-83
pubmed: 19820018
Am J Clin Nutr. 2016 Aug;104(2):389-96
pubmed: 27413126
Diabetologia. 2019 Aug;62(8):1412-1419
pubmed: 31214738
Stat Med. 2008 Apr 15;27(8):1133-63
pubmed: 17886233
Ann Nutr Metab. 2013;63(1-2):32-41
pubmed: 23887153
Lancet. 2002 Aug 10;360(9331):473-82
pubmed: 12241736
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
PLoS Med. 2017 Jan 24;14(1):e1002221
pubmed: 28118352
Nature. 2007 Oct 18;449(7164):851-61
pubmed: 17943122
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Int J Epidemiol. 2013 Feb;42(1):7-29
pubmed: 23508404
Diabetologia. 2018 Jan;61(1):242-252
pubmed: 29064033
Hypertension. 2014 Apr;63(4):683-91
pubmed: 24379180
Ann Epidemiol. 2007 Jul;17(7):511-3
pubmed: 17466535
Int J Epidemiol. 2016 Dec 1;45(6):1895-1903
pubmed: 28204514
Am J Hum Genet. 2008 Jul;83(1):132-5; author reply 135-9
pubmed: 18606306
Circulation. 2007 Jul 3;116(1):39-48
pubmed: 17576866
Nat Genet. 2016 Nov;48(11):1443-1448
pubmed: 27694958
Acta Paediatr. 2010 Apr;99(4):563-8
pubmed: 20064135
PLoS Med. 2019 Jun 11;16(6):e1002817
pubmed: 31185012
Am J Hum Genet. 2015 Oct 1;97(4):576-92
pubmed: 26430803
PLoS Med. 2015 Mar 31;12(3):e1001779
pubmed: 25826379
Am J Epidemiol. 2012 Jul 15;176(2):83-92
pubmed: 22771730
Int J Epidemiol. 2013 Aug;42(4):978-91
pubmed: 23064411
Am J Hum Genet. 2016 Mar 3;98(3):456-472
pubmed: 26924531
PLoS One. 2013 Dec 12;8(12):e82247
pubmed: 24349234
Nat Commun. 2015 Sep 14;6:8111
pubmed: 26368830
Nat Methods. 2013 Jan;10(1):5-6
pubmed: 23269371
Bioinformatics. 2015 Apr 15;31(8):1334-6
pubmed: 25431330
Genet Epidemiol. 2017 Sep;41(6):469-480
pubmed: 28480976
Nat Protoc. 2020 Sep;15(9):2759-2772
pubmed: 32709988
Cell. 2019 Apr 18;177(3):587-596.e9
pubmed: 31002795
Nat Rev Genet. 2013 Jul;14(7):507-15
pubmed: 23774735
Hum Mol Genet. 2009 Sep 15;18(18):3525-31
pubmed: 19553258
Hum Mol Genet. 2018 Aug 1;27(R2):R195-R208
pubmed: 29771313
Nature. 2015 Feb 12;518(7538):197-206
pubmed: 25673413