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

Thompson, William E.; Beaumont, Robin N; Kuang, Alan; Warrington, Nicole M.; Ji, Yingjie; Tyrrell, Jess; Wood, Andrew R.; Scholtens, Denise M.; Knight, Bridget; Evans, David M.; Lowe, Bill; Santorelli, Gillian; Azad, Rafaq; Mason, Dan; Hattersley, Andrew T.; Frayling, Timothy M.; Yaghootkar, Hanieh; Borges, Maria-Carolina; Lawlor, Deborah A; Freathy, Rachel M.

doi:10.1093/hmg/ddab356

Cited by 4 publications

(4 citation statements)

References 50 publications

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“…A GWAS analysis concerning birthweight performed by Luo et al [ 23 ] identified a variety of loci in both maternal and fetal genomes potentially affecting this parameter in four populations (Afro-Caribbean, European, Hispanic and Thai). Extensive meta-analyses [ 24 , 25 ], identified a variety of loci where fetal genotype was associated with birthweight and found their associations with height, body-mass index and some metabolic diseases in adulthood.…”

Section: Discussionmentioning

confidence: 99%

Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates

Szala-Poździej

Swierzko

Gajek

et al. 2022

IJMS

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Single nucleotide polymorphisms (SNPs) localised to the promoter region of the FCN2 gene are known to influence the concentration of ficolin-2 in human serum and therefore potentially have clinical associations. We investigated the relationships between SNPs at positions −986 (A > G), −602 (G > A), −64 (A > C) and −4 (A > G) and clinical complications in 501 preterms. Major alleles at positions −986 and −64 and A/A homozygosity for both polymorphisms were less frequent among babies with very low birthweight (VLBW, ≤1500 g) compared with the reference group (OR = 0.24, p = 0.0029; and OR = 0.49, p = 0.024, respectively for A/A genotypes). A lower frequency of G/G homozygosity at position −4 was associated with gestational age <33 weeks and VLBW (OR = 0.38, p = 0.047; and OR = 0.07, p = 0.0034, respectively). The AGAG haplotype was protective for VLBW (OR = 0.6, p = 0.0369), whilst the GGCA haplotype had the opposite effect (OR = 2.95, p = 0.0249). The latter association was independent of gestational age. The AGAG/GGAA diplotype favoured both shorter gestational age and VLBW (OR = 1.82, p = 0.0234 and OR = 1.95, p = 0.0434, respectively). In contrast, AGAG homozygosity was protective for lower body mass (OR = 0.09, p = 0.0155). Our data demonstrate that some FCN2 variants associated with relatively low ficolin-2 increase the risk of VLBW and suggest that ficolin-2 is an important factor for fetal development/intrauterine growth.

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Section: Discussionmentioning

confidence: 99%

Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates

Szala-Poździej

Swierzko

Gajek

et al. 2022

IJMS

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“…Our identification of rare LoF variants in two genes, ACVR1C and INHBE , that have fetal associations with higher birth weight and also a more metabolically favourable body fat distribution in adulthood is in line with recent findings that common genetic variants in the fetus, which predispose to higher metabolically favourable adiposity in adulthood, are also associated with higher birth weight. Variants with greater effects on adiposity have greater effects on birth weight 55 and we therefore hypothesise that the birth weight effects of ACVR1C and INHBE are due primarily to fetal fat accretion rather than effects on lean mass. A fetal genetic predisposition to greater birth weight and later favourable body fat distribution may underlie epidemiological associations between greater skinfold thickness at birth and favourable metabolic outcomes in early childhood, especially when controlling for exposure to maternal glucose levels in utero 56 .…”

Section: Discussionmentioning

confidence: 91%

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling

Kentistou,

Lim,

Kaisinger

et al. 2024

Preprint

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Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants.We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign testP=0.01).Of the genes identified,IGF1RandPAPPA2(fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling.PPARG, INHBEandACVR1C(all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role ofPPARGin both adipocyte differentiation and placental angiogenesis.NOS3, NRK,andADAMTS8(fetal and maternal-acting) have been implicated in both placental function and hypertension.Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors.

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“…Conversely, the PGS for birth weight was positively associated with BMI SDS and waist SDS, which is in line with previous findings of shared genetic loci between birth weight and childhood obesity. 39 A study in adults found that birth weight increasing variants were associated with increased adiposity in adulthood, but favourable metabolic outcomes. 39 The PGS for birth weight was not associated with lipid related traits in the present study, in line with previous studies, 10 suggesting that the association between lower birth weight and an unfavourable lipid metabolism later in life may mainly be due to fetal programming effects, as opposed to genetic effects.…”

Section: Discussionmentioning

confidence: 99%

The interplay between birth weight and obesity in determining childhood and adolescent cardiometabolic risk

Stinson,

Kromann Reim,

Lund

et al. 2024

eBioMedicine

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

Cited by 4 publications

References 50 publications

Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates

Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling

The interplay between birth weight and obesity in determining childhood and adolescent cardiometabolic risk

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