Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics

Abstract

Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about how maternal genetic variation influences fetal growth. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth.We meta-analysed GWAS data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects.Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9and CYP3A7) showed evidence of association with offspring birth weight at P<5x10 -8 . The SEM analyses showed at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration.The identified associations indicate effects of maternal glucose, cytochrome P450 activity and gestational duration, and potential effects of maternal blood pressure and immune function on fetal growth. Further characterization of these associations, for example in mechanistic and causal analyses, will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

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

“…The contribution of genotype-dependent maternal hyperglycaemia to BW is in line with the evidence, from a recent study, that maternal genotype scores for fasting glucose and T2D (conditional on foetal genotype) were causally associated with higher offspring BW16. It is also consistent with the observation that a subset of glucose-raising alleles is associated with higher BW7. For example, the T2D-risk variant at MTNR1B (which also has a particularly marked effect on fasting glucose levels in non-diabetic indivudals27,28) was amongst the subset of BW loci (5/60) for which the BW effect attributable to maternal genotype exceeded that associated with the foetal genotype (maternal: β=0.048, P =5.1x10 -15 ; foetal: β=0.023, P =2.9x10 -8 ) (Supplementary Table 10, Extended Data Figs 4, 5).…”

“…The maternal allelic effect on offspring BW was obtained from a maternal GWAS meta-analysis of 68,254 European mothers from the EGG Consortium (n=19,626)7 and the UK Biobank (n=48,628). In the UK Biobank, mothers were asked to report the BW of their first child.…”

“…For each BW locus, the following six effect sizes (with 95% CI) are shown, all aligned to the same BW-raising allele: foetal_GWAS = foetal allelic effect on BW (from European ancestry meta-analysis of up to n=143,677 individuals); foetal_unadjusted = foetal allelic effect on BW (unconditioned in n=12,909 mother-child pairs); foetal_adjusted = foetal effect (conditioned on maternal genotype, n=12,909); maternal_GWAS = maternal allelic effect on offspring BW (from meta-analysis of up to n=68,254 European mothers)7; maternal_unadjusted = maternal allelic effect on offspring BW (unconditioned, n=12,909); maternal_adjusted = maternal effect (conditioned on foetal genotype, n=12,909). The 60 BW loci are ordered by chromosome and position (Supplementary Tables 10, 11).…”

“…First, an analysis of the global contribution of maternal vs. foetal genetic variation, using a maternal-GCTA model6 (Methods) applied to 4,382 mother-child pairs, estimated that the child’s genotype (σ C 2 =0.24, SE=0.11) makes a larger contribution to BW variance than either the mother’s genotype (σ M 2 =0.04, SE=0.10), or the covariance between the two (σ CM =0.04, SE=0.08). Second, when we compared the point estimates of the BW effect size dependent on maternal genotype at each of the 60 loci (as measured in up to 68,254 women7) with those dependent on foetal genotype (using European ancestry data from 143,677 individuals in the present study), foetal variation had greater impact than maternal at 93% of loci (55/60; binomial P= 1x10 -11 ) (Supplementary Table 10, Extended Data Figs 4, 5; Methods). Power to further disentangle maternal and foetal contributions using analyses of foetal genotype conditional on maternal genotype was constrained by the limited sample size available (n=12,909 mother-child pairs) (Supplementary Table 11).…”

Evolutionary justifications for human reproductive limitations

“…Maternal imprinting reduces fetal size [25], and several Mendelian variants have negative growth effects, mostly acting through the mother [26], a point we will return to later.…”