Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Abstract

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed 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, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, 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 that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations 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.

Figure 1.

A schematic diagram illustrating that maternal genetic factors may influence fetal growth indirectly through the intra-uterine environment, or directly through inheritance by the fetus.

Figure 2.

Manhattan plot of associations between 8 723 755 maternal autosomal SNPs and 17 352 maternal X-chromosome SNPs (all MAF >1%) and offspring birth weight from the meta-analysis of up to 86 577 women. SNP position across the chromosomes (x-axis) and results of association tests between maternal genotype and offspring birth weight adjusted for sex and, where available, gestational duration (–log₁₀P-value; y-axis) are shown. The index maternal SNP from the current study and all SNPs within 500 kb of that SNP are highlighted either in red, or in purple. Those in purple indicate loci at which the index maternal SNP from the current study was within 500k of an index SNP associated previously with own birth weight (i.e. in a ‘fetal GWAS of birth weight’) at P < 5 × 10⁻⁸ (8). SNPs within 500 kb of the 54 other index SNPs previously identified in the fetal GWAS of birth weight are highlighted in green. The red, horizontal line indicates a P value of 5 × 10⁻⁸.

Figure 3.

Diagram of the SEM used to estimate the conditional fetal and maternal effects on birth weight for each of the genome-wide significant SNPs. The three observed variables (in rectangles) are the birth weight of the individual (BW), the birth weight of their offspring (BW_O) and the genotype of the individual (SNP). The latent variables (in circles) are the genotype of the individual’s mother (G_G) and the genotype of the individual’s first offspring (G_O). The total variance of the latent genotypes for the individual’s mother (G_G) and offspring (G_O) and for the observed SNP variable is set to Φ [i.e. variance (G_G) = Φ; variance (SNP) = 0.25Φ + 0.75Φ; variance(G_O) = 0.25 Φ + 0.75Φ]. The m and f path coefficients refer to maternal and fetal effects, respectively. The residual error terms for the birth weight of the individual and their offspring are represented by ɛ and ɛ_O, respectively, and we estimate the variance of both of these terms in the SEM. The covariance between residual genetic and environmental sources of variation is given by ρ.

Figure 4.

Independent maternal and fetal effects on birth weight at the 10 identified loci, estimated from a meta-analysis of results using an SEM in unrelated UK Biobank participants with results using conditional analysis in maternal–fetal pairs. All SNPs are aligned to the birth weight-raising allele reported in Table 1. The colour of each dot indicates the maternal genetic association P-value for birth weight, adjusted for the fetal genetic association: red, P < 0.0001; orange, 0.0001 ≤ P < 0.001; yellow, 0.001 ≤ P < 0.05.