Birth weight is an important factor in newborn survival; both low and high birth weights are
associated with adverse later-life health outcomes. Genome-wide association studies
(GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight.
Knowledge of underlying causal genes is crucial to understand how ...
Birth weight is an important factor in newborn survival; both low and high birth weights are
associated with adverse later-life health outcomes. Genome-wide association studies
(GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight.
Knowledge of underlying causal genes is crucial to understand how these loci influence birth
weight, and links between infant and adult morbidity. Numerous monogenic developmental
syndromes are associated with birth weights at the extreme ends of the distribution. Genes
implicated in those syndromes may provide valuable information to prioritise candidate genes
at GWAS loci. We examined the proximity of genes implicated in developmental disorders to
birth weight GWAS loci, using simulations to test whether they fall disproportionately close
to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs)
fall closer to such genes than expected, both when the developmental disorder gene is the
nearest gene to the birth weight SNP and also examining all genes within 258kb of the SNP.
This enrichment was driven by genes causing monogenic developmental disorders with
dominant modes of inheritance. We found examples of SNPs in the intron of one gene
marking plausible effects via different nearby genes, highlighting the closest gene to the SNP
not necessarily being the functionally relevant gene. This is the first application of this
approach to birth weight, which has helped identify GWAS loci likely to have direct fetal
effects on birth weight which could not previously be classified as fetal or maternal due to
insufficient statistical power.