Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Abstract

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 258 kb 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.

Genetic modifiers of rare variants in monogenic developmental disorder loci

“…We were interested in exploring whether there was an enrichment of DDG2P genes in EA GWAS loci. We hypothesized that the EA-PGS could include single-nucleotide polymorphisms (SNPs) in cis -regulatory regions of monogenic DDG2P genes; therefore, we examined the proximity between the 599 autosomal dominant DDG2P genes and 3,952 SNPs included in the EA-PGS, using simulations of matched SNPs (10,000 lists of matched SNPs per GWAS SNP, based on allele frequency and proximity to genes) to empirically test whether the genes fall disproportionately close to the GWAS loci 42 . As expected, we found that the GWAS loci were closer to DDG2P genes than expected by chance alone ( P = 0.005), suggesting that the large-effect rare variants and small-effect common variants may work through overlapping biological pathways.…”