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

This is the final version. Available on open access from Oxford University Press via the DOI in this recordData availability: This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from [email protected] 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.Wellcome TrustRoyal Societ

Corrigendum:Local and macroscopic electrostatic interactions in single α-helices

The non-covalent forces that stabilise protein structures are not fully understood. One way to address this is to study equilibria between unfolded states and α-helices in peptides. For these, electrostatic forces are believed to contribute, including interactions between: side chains; the backbone and side chains; and side chains and the helix macrodipole. Here we probe these experimentally using designed peptides. We find that both terminal backbone-side chain and certain side chain-side chain interactions (i.e., local effects between proximal charges, or interatomic contacts) contribute much more to helix stability than side chain-helix macrodipole electrostatics, which are believed to operate at larger distances. This has implications for current descriptions of helix stability, understanding protein folding, and the refinement of force fields for biomolecular modelling and simulations. In addition, it sheds light on the stability of rod-like structures formed by single α-helices that are common in natural proteins including non-muscle myosins