Aim: to replicate genetic associations showing parent-of-origin effects (POE) on birth weight, following initial analysis of UK Biobank data.

Proposal: Monogenic disorders of imprinted genes (e.g. IGF2/H19 disruption in Beckwith-Wiedemann syndrome or Silver-Russell syndrome) often show marked effects on birth weight. However, the role of imprinting (i.e. where the influence of an allele depends on whether it is maternally- or paternally- inherited) in common variation in birth weight is unknown. We hypothesise that there will be common variants at genetic loci which show POE on birth weight, and that known imprinted regions of the genome are enriched for these variants. Recently a method was published to investigate parent of origin effects (POE) in large genome-wide association study (GWAS) datasets of unrelated individuals (Hoggart et al 2014 PLoS Genetics).

We will be applying this method to the forthcoming GWAS data on birth weight in UK Biobank to identify POE across the genome, and to test whether POE on birth weight are more likely to occur in known imprinted regions.

Any loci showing evidence of association will require replication in independent studies. Ideally these studies would have mother, father and child genotype available, but there are few studies with these data. It is possible to gain a large amount of information, however, from the analysis of mother-child pairs. ALSPAC represents the best study in which to do this. We propose to replicate the identified loci from UK Biobank in ALSPAC and potentially other available studies including EFSOCH and HAPO. The replication sets will not have the statistical power comparable to Biobank but will have better quality phenotype data, the presence of maternal genotypes and will enable comparison of effect sizes of the associations observed in Biobank.