Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1-BP2) deletion in the UK Biobank

Deletion of a non-imprinted 500Kb genomic region at chromosome 15q11.2, between breakpoints 1 and 2 of the Prader-Willi/Angelman locus (BP1-BP2 deletion) has been associated in previous studies with phenotypes including congenital cardiovascular malformations (CVM). Previous studies investigating association between BP1-BP2 deletion and CVM have tended to recruit cases with rarer and more severe CVM phenotypes; the impact on CVM in relatively unselected population cohorts, anticipated to contain chiefly less severe but commoner CHD phenotypes, is relatively unexplored. More precisely defining the impact of BP1-BP2 deletion on CVM risk could be useful to guide genetic counselling, since the deletion is frequently identified in the neurodevelopmental clinic.

Using the UK Biobank (UKB) cohort of ~500,000 individuals, we identified individuals with CVM and investigated the association with deletions at the BP1-BP2 locus. In addition, we assessed the association of BP1-BP2 deletions with neuropsychiatric diagnoses, cognitive function and academic achievement. Cases of CVM had an increased prevalence of the deletion compared to controls (0.64%; OR=1.73 [95% CI 1.08 – 2.75]; p=0.03), as did those with neuropsychiatric diagnoses (0.68%; OR=1.84 [95% CI 1.23 – 2.75]; p=0.004). We conclude that BP1-BP2 deletion moderately increases the risk of the generally milder, but commoner, CVM phenotypes seen in this unselected population, in addition to its previously demonstrated association in case/control studies ascertained for CVM.