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 of CVM on 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 with 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.
Copy-number variants in Cardiovascular and Neuropsychiatric disorders
Rare genomic copy-number variants (CNVs) have been implicated as causative factors in a number of complex diseases including schizophrenia, autism and congenital heart disease (CHD). Many factors are known to increase the risk of these diseases and, in recent years, developments in sequencing and array-based platforms have enabled investigation into the genetic factors that contribute to these conditions. Previous studies have identified rare CNVs in specific regions that associate with these diseases but there has been relatively little investigation into the occurrence of these CNVs in the wider population. Using the data generated through the UK Biobank?s genotyping project, the aim of this study is to assess the prevalence of rare CNVs in the UK population. Improved characterisation of rare CNVs associated with disease will facilitate gene discovery and in turn develop increased understanding of the influence of genetics in complex disease. This will ultimately impact future healthcare as it will enable earlier diagnosis in children and families affected by these conditions, improving the development of personalised care pathways. Using the Biobank genotyping data, we will call CNVs and compare these with CNVs previously implicated in disease phenotypes to gain a greater insight into the prevalence of these 'rare' events in the wider population. This study would use the UK Biobank genotyping data (full cohort).
|Dr Simon Williams
|University of Manchester