Large-scale examination of neuropsychiatric, cognitive and cardiovascular phenotypic associations with 15q11.2 BP1-BP2 deletion in ∼500,000 UK Biobank individuals

Background 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 developmental delay, autism, schizophrenia and congenital cardiovascular malformations (CVM). The deletion has a low baseline population prevalence and large-scale data regarding the magnitude of these associations and any milder effects on cognition phenotypes, in populations not selected for disease, are limited. Methods Using the UK Biobank (UKB) cohort of ∼500,000 individuals, we identified individuals with neuropsychiatric and CVM diagnoses and investigated their association with deletions at the BP1-BP2 locus. In addition we assessed the association of BP1-BP2 deletions with cognitive function and academic achievement in individuals with no previous diagnosis. Results Cases of neurodevelopmental and CVM disease had an increased prevalence of the deletion compared to controls (0.68%; OR=1.84 [95% CI 1.23 – 2.75]; p=0.004 and 0.64%; OR=1.73 [95% CI 1.08 – 2.75]; p=0.03 respectively). Excluding participants diagnosed with neurodevelopmental or neuropsychiatric disease, deletion carriers had worse scores in four tests of cognitive function, and while 32.8% of UKB participants without BP1-BP2 deletion had a university or college degree as their highest educational qualification, only 22.8% of deletion carriers achieved this (OR 0.57 [95% CI 0.51-0.64]; p=5.60E-22). Conclusions We conclude that BP1-BP2 deletion has an appreciable population prevalence with important life-course impacts on undiagnosed carriers. These data are of potential utility in deciding the circumstances under which clinical testing for BP1-BP2 deletion may be helpful. Key messages