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

Abstract

BackgroundDeletion 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. MethodsUsing 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 Casesof 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). ConclusionsWe 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• Deletions at chromosome 15q11.2 between breakpoints 1 and 2 (BP1-BP2), which encompass four genes, have been associated with developmental delay, autism, schizophrenia and congenital cardiovascular malformations.• Here, we use the largest cohort studied to date: the UK Biobank cohort of ~500,000 individuals, to explore the association of this deletion with neuropsychiatric and cardiovascular phenotypes as well as its effects on cognitive function and academic achievement.• We find an appreciable population prevalence of the deletion with these phenotypes and demonstrate reduced cognitive function and lower academic achievements in those individuals with no prior diagnosis.

Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

“…Copy number variations (CNVs) and single-nucleotide variants (SNVs) in the cytoplasmic FMR1-interacting protein 1 (CYFIP1) gene have been associated with SCZ and ASD (Leblond et al, 2012;Stefansson et al, 2014;Tam et al, 2010;Vanlerberghe et al, 2015;Wang et al, 2015;Zhao et al, 2013). Furthermore, genomic instability at the 15q11.2 BP1-BP2 locus, which encompasses four genes, including CYFIP1, has also recently emerged as a recognized syndrome (Cafferkey et al, 2014;Cox and Butler, 2015;De Wolf et al, 2013;Nevado et al, 2014;Urraca et al, 2013;Williams et al, 2019;C Yuen et al, 2017). Among the four implicated genes, converging evidence suggests that CYFIP1 is a key factor mediating risk for the BP1-2-deletion disorders (Das et al, 2015;Nebel et al, 2016;Vanlerberghe et al, 2015;Wang et al, 2015;Woo et al, 2016;Yoon et al, 2014).…”