Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank

Kendall, Kimberley; Bracher-Smith, Matthew; Fitzpatrick, H. M.; Lynham, Amy; Rees, Elliott; Escott‐Price, Valentina; Owen, Michael John; Walters, James; Kirov, George

doi:10.1192/bjp.2018.301

Cited by 131 publications

(159 citation statements)

References 25 publications

(59 reference statements)

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“…We estimated the prevalence of the deletion and its associations with CVM and other diagnoses in the UKB cohort. We confirmed the association of the deletion with CVM (OR = 1.73 [95% CI 1.08-2.75]; p = 0.03) and, in broad agreement with recent findings from others [17], with neuropsychiatric disorders (OR = 1.84 [95% CI 1.23-2.75]; p = 0.0043), measures of cognitive function, academic achievement and fecundity. We confirmed the association of BP1-BP2 deletion with CVM, which has been observed in some but not all previous studies [25][26][27]36].…”

Section: Discussionsupporting

confidence: 91%

“…Penetrance of any phenotype with 15q11 BP1-BP2 deletion has been estimated at~10-12% [2,12], which is relatively low compared with other CNVs commonly associated with genetic disorders. Taken together, previous studies estimate the prevalence of BP1-BP2 deletion as between 0.19% and 0.47% in apparently healthy controls [2,8,[12][13][14][15][16][17].…”

Section: Introductionsupporting

confidence: 56%

“…Tests for 'reaction time', 'numeric memory', 'fluid intelligence' and 'pairs matching' met these criteria with varying amounts of missing data (Supplementary Table 3). Our methodology broadly corresponded with previous work in the cohort by others [15,17]. We removed samples from the whole cohort with ICD10 codes indicating specific diagnoses relating to mental and behavioural disorders previously associated with 15q11.2 deletion ( Supplementary Table 2A).…”

Section: Cognitive Functionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionsupporting

confidence: 56%

Section: Cognitive Functionmentioning

confidence: 99%

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

et al. 2020

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“…All schizophrenia-associated CNVs are also associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder, and in fact penetrance is higher in these disorders 43 . Furthermore, CNVs in UK Biobank have been associated with a range of outcomes including cognitive performance 41,53 and depression 54 , adding strength to our findings of a lack of specificity for psychotic experiences genetic risk.…”

Section: Discussionmentioning

confidence: 66%

Genetic association study of psychotic experiences in UK Biobank

Legge

Jones²,

Kendall

et al. 2019

Preprint

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Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5%-10% of the general population, though only a small proportion of individuals develop psychotic disorders such as schizophrenia or bipolar disorder. Studying the genetic aetiology of psychotic experiences in the general population, and its relationship with the genetic aetiology of other disorders, may increase our understanding of their pathological significance. Using the population-based UK Biobank sample, we performed the largest genetic association study of psychotic experiences in individuals without a psychotic disorder. We conducted three genomewide association studies (GWAS) for (i) any psychotic experience (6123 cases vs. 121,843 controls), (ii) distressing psychotic experiences (2143 cases vs. 121,843 controls), and (iii) multiple occurrence psychotic experiences (3337 cases vs. 121,843 controls). Analyses of polygenic risk scores (PRS), genetic correlation, and copy number variation (CNV) were conducted to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. GWAS analyses identified four loci associated with psychotic experiences including a locus in Ankyrin-3 (ANK3, OR=1.16, p=3.06x 10 -8 ) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2, OR=0.66, p=3.78x10 -8 ) with distressing psychotic experiences. PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, and bipolar disorder, and these associations were stronger for distressing psychotic experiences. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder, schizophrenia, autism spectrum disorder and a cross-disorder GWAS. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04, p=2.49x10 -4 ) and of those associated with neurodevelopmental disorders more widely (OR=1.75, p=1.41x10 -3 ). In conclusion, we identified four genome-wide significant loci in the largest GWAS of psychotic experiences from the population-based UK Biobank sample and found support for a shared genetic aetiology between psychotic experiences and schizophrenia, but also major depressive disorder, bipolar disorder and neurodevelopmental disorders.

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“…Schizophrenia-associated CNVs were associated with larger impairments 13,14 . However, the vast majority of pathogenic CNVs reported back to patients are ultra-rare (non-recurrent) and there is no data to quantify their effect-size on cognitive function.…”

Section: Introductionmentioning

confidence: 96%

Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Huguet

Schramm

Douard

et al. 2020

Preprint

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Rare genomic Copy Number Variants (CNVs) are major contributors to neurodevelopmental disorder. The vast majority of pathogenic CNVs reported back to patients are ultra-rare and their quantitative effects on traits such as intelligence are undocumented.Here, we identified all CNVs ≥ 50 kilobase in 24,092 individuals from unselected and autism cohorts. We developed statistical models to estimate the effect-size of CNVs on intelligence based on their coding and non-coding characteristics.Measures of intolerance to haploinsufficiency best explained the effect of any deletion or duplication on general intelligence. There was no heterogeneity across unselected and autism cohorts. Validation was performed using an intraclass concordance and showed that model estimates of general intelligence were 78% accurate with mean effect-sizes previously published for 47 CNVs.Inheritance data on 27,766 CNVs showed that deletions and duplications with the same large effect-size on intelligence occur de novo at the same frequency.Our first outline for the effect sizes of all coding genes on intelligence suggests that around 10,000 genes affect this trait.

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Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank

Cited by 131 publications

References 25 publications

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

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

Genetic association study of psychotic experiences in UK Biobank

Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

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