Cognitive Performance Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects

Kendall, Kimberley; Rees, Elliott; Escott‐Price, Valentina; Einon, Mark; Thomas, Rhys H.; Hewitt, Jonathan; O'Donovan, Michael Conlon; Walters, James; Kirov, George

doi:10.1016/j.biopsych.2016.08.014

Cited by 197 publications

(265 citation statements)

References 33 publications

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“…In contrast, 32 of 39 (82%) (61.5% females, 38.5% males) carrier parents showed mild cognitive, behavioral and/or psychiatric features (Table S5), consistent with previous reports of cognitive impairment and increased risk for schizophrenia in carriers of the 16p12.1 deletion 7,81,82 .…”

Section: Secondary Variants Account For Disease Expressivity In 16p12supporting

confidence: 72%

“…For example, in 2002 only 2-3% of autism cases were explained by genetic factors, whereas current studies suggest that rare disruptive mutations, including copy-number variants (CNVs) and singlenucleotide variants (SNVs), account for 10-30% of autism cases [1][2][3][4][5] . Despite initial claims of association with a specific disorder or syndrome, several of these pathogenic variants show incomplete penetrance and variable expressivity [6][7][8][9] . For example, the 16p11.2 BP4-BP5 deletion (OMIM #611913) 10 was first described in children with autism, but further studies on other clinical and population cohorts demonstrated that this deletion is also associated with individuals with intellectual disability and developmental delay (ID/DD), obesity, epilepsy, cardiac disease, and scoliosis, and only about 24% of cases manifest an autism phenotype [10][11][12][13][14][15][16][17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

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Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Pizzo

Jensen

Polyak

et al. 2018

Preprint

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Rare copy-number variants (CNVs) and gene-disruptive mutations associated with neurodevelopmental disease are characterized by phenotypic heterogeneity. When affected children inherit these mutations, they usually present more severe features than carrier parents, leading to challenges in diagnosis and management. To understand how the genetic background modulates phenotypes of these variants, we analyzed clinical and exome-sequencing data from 757 probands and 233 parents and siblings who carry disease-associated mutations. We found that the number of rare pathogenic secondary mutations in developmental genes (second-hits) modulates the expressivity of disease in probands with 16p12.1 deletion (n=26, p=0.014) and in autism probands with gene-disruptive mutations (n=184, p=0.031) when compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history of neuropsychiatric disease were more likely to manifest multiple and more severe clinical features (p=0.035) and carry a higher burden of second-hits compared to those with mild or no family history (p=0.001). The amount of secondary variants determined the severity of cognitive impairment in 432 probands carrying pathogenic rare CNVs or de novo mutations in disease genes and negatively correlated with head size in 84 probands with 16p11.2 deletion, suggesting an effect of the genetic background across multiple phenotypic domains. These second-hits involved known disease genes, such as SETD5, AUTS2, and NRXN1, and novel candidate modifiers, such as CDH23, RYR3, and DNAH3, affecting core developmental processes. Our findings suggest that in the era of personalized medicine, accurate diagnosis will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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Section: Secondary Variants Account For Disease Expressivity In 16p12supporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Pizzo

Jensen

Polyak

et al. 2018

Preprint

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“…The list of 93 pathogenic CNVs was compiled from two widely accepted sources (Coe et al 2014, Dittwald et al 2013) as we have previously reported (Kendall et al 2016). The CNV calls for UK Biobank participants were made in-house as we have previously reported in a UK Biobank CNV study (Kendall et al 2016). …”

Section: Methodsmentioning

confidence: 99%

“…Although the contribution to liability from CNVs at a population level (Purcell et al 2014) is much smaller than that of common alleles, for completeness we also tested whether the frequencies of 93 pathogenic CNVs that have been linked with neurodevelopmental disorders (Coe et al 2014, Dittwald et al 2013, Kendall et al 2016 …”

Section: Introductionmentioning

confidence: 99%

Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

et al. 2018

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“…http://dx.doi.org/10.1101/160499 doi: bioRxiv preprint first posted online Jul. 7, 2017; this direction, for example deCODE 53 , UK biobank 54 , Geisinger 55 , and the All of Us Research Program (formerly the Precision Medicine Initiative).…”

Section: Strategies To Improve Locus Discovery In Wgsmentioning

confidence: 99%

Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

Sanders

Neale

Huang

et al. 2017

Preprint

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As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

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Cognitive Performance Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects

Abstract: This is the largest study on the cognitive phenotypes of CNVs to date. Adult carriers of neurodevelopmental CNVs from the general population have significant cognitive deficits. The UK Biobank will allow unprecedented opportunities for analysis of further phenotypic consequences of CNVs.

Cited by 197 publications

References 33 publications

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

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