scholarly journals The role of rare copy number variants in depression

2018 ◽  
Author(s):  
Kimberley M Kendall ◽  
Elliott Rees ◽  
Matthew Bracher-Smith ◽  
Lucy Riglin ◽  
Stanley Zammit ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Genetic Risk ◽  
Copy Number ◽  
Social Deprivation ◽  
Copy Number Variants ◽  
Uk Biobank ◽  
Education Attainment ◽  
Increased Risk ◽  
Deletion 16P11.2

AbstractThe role of large, rare copy number variants (CNVs) in neurodevelopmental disorders is well-established,1–5 but their contribution to common psychiatric disorders, such as depression, remains unclear. We have previously shown that a substantial proportion of CNV enrichment in schizophrenia is explained by CNVs associated with neurodevelopmental disorders.6, 7 Depression shares genetic risk with schizophrenia8, 9 and is frequently comorbid with neurodevelopmental disorders10, 11, suggesting to us the hypothesis that if CNVs play a role in depression, neurodevelopmental CNVs are those most likely to be associated. We confirmed this in UK Biobank by showing that neurodevelopmental CNVs were associated with depression (24,575 cases, 5.87%; OR=1.36, 95% CI 1.22-1.51, p=1.61×10-8), whilst finding no evidence implicating other CNVs. Four individual neurodevelopmental CNVs increased risk of depression (1q21.1 duplication, PWS duplication, 16p13.11 deletion, 16p11.2 duplication). The association between neurodevelopmental CNVs and depression was partially explained by social deprivation but not by education attainment or physical illness.

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

2019 ◽  
Vol 214 (5) ◽  
pp. 297-304 ◽  
Author(s):  
Kimberley M. Kendall ◽  
Matthew Bracher-Smith ◽  
Harry Fitzpatrick ◽  
Amy Lynham ◽  
Elliott Rees ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Cognitive Test ◽  
Carrier Status ◽  
Cognitive Tests ◽  
Uk Biobank ◽  
The Uk

BackgroundRare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.AimsWe aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.MethodWe called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.ResultsMost CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.ConclusionsCNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.Declaration of interestNone.

scholarly journals Update on the genetic architecture of schizophrenia

2020 ◽  
Vol 32 (1) ◽  
pp. 19-24
Author(s):  
Franziska Degenhardt
Keyword(s):  
Neurodevelopmental Disorders ◽  
Genetic Risk ◽  
Copy Number ◽  
Genetic Architecture ◽  
Genetic Variant ◽  
Chromosomal Region ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Diagnostic Investigation ◽  
Rare Alleles

Abstract A long-established hypothesis is that schizophrenia has a strong genetic component. In the early 1990s, the first genetic variant that substantially increases risk for psychosis was identified. Since this initial reporting of deletions in the chromosomal region 22q11.2, nearly two decades passed until substantial insights into schizophrenia’s genetic architecture were gained. Schizophrenia is a polygenic disorder and genetic risk is conferred by both common and rare alleles distributed across the genome. A small number of rare, deleterious copy number variants (CNVs) are associated with moderate to substantial increases in individual risk to schizophrenia. These deletions and duplications are also associated with a range of neurodevelopmental disorders. The diagnostic investigation of CNVs in patients with schizophrenia is likely to represent one of the first examples of genetic testing in clinical psychiatry. The prerequisites for this are currently being defined.

scholarly journals Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1514
Author(s):  
Shing Fung Lee ◽  
Maja Nikšić ◽  
Bernard Rachet ◽  
Maria-Jose Sanchez ◽  
Miguel Angel Luque-Fernandez
Keyword(s):  
Cancer Patients ◽  
Socioeconomic Inequalities ◽  
Uk Biobank ◽  
Incident Cancer ◽  
Increased Risk ◽  
Exposure Variable ◽  
Independent Risk Factors ◽  
The Uk ◽  
Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

scholarly journals Prevalence of pathogenic copy number variants among children conceived by donor oocyte

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sandra Monfort ◽  
Carmen Orellana ◽  
Silvestre Oltra ◽  
Mónica Rosello ◽  
Alfonso Caro-Llopis ◽  
...  
Keyword(s):  
In Vitro Fertilization ◽  
Copy Number ◽  
Assisted Reproductive Technologies ◽  
Copy Number Variants ◽  
Reproductive Technologies ◽  
Significant Excess ◽  
Vitro Fertilization ◽  
Donor Oocyte ◽  
Increased Risk

AbstractDevelopment of assisted reproductive technologies to address infertility has favored the birth of many children in the last years. The majority of children born with these treatments are healthy, but some concerns remain on the safety of these medical procedures. We have retrospectively analyzed both the fertilization method and the microarray results in all those children born between 2010 and 2019 with multiple congenital anomalies, developmental delay and/or autistic spectrum disorder (n = 486) referred for array study in our center. This analysis showed a significant excess of pathogenic copy number variants among those patients conceived after in vitro fertilization with donor oocyte with respect to those patients conceived by natural fertilization (p = 0.0001). On the other hand, no significant excess of pathogenic copy number variants was observed among patients born by autologous oocyte in vitro fertilization. Further studies are necessary to confirm these results and in order to identify the factors that may contribute to an increased risk of genomic rearrangements, as well as consider the screening for genomic alterations after oocyte donation in prenatal diagnosis.

scholarly journals Actionable and incidental neuroradiological findings in twins with neurodevelopmental disorders

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lynnea Myers ◽  
Mai-Lan Ho ◽  
Elodie Cauvet ◽  
Karl Lundin ◽  
Torkel Carlsson ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number Variants ◽  
Cross Sectional Study ◽  
Autism Spectrum ◽  
Molecular Signaling ◽  
Mri Findings ◽  
Cross Sectional ◽  
Increased Risk ◽  
Magnetic Resonance Imaging Mri ◽  
Morphological Variants

AbstractWhile previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.

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

2018 ◽  
Vol 49 (15) ◽  
pp. 2499-2504 ◽  
Author(s):  
Valentina Escott-Price ◽  
Daniel J. Smith ◽  
Kimberley Kendall ◽  
Joey Ward ◽  
George Kirov ◽  
...  
Keyword(s):  
Environmental Exposure ◽  
Copy Number Variants ◽  
Season Of Birth ◽  
Uk Biobank ◽  
Month Of Birth ◽  
Risk Alleles ◽  
Gene Environment ◽  
Increased Risk ◽  
The Uk ◽  
Pathogenic Process

AbstractBackgroundThere is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.MethodsHere we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.ResultsNeither genetic measure was associated with season or month of birth within the UKBB sample.ConclusionsAs our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.

Role of Copy Number Variants in Structural Birth Defects: TABLE 1

PEDIATRICS ◽  
2012 ◽  
Vol 129 (4) ◽  
pp. 755-763 ◽  
Author(s):  
Abigail E. Southard ◽  
Lisa J. Edelmann ◽  
Bruce D. Gelb
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Copy Number Variants

scholarly journals Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders

2014 ◽  
Author(s):  
Janani Iyer ◽  
Santhosh Girirajan
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Molecular Genetic ◽  
Copy Number Variants ◽  
Fruit Fly ◽  
Functional Evaluation ◽  
Rare Cnvs ◽  
Molecular Genetic Basis ◽  
Causal Genes ◽  
Genomic Regions

Rare copy-number variants (CNVs) are a significant cause of neurodevelopmental disorders. The sequence architecture of the human genome predisposes certain individuals to deletions and duplications within specific genomic regions. While assessment of individuals with different breakpoints has identified causal genes for certain rare CNVs, deriving gene-phenotype correlations for rare CNVs with similar breakpoints has been challenging. We present a comprehensive review of the literature related to genetic architecture that is predisposed to recurrent rearrangements, and functional evaluation of deletions, duplications, and candidate genes within rare CNV intervals using mouse, zebrafish, and fruit fly models. It is clear that phenotypic assessment and complete genetic evaluation of large cohorts of individuals carrying specific CNVs and functional evaluation using multiple animal models are necessary to understand the molecular genetic basis of neurodevelopmental disorders.

scholarly journals Bayesian copy number detection and association in large-scale studies

2020 ◽  
Author(s):  
Stephen Cristiano ◽  
David McKean ◽  
Jacob Carey ◽  
Paige Bracci ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
Disease Risk ◽  
Copy Number Variants ◽  
Regulatory Elements ◽  
Cancer Case ◽  
Tumor Supressor ◽  
Increase Risk ◽  
Control Study

AbstractGermline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

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