Copy number variation and neurodevelopmental problems in females and males in the general population

AbstractObjectiveNeurodevelopmental problems (NPs) are childhood phenotypes that are more common in males. Conversely, anxiety and depression (which are frequently comorbid with NPs) are more common in females. Rare copy number variants (CNVs) have been implicated in clinically-defined NPs. Here, we aimed to characterise the relationship between rare CNVs with NPs and anxiety/depression in a population sample of twin children. Additionally, we examined whether sex-specific CNV effects underlie the sex bias of these disorders.MethodWe analysed a sample of N=12,982 children, of whom 5.3% had narrowly-defined NPs (clinically-diagnosed), 20.9% had broadly-defined NPs (based on validated screening measures, but no diagnosis) and 3.0% had clinically-diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorised by size (medium: 100-500kb or large: >500kb), type (duplication or deletion) and putative relevance to NPs (affecting previously implicated loci or evolutionarily-constrained genes). We tested for associations between the different CNV categories with NPs and anxiety/depression, followed by examination of sex-specific effects.ResultsMedium deletions (OR(CI)=1.18(1.05-1.33),p=0.0053) and large duplications (OR(CI)=1.45(1.19-1.75),p=0.00017) were associated with broadly-defined NPs. Large deletions (OR(CI)=1.85(1.14-3.01),p=0.013) were associated with narrowly-defined NPs. The effect sizes increased for large NP-relevant CNVs (broadly-defined: OR(CI)=1.60(1.06-2.42),p=0.025; narrowly-defined: OR(CI)=3.64(2.16-6.13),p=1.2E-6). No sex differences in CNV burden were found in individuals with NPs (p>0.05). In individuals diagnosed with anxiety or depression, females were more likely to have large CNVs (OR(CI)=3.75(1.45-9.68),p=0.0064).ConclusionRare CNVs are significantly associated with both narrowly- and broadly-defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.

Download Full-text

COPY NUMBER VARIATION AND NEURODEVELOPMENTAL PROBLEMS IN FEMALES AND MALES IN THE GENERAL POPULATION

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2018.07.005 ◽

2019 ◽

Vol 29 ◽

pp. S1022

Author(s):

Joanna Martin ◽

Kristiina Tammimies ◽

Robert Karlsson ◽

Lu Yi ◽

Henrik Larsson ◽

...

Keyword(s):

General Population ◽

Copy Number Variation ◽

Copy Number ◽

Number Variation ◽

Neurodevelopmental Problems

Download Full-text

Copy Number Variation in Neuropsychiatric Disorders

10.1093/oxfordhb/9780199753888.013.005 ◽

2013 ◽

Author(s):

James J. H. Rucker ◽

Peter McGuffin

Keyword(s):

Copy Number ◽

Molecular Mechanisms ◽

Copy Number Variants ◽

Genetic Material ◽

Unipolar Depression ◽

Genomic Variation ◽

Rare Cnvs ◽

Clear Cut ◽

Number Variation ◽

Rare Phenomena

It has long been known that the human genome is subject to deletion and duplication of genetic material by various molecular mechanisms. Until recently, such events were assumed to be relatively rare phenomena. It is now known that submicroscopic deletions or duplications calledcopy number variants(CNVs) are a major source of genomic variation. Rare CNVs (defined as occurring in less than 1 percent of the population) have been implicated in schizophrenia and autism. Measured in terms of odds ratios, individual CNVs have been shown to have large effects, some increasing the risk of disorder several-fold. But they are incompletely penetrant, no one CNV is either necessary or sufficient to cause the disorder. The findings are less clear-cut with bipolar disorder but, here, too, rare CNVs probably play a role. In unipolar depression, initial evidence suggests an overall increase in rare CNVs that disrupt exons, the coding regions of genes.

Download Full-text

Population-wide copy number variation calling using variant call format files from 6,898 individuals

10.1101/504209 ◽

2018 ◽

Author(s):

Grace Png ◽

Daniel Suveges ◽

Young-Chan Park ◽

Klaudia Walter ◽

Kousik Kundu ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Copy Number Variants ◽

Regression Tree ◽

Low Frequency ◽

Protein Product ◽

Supplementary Information ◽

Variant Call ◽

Large Deletions ◽

Number Variation

MotivationCopy number variants (CNVs) are large deletions or duplications at least 50 to 200 base pairs long. They play an important role in multiple disorders, but accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process.ResultsWe use a regression tree-based approach to call CNVs from whole-genome sequencing (WGS, > 18x) variant call-sets in 6,898 samples across four European cohorts, and describe a rich large variation landscape comprising 1,320 CNVs. 61.8% of detected events have been previously reported in the Database of Genomic Variants. 23% of high-quality deletions affect entire genes, and we recapitulate known events such as theGSTM1andRHDgene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe the LD structure and copy number variation underlying the association between levels of the CCL3 protein and a complex structural variant (MAF = 0.15, p = 3.6×10-12) affectingCCL3L3, a paralog of theCCL3gene. We also identify acis-association between a low-frequencyNOMO1deletion and the protein product of this gene (MAF = 0.02, p = 2.2×10-7), for which nocis-ortrans-single nucleotide variant-driven protein quantitative trait locus (pQTL) has been documented to date. This work demonstrates that existing population-wide WGS call-sets can be mined for CNVs with minimal computational overhead, delivering insight into a less well-studied, yet potentially impactful class of genetic variant.AvailabilityThe regression tree based approach, UN-CNVc, is available as an R and bash executable on GitHub athttps://github.com/agilly/[email protected];[email protected] InformationSupplementary information is appended.

Download Full-text

HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity

Frontiers in Genetics ◽

10.3389/fgene.2021.731355 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jinghang Zhou ◽

Liyuan Liu ◽

Thomas J. Lopdell ◽

Dorian J. Garrick ◽

Yuangang Shi

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

R Package ◽

Copy Number Variation Region ◽

Runs Of Homozygosity ◽

Number Variation ◽

Genomic Studies ◽

Computing Platforms ◽

Analysis System

Detection of CNVs (copy number variants) and ROH (runs of homozygosity) from SNP (single nucleotide polymorphism) genotyping data is often required in genomic studies. The post-analysis of CNV and ROH generally involves many steps, potentially across multiple computing platforms, which requires the researchers to be familiar with many different tools. In order to get around this problem and improve research efficiency, we present an R package that integrates the summarization, annotation, map conversion, comparison and visualization functions involved in studies of CNV and ROH. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving, and user-friendly for researchers in humans and most diploid livestock species.

Download Full-text

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

10.1101/011510 ◽

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.

Download Full-text

The Role of Copy Number Variation in Psychiatric Disorders

Psychiatric Genetics ◽

10.1093/med/9780190221973.003.0006 ◽

2018 ◽

pp. 84-95

Author(s):

Elliott Rees ◽

George Kirov

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Selection Pressure ◽

Copy Number Variants ◽

Autism Spectrum ◽

High Odds ◽

Strong Selection ◽

Increase Risk ◽

Number Variation

Copy number variants (CNVs) are deletions, duplications, inversions, or translocations of large DNA segments. They can play a significant role in human disease. Thirteen CNVs have received strong statistical support for involvement in schizophrenia. They are all rare in cases (<1%), much rarer among controls, and have high odds ratios (ORs) for causing disease. The same CNVs also increase risk for autism spectrum disorders, developmental delay, and medical/physical comorbidities. The penetrance of these CNVs for any disorder is relatively high, ranging from 10% for 15q11.2 deletions to nearly 100% for deletions at 22q11.2. Strong selection pressure operates against carriers of these CNVs. Most of these are formed by non-allelic homologous recombination (NAHR), which leads to high mutation rates, thus maintaining the rates of these CNVs in the general population, despite the strong selection forces.

Download Full-text

Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17249253 ◽

2020 ◽

Vol 17 (24) ◽

pp. 9253

Author(s):

Natália Oliva-Teles ◽

Maria Chiara de Stefano ◽

Louise Gallagher ◽

Severin Rakic ◽

Paula Jorge ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Copy Number ◽

Chromosomal Region ◽

Current Knowledge ◽

Copy Number Variants ◽

Inclusion Criteria ◽

Rare Disorders ◽

Number Variation ◽

Malformation Syndromes ◽

Neuropsychiatric Conditions

Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4–BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers’ cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.

Download Full-text

Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population

The Pharmacogenomics Journal ◽

10.1038/tpj.2010.38 ◽

2010 ◽

Vol 11 (4) ◽

pp. 292-299 ◽

Cited By ~ 23

Author(s):

M S Nørskov ◽

R Frikke-Schmidt ◽

S E Bojesen ◽

B G Nordestgaard ◽

S Loft ◽

...

Keyword(s):

Bladder Cancer ◽

General Population ◽

Copy Number Variation ◽

Copy Number ◽

Glutathione S Transferase ◽

Corpus Uteri ◽

Number Variation

Download Full-text

Genetics of Schizophrenia and Bipolar Disorder

10.1093/med/9780190681425.003.0013 ◽

2017 ◽

Author(s):

Alexander Charney ◽

Pamela Sklar

Keyword(s):

Bipolar Disorder ◽

Copy Number ◽

Psychotic Disorders ◽

Copy Number Variants ◽

Nucleotide Polymorphisms ◽

Common Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

Download Full-text