Genotype-phenotype relationships in children with Copy Number Variants associated with high neuropsychiatric risk Findings from the case-control IMAGINE-ID cohort in the United Kingdom, bioRxiv, 2019-01-31
AbstractBackgroundA variety of Copy Number Variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). We aimed to characterise the impact of ND-CNVs on childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes.Methods258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments.Outcomes79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls) the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait).InterpretationThe 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry.FundingThe Medical Research Council and the Waterloo FoundationResearch in contextEvidence before this studySeveral Copy Number Variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for English language studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included “CNV”, “genomics”, “1q21.1”, “2p16.3”, “NRXN1”, “9q34”, “Kleefstra Syndrome”, “15q11.2”, “15q13.3”, “16p11.2”, “22q11.2”, “psychiatry”, and “cognition”. Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains.Added value of this studyWe found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention) whereas for other traits there was evidence of genotype specific effects on severity (e.g., IQ, spatial planning, processing speed, subclinical psychotic experiences, ASD traits, motor coordination total psychiatric symptomatology, particularly anxiety, ADHD, and conduct related traits). However the proportion of variance explained by genotype was low, 5-20% depending on trait, indicating that overall ND-CNVs lead to similar neurodevelopmental outcomes. It is important that genotype-phenotype relationships are viewed through a developmental lens as some phenotypic outcomes were found to be associated with age.Implications of all the available evidenceOur work highlights that children who carry a ND-CNV represent a patient group that warrants clinical and educational attention for a broad range of cognitive and behavioural impairments and that commonalities in clinically relevant neurodevelopmental impairments exist across ND-CNVs. This group of young people could benefit from the development of a general care pathway, to which genotype-specific recommendations can be added where needed. Our work indicates that the relationship between genotype and neurodevelopmental phenotype is complex and that future research will need to take a global systems approach and not be narrowly focused on single phenotypes.
biorxiv genomics 100-200-users 2019Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk Findings from the Intellectual Disability & Mental Health Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study, bioRxiv, 2019-01-31
AbstractBackgroundA variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking.Methods258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments.Outcomes79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls) the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait).InterpretationThe 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry.FundingThe Medical Research Council and the Medical Research FoundationResearch in contextEvidence before this studySeveral copy number variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included “CNV”, “genomics”, “1q21.1”, “2p16.3”, “NRXN1”, “9q34”, “Kleefstra Syndrome”, “15q11.2”, “15q13.3”, “16p11.2”, “22q11.2”, “psychiatry”, and “cognition”. Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains.Added value of this studyWe found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention) whereas for other traits there was evidence of genotype specific effects on severity (e.g., IQ, spatial planning, processing speed, subclinical psychotic experiences, ASD traits, motor coordination total psychiatric symptomatology, particularly anxiety, ADHD, and conduct related traits). However the proportion of variance explained by genotype was low, 5-20% depending on trait, indicating that overall ND-CNVs lead to similar neurodevelopmental outcomes. It is important that genotype-phenotype relationships are viewed through a developmental lens as some phenotypic outcomes were found to be associated with age.Implications of all the available evidenceChildren who carry a ND-CNV represent a patient group that warrants clinical and educational attention for a broad range of cognitive and behavioural impairments. Although qualitative and quantitative differences exist between ND-CNVs, our findings point to commonalities in clinical outcomes with neurodevelopmental impairments being present across all ND-CNVs. This group of young people could benefit from the development of a general intervention plan, to which genotype-specific recommendations can be added where needed. Our findings do not support a model whereby different ND-CNVs represent discrete forms of neuropsychiatric disorder and suggest that multiple processes and neural circuits are affected by ND-CNVs. The pleiotropic effects of ND-CNVs emphasises that research aiming to identify causal pathways between genetic variation and psychiatric outcomes via intermediary (or endo-)phenotypes needs to take a global perspective and not be narrowly focused on single phenotypes.
biorxiv genomics 100-200-users 2019Is it time to change the reference genome?, bioRxiv, 2019-01-30
The use of the human reference genome has shaped methods and data across modern genomics. This has offered many benefits while creating a few constraints. In the following piece, we outline the history, properties, and pitfalls of the current human reference genome. In a few illustrative analyses, we focus on its use for variant-calling, highlighting its nearness to a type specimen. We suggest that switching to a consensus reference offers important advantages over the current reference with few disadvantages.
biorxiv genomics 100-200-users 2019Evaluating potential drug targets through human loss-of-function genetic variation, bioRxiv, 2019-01-29
AbstractHuman genetics has informed the clinical development of new drugs, and is beginning to influence the selection of new drug targets. Large-scale DNA sequencing studies have created a catalogue of naturally occurring genetic variants predicted to cause loss of function in human genes, which in principle should provide powerful in vivo models of human genetic “knockouts” to complement model organism knockout studies and inform drug development. Here, we consider the use of predicted loss-of-function (pLoF) variation catalogued in the Genome Aggregation Database (gnomAD) for the evaluation of genes as potential drug targets. Many drug targets, including the targets of highly successful inhibitors such as aspirin and statins, are under natural selection at least as extreme as known haploinsufficient genes, with pLoF variants almost completely depleted from the population. Thus, metrics of gene essentiality should not be used to eliminate genes from consideration as potential targets. The identification of individual humans harboring “knockouts” (biallelic gene inactivation), followed by individual recall and deep phenotyping, is highly valuable to study gene function. In most genes, pLoF alleles are sufficiently rare that ascertainment will be largely limited to heterozygous individuals in outbred populations. Sampling of diverse bottlenecked populations and consanguineous individuals will aid in identification of total “knockouts”. Careful filtering and curation of pLoF variants in a gene of interest is necessary in order to identify true LoF individuals for follow-up, and the positional distribution or frequency of true LoF variants may reveal important disease biology. Our analysis suggests that the value of pLoF variant data for drug discovery lies in deep curation informed by the nature of the drug and its indication, as well as the biology of the gene, followed by recall-by-genotype studies in targeted populations.
biorxiv genomics 100-200-users 2019Regular cycling between representations of alternatives in the hippocampus, bioRxiv, 2019-01-29
Cognitive faculties such as imagination, planning, and decision-making require the ability to represent alternative scenarios. In animals, split-second decision-making implies that the brain can represent alternatives at a commensurate speed. Yet despite this insight, it has remained unknown whether there exists neural activity that can consistently represent alternatives in <1 s. Here we report that neural activity in the hippocampus, a brain structure vital to cognition, can regularly cycle between representations of alternative locations (bifurcating paths in a maze) at 8 Hz. This cycling dynamic was paced by the internally generated 8 Hz theta rhythm, often occurred in the absence of overt deliberative behavior, and unexpectedly also governed an additional hippocampal representation defined by alternatives (heading direction). These findings implicate a fast, regular, and generalized neural mechanism underlying the representation of competing possibilities.
biorxiv neuroscience 100-200-users 2019Comparison of long-read sequencing technologies in the hybrid assembly of complex bacterial genomes, bioRxiv, 2019-01-27
Illumina sequencing allows rapid, cheap and accurate whole genome bacterial analyses, but short reads (<300 bp) do not usually enable complete genome assembly. Long read sequencing greatly assists with resolving complex bacterial genomes, particularly when combined with short-read Illumina data (hybrid assembly); however, it is not clear how different long-read sequencing methods impact on assembly accuracy. Relative automation of the assembly process is also crucial to facilitating high-throughput complete bacterial genome reconstruction, avoiding multiple bespoke filtering and data manipulation steps. In this study, we compared hybrid assemblies for 20 bacterial isolates, including two reference strains, using Illumina sequencing and long reads from either Oxford Nanopore Technologies (ONT) or from SMRT Pacific Biosciences (PacBio) sequencing platforms. We chose isolates from the Enterobacteriaceae family, as these frequently have highly plastic, repetitive genetic structures and complete genome reconstruction for these species is relevant for a precise understanding of the epidemiology of antimicrobial resistance. We de novo assembled genomes using the hybrid assembler Unicycler and compared different read processing strategies. Both strategies facilitate high-quality genome reconstruction. Combining ONT and Illumina reads fully resolved most genomes without additional manual steps, and at a lower cost per isolate in our setting. Automated hybrid assembly is a powerful tool for complete and accurate bacterial genome assembly.
biorxiv bioinformatics 100-200-users 2019