Biology subjects

Holmans, P.

Publications and source records attributed to Holmans, P..

At least 19 recordsLinked to original sources

bioRxiv2026

New Human IPSC Models of Late-onset Alzheimer's Disease Polygenic Risk Identify Multiple Impairments of Microglial Function

Genetic discoveries implicate microglia in late-onset Alzheimers disease (AD). We modelled AD in a powerful study of 51 human induced pluripotent stem cell (iPSC) microglia derived from high-polygenic risk AD or low-risk cognitively well individuals, sampled from a large cohort. We explored mitochondrial function, cytokine secretion, endocytosis, phagocytosis, lipid accumulation, calcium store release, and chemotaxis under basal conditions and immune challenge. High polygenic risk was independently associated with significant functional deficits in iPSC microglia under immune challenge, in mitochondrial ATP production (p=0.005, -13%), and inflammatory cytokine release (IL-6: p=0.018, -42%; TNF p=0.026, -38.5%). Furthermore, a selective deficit in amyloid-{beta} uptake was identified (p=0.00477, -5.9%). Deficits in inflammatory cytokine release were driven by APOE {varepsilon}4. These findings reflect primary changes in AD pathogenesis predating plaque formation and validate a human in vitro platform for late-onset AD to further understand disease mechanisms and screen drug or genetic therapies.

neuroscience↗

bioRxiv2025

Developmental, neuroanatomical and cellular expression of genes causing dystonia

ObjectiveDystonia is one of the most common forms of movement disorder with >50 genes identified as causative. However, an understanding of which developmental stages, brain regions and cell types are most relevant is crucial for developing relevant disease models and therapeutics. One approach is to examine the timing and anatomical expression of dystonia-causing genes, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed. MethodsWe investigated the expression patterns of 44 dystonia-causing genes across two bulk- and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue. ResultsDystonia genes were most strongly enriched in those with higher expression in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and for higher postnatal expression. Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex). Single-nuclei RNA-sequencing data analyses from human frontal cortex, striatum and cerebellum indicated that dystonia genes are predominantly expressed in neurons (both glutamatergic and GABAergic), rather than glia. Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons, presynapse and neuron projection. InterpretationThese analyses provide important insights into the anatomical, developmental and cellular expression patterns of dystonia-causing genes, potentially guiding the development of disease-relevant models and improving the timing and targeting of future therapeutic interventions.

neuroscience↗

bioRxiv2024

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects

Huntingtons disease (HD), due to expansion of a CAG repeat in HTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

genetics↗

bioRxiv2022

Effector Th1 cells alter the transcriptional output of IL-6 in acute resolving inflammation

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, anti-microbial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA-seq, ChIP-seq, and ATAC-seq to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focussed on the transcriptional signature of the immuno-modulatory cytokine IL-6 in both settings and examined how pro-fibrotic IFN{gamma}-secreting CD4+ T-cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting anti-microbial immunity and tissue homeostasis. The introduction of IFN{gamma}-secreting CD4+ T-cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent GAS motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T-cells re-tune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

immunology↗

bioRxiv2021

The impact of genetic risk for Alzheimers disease on the structural brain networks of young adults

We investigated the structural brain networks of 562 young adults in relation to polygenic risk for Alzheimers disease, using magnetic resonance imaging (MRI) and genotype data from the Avon Longitudinal Study of Parents and Children. Diffusion MRI data were used to perform whole-brain tractography and to generate structural brain networks for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. The mean clustering coefficient, mean betweenness centrality, characteristic path length, global efficiency and mean nodal strength were calculated for these networks, for each participant. The connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating each participants genetic risk, were calculated at genome-wide level and for nine specific disease pathways. Correlations were calculated between the PRS and a) the graph theoretical metrics of the structural networks and b) the rich-club, feeder and local connectivity of the whole-brain networks. In the visual subnetwork, the mean nodal strength was negatively correlated with the genomewide PRS (r=-0.19, p=1.3x10-5), the mean betweenness centrality was positively correlated with the plasma lipoprotein particle assembly PRS (r=0.16, p=9.2x10-4), and the mean clustering coefficient was negatively correlated with the tau protein binding PRS (r=-0.16, p=9.2x10-4). In the default mode network, the mean nodal strength was negatively correlated with the genomewide PRS (r=-0.14, p=1.5x10-3). The rich-club and feeder connectivities were negatively correlated with the genome-wide PRS (r=-0.16, p=3.7x10-4; r=-0.15, p=8.8x10-4). Our results indicate small reductions in brain connectivity in young adults at risk of developing Alzheimers disease in later life.

neuroscience↗

bioRxiv2021

Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

BackgroundHuntingtons disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntingtons disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. MethodsWe developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntingtons disease via regression analysis. ResultsWe found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1x10-9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. ConclusionsThe association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

genetics↗

bioRxiv2021

FAN1 nuclease activity affects CAG expansion and age at onset of Huntington's disease

The age at onset of motor symptoms in Huntingtons disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

neuroscience↗

bioRxiv2021

Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimers disease

Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimers Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests altered levels of SPi1 may alter microglial phenotype potentially impacting AD. This study determined how the mouse microglial transcriptome was altered following modest changes to Spi1 expression in primary microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.

neuroscience↗

bioRxiv2020

Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

genetics↗

bioRxiv2020

Monocyte-specific changes in gene expression implicate LACTB2 and PLIN2 in Alzheimer's disease.

More than 50 genetic loci have been identified as being associated with Alzheimers disease (AD) from genome-wide association studies (GWAS) and many of these are involved in immune pathways and lipid metabolism. Therefore, we performed a transcriptome-wide association study (TWAS) of immune-relevant cells, to study the mis-regulation of genes implicated in AD. We used expression and genetic data from naive and induced CD14+ monocytes and two GWAS of AD to study genetically controlled gene expression in monocytes at different stages of differentiation and compared the results with those from TWAS of brain and blood. We identified nine genes with statistically independent TWAS signals, seven are known AD risk genes from GWAS: BIN1, PTK2B, SPI1, MS4A4A, MS4A6E, APOE and PVR and two, LACTB2 and PLIN2/ADRP, are novel candidate genes for AD. Three genes, SPI1, PLIN2 and LACTB2, are TWAS significant specifically in monocytes. LACTB2 is a mitochondrial endoribonuclease and PLIN2/ADRP associates with intracellular neutral lipid storage droplets (LSDs) which have been shown to play a role in the regulation of the immune response. Notably, LACTB2 and PLIN2 were not detected from GWAS alone.

neuroscience↗

bioRxiv2020

The onset and prevalence of motor and psychiatric symptoms in Huntingtons disease

ObjectiveTo assess the prevalence, timing and functional impact of psychiatric, cognitive and motor abnormalities in Huntingtons disease (HD) gene carriers, we analysed retrospective clinical data from individuals with manifest HD. MethodsClinical features of HD patients were analysed for 6316 individuals in the European REGISTRY study from 161 sites across 17 countries. Data came from clinical history and the patient-completed Clinical Characteristics Questionnaire that assessed eight symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis. Multiple logistic regression was used to analyse relationships between symptoms and functional outcomes. ResultsThe initial manifestation of HD is increasingly likely to be motor, and less likely to be psychiatric, as age at presentation increases, and is independent of pathogenic CAG repeat length. The Clinical Characteristics Questionnaire captures data on non-motor symptom prevalence that correlate specifically with validated clinical measures. Psychiatric and cognitive symptoms are common in HD gene carriers, with earlier onsets associated with longer CAG repeats. 42.4% of HD patients reported at least one psychiatric or cognitive symptom before motor symptoms, with depression most common. Each non-motor symptom was associated with significantly reduced total functional capacity scores. ConclusionsPsychiatric and cognitive symptoms are common and functionally debilitating in HD gene carriers. They require recognition and targeting with clinical outcome measures and treatments. However, as it is impossible to distinguish confidently between non-motor symptoms arising from HD and primary psychiatric disorders, particularly in younger pre-manifest patients, non-motor symptoms should not be used to make a clinical diagnosis of HD.

neuroscience↗

bioRxiv2020

Genetic association of FMRP targets with psychiatric disorders

AO_SCPLOWBSTRACTC_SCPLOWGenes encoding the mRNA targets of Fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. We then explored the partitioning of genetic association between overrepresented functional categories. High-confidence targets of FMRP were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by membership of other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders, across traditional diagnostic boundaries.

neuroscience↗

bioRxiv2019

Genetic overlap between psychiatric disorders and neuropsychiatric symptoms in HD

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

genetics↗

bioRxiv2019

Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes.

Schizophrenia is a highly polygenic disorder with important contributions coming from both common and rare risk alleles, the latter including CNVs and rare coding variants (RCVs), sometimes occurring as de novo variants (DNVs). We performed DNV analysis in whole exome-sequencing data obtained from a new sample of 613 schizophrenia trios, and combined this with published data for a total of 3,444 trios. Loss-of-function (LoF) DNVs were significantly enriched among 3,488 LoF intolerant genes in our new trio data (rate ratio (RR) (95% CI) = 2.23 (1.31, 3.79); p = 2.2 x 10-3), supporting previous findings. In the full dataset, genes associated with neurodevelopmental disorders (NDD; n=160) were significantly enriched for LoF DNVs (RR (95% CI) = 3.32 (2.0, 5.21); p = 7.4 x 10-6). Within this set of NDD genes, SLC6A1, encoding a gamma-aminobutyric acid transporter, was associated with missense-damaging DNVs (p = 5.2 x 10-5). Using data from a subset of 1,122 trios for which we had genome-wide common variant data, schizophrenia polygenic risk was significantly over-transmitted to probands (p = 2.6 x 10-60), as was bipolar disorder common variant polygenic risk (p = 5.7 x 10-17). We defined carriers of candidate schizophrenia-related DNVs as those with LoF or deletion DNVs in LoF intolerant or NDD genes. These individuals had significantly less over-transmission of common risk alleles than non-carriers (p = 3.5 x 10-4), providing robust support for the hypothesis that this set of DNVs is enriched for those related to schizophrenia.

genetics↗

bioRxiv2019

Genetic association study of psychotic experiences in UK Biobank

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 genome-wide 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=3.06 x 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.

genetics↗

bioRxiv2019

Characterization of single gene copy number variants in schizophrenia

Genetic studies of schizophrenia (SCZ) have now implicated numerous genomic loci that contribute to risk including several copy number variants (CNV) of large effect and hundreds of associated loci of small effect. However, in only a few cases has a specific gene been clearly identified. Rare CNV that affect only a single gene offer a potential avenue to discovering specific SCZ risk genes. Here, we use CNV generated from exome-sequencing of 4,913 SCZ cases and 6,188 controls in a homogenous Swedish cohort to assess the contribution of single-gene deletions and duplications to SCZ risk. As previously seen, we found an excess of rare deletions (p = 0.0004) and duplications (p = 0.0006) in SCZ cases compared to controls. When limiting to only single-gene CNV we identified nominally significant excess of deletions (p = 0.04) and duplications (p = 0.03). In an effort to increase the number of single-gene CNV, we reduced strict filtering criteria but required support from two independent CNV calling methods to create an expanded set that showed a significant burden of deletions in 11 out of 22 gene sets previously implicated in SCZ and in the combined set of genes across those sets (p = 0.008). Finally, for the significantly enriched set of voltage-gated calcium channels, we performed an extensive validation of all deletions generated from exome-sequencing as well as any deletion with evidence from previously analyzed genotyping arrays. In total, 4 exonic, single-gene deletions validated in cases and none in controls (p = 0.039), of which all were identified by exome-sequencing. Broadly, these results point to the potential contribution of single-gene CNV to SCZ and the added value of a deeper dive into CNV calls from exome-sequencing.

genetics↗

bioRxiv2019

Genotype-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

BackgroundA 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 Foundation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeveral 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.

genomics↗

bioRxiv2019

Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtins polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".

genetics↗