Biology subjects

Walters, J. T.

Publications and source records attributed to Walters, J. T..

4 recordsLinked to original sources

bioRxiv2018

A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia

Schizophrenia is a complex highly heritable disorder. Genome-wide association studies have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. Here we link genetic findings to gene expression in the human brain by performing a transcriptome-wide association study (TWAS) in which we integrate the largest published genome-wide association dataset of schizophrenia, with publically available post mortem expression data from the dorsolateral prefrontal cortex (DLPFC). We identify a significant correlation between schizophrenia risk and expression at eighty-nine genes in DLPFC, including forty-two genes not identified in earlier TWAS of this transcriptomic resource. Genes whose expression correlate with schizophrenia were enriched for those involved in nervous system development, abnormal synaptic transmission, reduced long term potentiation, and calcium-dependent cell-cell adhesion. Previous genetic studies have implicated post-synaptic glutamatergic and gabaergic processes in schizophrenia; here we extend this to include molecules that regulate presynaptic transmitter release. We identify specific candidate genes to which we assign predicted directions of effect in terms of expression level, facilitating downstream experimental studies geared towards a better mechanistic understanding of schizophrenia pathogenesis.

genetics↗

bioRxiv2018

The role of rare copy number variants in depression

The 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=1.61x10-8), 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.

neuroscience↗

bioRxiv2018

Dynamic expression of risk genes for schizophrenia and bipolar disorder across development

AO_SCPCAPBSTRACTC_SCPCAPCommon genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between schizophrenia and bipolar disorder. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genes associated with schizophrenia have a strong bias towards increased expression in the prefrontal cortex during early midfetal development and early infancy, and decreased expression during late childhood which normalises in adolescence. Risk-associated genes for bipolar disorder shared this postnatal expression profile but did not exhibit a bias towards expression at any prenatal stage. These results emphasise the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the view that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.

neuroscience↗

bioRxiv2018

Medical consequences of pathogenic CNVs in adults: Analysis of the UK Biobank.

BackgroundGenomic copy number variants (CNVs) increase risk for early-onset neurodevelopmental disorders but their impact on medical outcomes in later life is poorly understood. The UK Biobank, with half a million well-phenotyped adults, presents an opportunity to study the medical consequences of CNV in middle and old age.\n\nMethodsWe called 54 CNVs associated with clinical phenotypes or genomic disorders, including their reciprocal deletions or duplications, in all Biobank participants. We used logistic regression analysis to test CNVs for associations with 58 common medical phenotypes.\n\nFindingsCNV carriers had an increased risk of developing 37 of the 58 phenotypes at nominal levels of statistical significance, with 19 associations surviving Bonferroni correction (p<8{middle dot}6x10-4). Tests of each of the 54 CNVs for association with each of the 58 phenotypes identified 18 associations that survived Bonferroni correction (p<1{middle dot}6x10-5) and a further 57 that were associated at a false discovery rate (FDR) threshold of 0{middle dot}1. Thirteen CNVs had three or more significant associations at FDR=0{middle dot}1, with the largest number of phenotypes (N=15) found for deletions at 16p11{middle dot}2. The most common CNVs (frequency 0{middle dot}5-0{middle dot}7%) have no or minimal impact on medical outcomes in adults.\n\nInterpretationSome of the 54 tested CNVs have profound effects on physical health, even in people who have largely escaped early neurodevelopmental outcomes. Our work provides clinicians with a morbidity map of potential outcomes among carriers of these CNVs.\n\nFundingMRC UK, Wellcome Trust UK

genomics↗