Genome-wide association studies in schizophrenia: Recent advances, challenges and future perspective

Dennison, Charlotte; Legge, Sophie E.; Pardiñas, Antonio F.; Walters, James

doi:10.1016/j.schres.2019.10.048

Cited by 58 publications

(35 citation statements)

References 84 publications

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“…Schizophrenia is driven by genetic factors, as the risk for developing this disorder increases from 1% in the general populationto 50% in individuals with a diagnosed twin ( Cardno and Gottesman, 2000 ; Stefansson et al, 2009 ). Recent ground-breaking genome-wide association studies (GWAS) have made progress in discovering loci throughout the genome that are associated with SCZ ( Schizophrenia Psychiatric Genome-Wide Association Study Consortium, 2011 ; Ripke et al, 2013 ; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014 ; Li et al, 2017 ; Dennison et al, 2019 ). These studies reveal that SCZ has a heterogeneous etiology, with genes likely conferring risk across the entire genome.…”

Section: Genetic Risk Factors That Interplay With Immunological Respomentioning

confidence: 99%

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

Comer

Carrier

Tremblay

et al. 2020

Front. Cell. Neurosci.

154

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Section: Genetic Risk Factors That Interplay With Immunological Respomentioning

confidence: 99%

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

Comer

Carrier

Tremblay

et al. 2020

Front. Cell. Neurosci.

154

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“…Our understanding of the origin of psychiatric pathologies such as schizophrenia and ASDs has recently progressed substantially thanks to large Genome Wide Association studies (GWAs) which have shown that, beyond some specific cases where monogenic mutations cause highly penetrant phenotypes, psychiatric conditions are complex polygenic disorders associated with hundreds of common genetic loci involving genes associated to synaptic function and neural development (Huguet, et al 2016;Dennison, et al 2019). Module analysis of gene-networks implicated in interneuron-dependent ASD and schizophrenia has identified gene expression variations and splicing of DLX5, DLX6 and asDLX6nc.…”

Section: Discussionmentioning

confidence: 99%

DLX5/6GABAergic expression affects social vocalization: implications for human evolution

Levi

Lombares

Giuliani

et al. 2020

Preprint

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DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated to neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioural and metabolic phenotypes notably increasing lifespan by 33%.Here, we show that Dlx5/6VgatCre mice present an hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1400 calls/10min with longer, uninterrupted, call sequences and a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time they spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals.We then compared the DLX5/6 genomic regions from Neanderthal and modern humans to examine if DLX5/6 GABAergic expression could have been involved in human social evolution. We identify an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype is not significantly associated to Autism Spectrum Disorders (ASDs) but includes the binding site for GTF2I, a gene associated to Williams-Beuren syndrome, a neurodevelopmental disorder characterized by hyper-sociability and hyper-vocalization. Interestingly, the DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (>105y of age), a well-established human model of healthy ageing and longevity, suggesting its potential involvement in the co-evolution of longevity, sociability and speech.

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“…This is primarily due to the challenge of bridging the large-scale gap, i.e., the gap between the nano-and micro-scales, where chemical and molecular principles govern, and the much larger macroscale of the symptomatic phenomena we wish to understand (Figure 1). Previous genetic studies have demonstrated that schizophrenia is a highly heritable disorder [1][2][3]. However, genetic association does not provide insights into the network of causality between the synapse, cell, circuit, and behavioral scales of the disorder.…”

Section: Introductionmentioning

confidence: 99%

Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia

2020

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Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale). It is likely that each scale affects the others, from the microscale to the mesoscale to the macroscale, and vice versa. Thus, to consider the intricate complexity of schizophrenia across multiple layers, we introduce a multi-scale, hierarchical view of the nature of this disorder, focusing especially on N-methyl-D-aspartate-type glutamate receptors (NMDARs). The reason for placing emphasis on NMDAR is its clinical relevance to schizophrenia, as well as its diverse functions in neurons, including the robust supralinear synaptic integration provided by N-methyl-D-aspartate-type glutamate (NMDA) spikes and the Ca2+ permeability of the NMDAR, which facilitates synaptic plasticity via various calcium-dependent proteins. Here, we review recent evidence implicating NMDARs in the pathophysiology of schizophrenia from the multi-scale perspective. We also discuss recent advances from optical techniques, which provide a powerful tool for uncovering the mechanisms of NMDAR synaptic pathology and their relationships, with subsequent behavioral manifestations.

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Genome-wide association studies in schizophrenia: Recent advances, challenges and future perspective

Cited by 58 publications

References 84 publications

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

DLX5/6GABAergic expression affects social vocalization: implications for human evolution

Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia

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