Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

@article{Johnson2016SystemsGI,
  title={Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease},
  author={Michael R. Johnson and Kirill Shkura and Sarah R. Langley and A. Delahaye-Duriez and P. Srivastava and W. Hill and O. Rackham and G. Davies and S. Harris and Aida Moreno-Moral and M. Rotival and D. Speed and S. Petrovski and Ana{\"i}s Katz and C. Hayward and D. Porteous and Blair H. Smith and S. Padmanabhan and L. Hocking and J. Starr and D. Liewald and A. Visconti and M. Falchi and L. Bottolo and Tiziana Rossetti and B. Danis and M. Mazzuferi and P. Foerch and A. Grote and C. Helmstaedter and A. Becker and R. Kaminski and I. Deary and E. Petretto},
  journal={Nature Neuroscience},
  year={2016},
  volume={19},
  pages={223-232}
}
Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6… Expand
Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions
TLDR
The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions. Expand
Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions
TLDR
The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions. Expand
The architecture of brain co-expression reveals the brain-wide basis of disease susceptibility
TLDR
This work identifies enrichment of neuropsychiatric disease risk variants in brain wide and multi-regional modules, consistent with their broad impact on cell classes, and highlights specific roles in neuronal proliferation and activity-dependent processes. Expand
An Automated Functional Annotation Pipeline That Rapidly Prioritizes Clinically Relevant Genes for Autism Spectrum Disorder
TLDR
Results from this work should rapidly prioritize potentially actionable results from genetic studies and, in turn, inform future work toward clinical decision support for personalized care based on genetic testing. Expand
Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery
TLDR
Functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly is suggested. Expand
Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics
TLDR
The current results represent the first efforts to apply a multi-method approach to integrate gene expression and SNP level data to identify credible actionable genes for general cognitive ability. Expand
Prefrontal co-expression of schizophrenia risk genes is associated with treatment response in patients
TLDR
Findings in a large sample of human post-mortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. Expand
Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders
TLDR
It is shown that individuals with schizophrenia carry a significant burden of rare damaging variants in a subset of 3,230 “highly constrained” genes previously identified as having near-complete depletion of protein truncating variants, and that schizophrenia risk loci of large effect across a range of variant types implicate a common set of genes shared with broader neurodevelopmental disorders. Expand
Prefrontal Coexpression of Schizophrenia Risk Genes Is Associated With Treatment Response in Patients
TLDR
The findings in 1983 samples of human postmortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. Expand
Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders
TLDR
A pipeline used in ASD studies is extended and applied to infer rare genetic parameters for SCZ and four NDDs, finding many new DD risk genes, supported by gene set enrichment and PPI network connectivity analyses. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 91 REFERENCES
De novo mutations in schizophrenia implicate synaptic networks
TLDR
Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways, and pathophysiology shared with other neurodevelopmental disorders. Expand
Synaptic, transcriptional, and chromatin genes disrupted in autism
TLDR
Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30). Expand
Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology
TLDR
Results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease. Expand
Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins
TLDR
The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence. Expand
Mutation Burden of Rare Variants in Schizophrenia Candidate Genes
TLDR
The absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion supported by the moderate success of Genome-Wide Association Studies (GWAS). Expand
Genetic variability in the regulation of gene expression in ten regions of the human brain
TLDR
This study presents a large, exon-specific eQTL data set covering ten human brain regions and finds that cis-eQTL signals (within 1 Mb of their target gene) were numerous, and many acted heterogeneously among regions and exons. Expand
Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence
TLDR
Evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term used to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders. Expand
Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice
TLDR
Evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. Expand
De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia
TLDR
It is shown that de novo mutations affect genes with diverse functions and developmental profiles, but it is also found a substantial contribution of mutations in genes with higher expression in early fetal life. Expand
Spatial and Temporal Mapping of De Novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network
TLDR
It is suggested that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia and the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain is supported. Expand
...
1
2
3
4
5
...