Genetic Approaches to Understanding Psychiatric Disease

Michaelson, Jacob J.

doi:10.1007/s13311-017-0551-x

Cited by 6 publications

(3 citation statements)

References 249 publications

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“…Schizophrenia is known to have high heritability (60–90%; [ 85 , 86 ]) so ascertainment of specific risk genes is critical to understanding its etiology and pathophysiology. Three general approaches have been predominantly employed to detect specific genetic risk factors in schizophrenia studies: GWAS for common variants (each conferring very low risk); whole exome examination of ultra-rare coding variants (potentially conferring substantial risk); and rare CNVs (also with low risk; see O’Donovan et al [ 87 ] and Michaelson [ 88 ], for reviews on technical issues in psychiatric genetics [ 87 , 88 ]).…”

Section: Genetic Studiesmentioning

confidence: 99%

Glutamatergic dysfunction in Schizophrenia

Kruse

Bustillo

2022

Transl Psychiatry

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The NMDA-R hypofunction model of schizophrenia started with the clinical observation of the precipitation of psychotic symptoms in patients with schizophrenia exposed to PCP or ketamine. Healthy volunteers exposed to acute low doses of ketamine experienced mild psychosis but also negative and cognitive type symptoms reminiscent of the full clinical picture of schizophrenia. In rodents, acute systemic ketamine resulted in a paradoxical increase in extracellular frontal glutamate as well as of dopamine. Similar increase in prefrontal glutamate was documented with acute ketamine in healthy volunteers with 1H-MRS. Furthermore, sub-chronic low dose PCP lead to reductions in frontal dendritic tree density in rodents. In post-mortem ultrastructural studies in schizophrenia, a broad reduction in dendritic complexity and somal volume of pyramidal cells has been repeatedly described. This most likely accounts for the broad, subtle progressive cortical thinning described with MRI in- vivo. Additionally, prefrontal reductions in the obligatory GluN1 subunit of the NMDA-R has been repeatedly found in post-mortem tissue. The vast 1H-MRS literature in schizophrenia has documented trait-like small increases in glutamate concentrations in striatum very early in the illness, before antipsychotic treatment (the same structure where increased pre-synaptic release of dopamine has been reported with PET). The more recent genetic literature has reliably detected very small risk effects for common variants involving several glutamate-related genes. The pharmacological literature has followed two main tracks, directly informed by the NMDA-R hypo model: agonism at the glycine site (as mostly add-on studies targeting negative and cognitive symptoms); and pre-synaptic modulation of glutamatergic release (as single agents for acute psychosis). Unfortunately, both approaches have failed so far. There is little doubt that brain glutamatergic abnormalities are present in schizophrenia and that some of these are related to the etiology of the illness. The genetic literature directly supports a non- specific etiological role for glutamatergic dysfunction. Whether NMDA-R hypofunction as a specific mechanism accounts for any important component of the illness is still not evident. However, a glutamatergic model still has heuristic value to guide future research in schizophrenia. New tools to jointly examine brain glutamatergic, GABA-ergic and dopaminergic systems in-vivo, early in the illness, may lay the ground for a next generation of clinical trials that go beyond dopamine D2 blockade.

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Section: Genetic Studiesmentioning

confidence: 99%

Glutamatergic dysfunction in Schizophrenia

Kruse

Bustillo

2022

Transl Psychiatry

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“…During the past decade, rapid advances in high throughput technologies have helped investigators, aiming to uncover disease causal genes and their actions in complex diseases. Specifically, in psychiatric genetics, there have been numerous datasets from different platforms or sources such as association studies, including genome‐wide association studies, genome‐wide linkage scans, microarray gene expression, and copy number variation (Michaelson, ). Large‐scale and individual genetic studies revealed various polymorphisms and overexpression of certain genes in patients presenting with depressive symptoms (Lacerda‐Pinheiro et al, ; Milanesi et al, ).…”

Section: Introductionmentioning

confidence: 99%

Prioritization and comprehensive analysis of genes related to major depressive disorder

Liu

Fan

Zhang

et al. 2019

Molec Gen & Gen Med

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Background Major depressive disorder (MDD) is a serious mental health problem in modern society, which is difficult to identify and diagnose in the early stages. Despite strong evidence supporting the heritability of MDD, progresses in large‐scale and individual genetic studies remain preliminary. Methods In this study, a multi‐data source‐based prioritization (MDSP) method was proposed, and an appropriate threshold was determined for the optimization of depression‐related genes (DEPgenes). Analyses on Gene Ontology biological processes, KEGG pathway and the specific pathway crosstalk network were further proposed. Results A total of 143 DEPgenes were identified and the MDD‐specific network was constructed for the pathogenesis investigation and therapeutic methods development of MDD. Comparing with existing research strategies, the genetic optimization and analysis results were confirmed to be reliable. Finally, the pathway enrichment and crosstalk analyses revealed two unique pathway interaction modules that were significantly enriched with MDD genes. The related core pathways of neuroactive ligand‐receptor interaction and dopaminergic synapse supported the neuropathology hypothesis of MDD. And the pathways of serotonergic synapse and morphine addiction indicated the mechanism of drug addiction caused by serotonin used in the treatment. Conclusions This work provided a reference for the study of MDD, although future validation by extensive experimentation is still required.

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“…Given the complexity of this topic, the first article in this section, by Jacob Michaelson [4], provides an accessible overview of the field along with in-depth discussion of the applicat i o n o f g e n o m i c s t o s t u d y i n g t h e e t i o l o g y o f neurodevelopmental disorders. The second article in this section, by Benjamin Pickard [5], describes modern genomic approaches that are being used to identify and explore key differences between patients that do or do not respond to lithium.…”

mentioning

confidence: 99%