Shared Molecular Neuropathology Across Major Psychiatric Disorders Parallels Polygenic Overlap

Gandal, Michael J.; Haney, Jillian R.; Parikshak, Neelroop N.; Leppä, Virpi; Ramaswami, Gokul; Hartl, Christopher; Schork, Andrew J.; Appadurai, Vivek; Buil, Alfonso; Werge, Thomas; Liu, Chunyu; White, Kevin P.; Geschwind, Daniel H.

doi:10.1176/appi.focus.17103

Cited by 154 publications

(283 citation statements)

References 96 publications

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“…Accumulating evidence suggests that mental disorders that are diagnosed by psychiatrists as different entities are closely related from a biological point of view. Genetic risk factors overlap across these disorders [1,2], and common structural changes in the brain and deficits in cognitive circuits are seen despite potentially different etiologies [3,4]. On the other hand, advanced brain imaging and high-throughput genomic studies of psychiatric patients have provided evidence that each of these major mental disorders can be stratified into different biological subclasses based on specific genetic components and so called endophenotypes, i.e., quantitative biological traits, such as gene expression, anatomical alterations, specific behavior, etc.…”

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confidence: 99%

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

et al. 2019

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Canonical Wnt signaling, which is transduced by β‐catenin and lymphoid enhancer factor 1/T cell‐specific transcription factors (LEF1/TCFs), regulates many aspects of metazoan development and tissue renewal. Although much evidence has associated canonical Wnt/β‐catenin signaling with mood disorders, the mechanistic links are still unknown. Many components of the canonical Wnt pathway are involved in cellular processes that are unrelated to classical canonical Wnt signaling, thus further blurring the picture. The present review critically evaluates the involvement of classical Wnt/β‐catenin signaling in developmental processes that putatively underlie the pathology of mental illnesses. Particular attention is given to the roles of LEF1/TCFs, which have been discussed surprisingly rarely in this context. Highlighting recent discoveries, we propose that alterations in the activity of LEF1/TCFs, and particularly of transcription factor 7‐like 2 (TCF7L2), result in defects previously associated with neuropsychiatric disorders, including imbalances in neurogenesis and oligodendrogenesis, the functional disruption of thalamocortical circuitry and dysfunction of the habenula.

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confidence: 99%

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

et al. 2019

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“…Autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD) are common conditions of childhood, and the aetiology includes both genetic and environmental factors. 1,2 Epidemiological studies have reported a higher rate of maternal autoimmunity in children with ASD and Tourette syndrome. 3,4 It has been hypothesized that maternal autoimmunity and other maternal immune factors may pose a risk to the fetus through 'maternal immune activation', 5,6 whereby the inflammatory milieu in utero is thought to result in epigenetic alteration of expression of genes involved in neuronal development and/or activation of the resident immune cells of the brain, the microglia.…”

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confidence: 99%

Maternal thyroid autoimmunity associated with acute‐onset neuropsychiatric disorders and global regression in offspring

Jones

Sharma

et al. 2019

Develop Med Child Neuro

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Epidemiological studies, animal models, and case–control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive–compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4–15y]; six males and two females) referred over a 2‐year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre‐existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing‐remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. What this paper adds Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.

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“…This finding is congruent with the evolving concept of shared molecular neuropathology across SMI. 19 These, along with other identified genes known to be involved in neurodevelopmental processes (e.g., PLXND1) or known to have manifold higher brain expression (e.g., ANLN, LRRC8B) are potential targets to be examined in future studies of SMI. Lastly, of the 12 genes encoding highly conserved epidermal growth factor-like domains and showing nominally significant enrichment to this domain, many encode for proteins that play critical roles during embryogenesis and neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

“…7 Such overlaps have also been observed across diverse neuropsychiatric syndromes, for both common and rare genetic variations, as well as in gene expression profiles in the cerebral cortex. 19,20 These findings indicate an underlying shared molecular pathology in the pathobiology of SMI.…”

mentioning

confidence: 92%

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

Ganesh

Pallikonda

Nadella

et al. 2018

Psychiatry Clin Neurosci

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Aim Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome‐wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next‐generation sequencing may add to the understanding of the genetic architecture of SMI. Methods We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole‐exome sequencing. Prioritized variants were selected by a three‐step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool. Results We identified 42 rare, non‐synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome. Conclusion Next‐generation sequencing approaches in family‐based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

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Shared Molecular Neuropathology Across Major Psychiatric Disorders Parallels Polygenic Overlap

Cited by 154 publications

References 96 publications

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

Maternal thyroid autoimmunity associated with acute‐onset neuropsychiatric disorders and global regression in offspring

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

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