Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders

Nishioka, M.; Bundo, Miki; Ueda, Junko; Katsuoka, Fumiki; Kuroki, Yoshio; Ishii, Takao; Ukai, Wataru; Murayama, Shigeo; Hashimoto, Eri; Nagasaki, Masao; Yasuda, Jun; Kasai, Kiyoto; Kato, Takeshi; Iwamoto, Kazuya

doi:10.1111/pcn.12632

Cited by 9 publications

(10 citation statements)

References 61 publications

(101 reference statements)

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“…Previous research has indicated that C>T transitions account for ~80% of somatic SNVs in single neurons [44]. Although some of these C>T transitions were likely derived from artificial C>U deamination due to cell lysis during the preparation of single-cell samples [48], we also observed the same bias for C>T transition following a WGS analysis of bulk brain tissues, which were free from deamination during cell lysis [52]. Neurons have a characteristic 5mC at non-CpG sites and a relatively greater amount of 5-hydroxymethylcytosine (5hmC) than other tissues [72, 73].…”

Section: Biological Mechanisms Underlying Somatic Mutations In the Brainsupporting

confidence: 59%

“…In a recent study, we explored somatic mutations in human brain tissue from three healthy individuals via WGS at a depth of ~100×. Allele fractions were assayed and validated via target amplicon sequencing (TAS), ranging from 0.5 to 14% in bulk tissue obtained from the cortex, cerebellum, and liver [52]. The somatic mutations exhibited considerable spatial diversity; some mutations were observed in the brain but not the liver, while others were observed in the cortex but not the cerebellum.…”

Section: Somatic Mutations In the Brains Of Individuals Without Neuromentioning

confidence: 99%

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Somatic mutations in the human brain: implications for psychiatric research

et al. 2018

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Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene-environment interactions. While recent advances in genomic technologies have enabled the identification of several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions. Somatic mutations in the brain may also explain how stochastic developmental events and environmental insults confer risk for a psychiatric disorder following fertilization. Here, we review evidence regarding somatic mutations in the brains of individuals with and without neuropsychiatric diseases. We further discuss the potential biological mechanisms underlying somatic mutations in the brain as well as the technical issues associated with the detection of somatic mutations in psychiatric research.

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Section: Biological Mechanisms Underlying Somatic Mutations In the Brainsupporting

confidence: 59%

Section: Somatic Mutations In the Brains Of Individuals Without Neuromentioning

confidence: 99%

Somatic mutations in the human brain: implications for psychiatric research

et al. 2018

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“…Somatic mutations in the brain are often found in genes expressed in neurons 80 and, thus, may be involved in psychiatric disorders. 81 Increases of partially deleted mtDNA were reported in postmortem BD brains.…”

Section: Somatic Mutationsmentioning

confidence: 99%

“…Somatic mutations in the brain are often found in genes expressed in neurons and, thus, may be involved in psychiatric disorders …”

Section: Post‐mortem Brain Studiesmentioning

confidence: 99%

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Kato

2019

Psychiatry Clin Neurosci

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Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell‐derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.

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“…We focused on refining the analysis to mainly discard false positives. Our filtering criteria were tailored to discard sequencing artifacts, similar to other studies using Haloplex and common sequencing datasets (22)(23)(24)(25)(26). Advantages of visual analysis are the comprehensive analysis for each variant, easy implementation across datasets; however, it can become labor-intensive.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Somatic Mutations in Human Brains Targeting Genes Associated With Parkinson's Disease

et al. 2020

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Background: Somatic single nucleotide variant (SNV) mutations occur in neurons but their role in synucleinopathies is unknown. Aim: We aimed to identify disease-relevant low-level somatic SNVs in brains from sporadic patients with synucleinopathies and a monozygotic twin carrying LRRK2 G2019S, whose penetrance could be explained by somatic variation. Methods and Results: We included different brain regions from 26 Parkinson's disease (PD), one Incidental Lewy body, three multiple system atrophy cases, and 12 controls. The whole SNCA locus and exons of other genes associated with PD and neurodegeneration were deeply sequenced using molecular barcodes to improve accuracy. We selected 21 variants at 0.33-5% allele frequencies for validation using accurate methods for somatic variant detection. Conclusions: We could not detect disease-relevant somatic SNVs, however we cannot exclude their presence at earlier stages of degeneration. Our results support that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies.

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Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders

Abstract: Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.

Cited by 9 publications

References 61 publications

Somatic mutations in the human brain: implications for psychiatric research

Somatic mutations in the human brain: implications for psychiatric research

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Investigation of Somatic Mutations in Human Brains Targeting Genes Associated With Parkinson's Disease

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