Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease

Morimoto, Yoshiro; Ono, Shinji; Imamura, Akira; Okazaki, Yuji; Kinoshita, Akira; Mishima, Hiroyuki; Nakane, Hideyuki; Ozawa, Hiroki; Yoshiura, Koh-ichiro; Kurotaki, Naohiro

doi:10.1038/hgv.2017.32

Cited by 23 publications

(18 citation statements)

References 37 publications

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“…Trying to disentangle environmental influences on complex human behavior is difficult due to gene-environment interplay and the heritability of environmental assessments, such as socioeconomic status, stress, exercise, and nutrition. MZ twins share identical genomes except for somatic mutations that may confer differential disease risk between co-twins [36]. However, MZ twin difference designs are still the best method for assessing the influence of environment while controlling for genetic influence on complex phenotypes [37].…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

et al. 2019

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Individual differences in cognitive function are due to a combination of heritable and non-heritable factors. A large body of evidence from clinical, cognitive, and pharmacological neuroscience implicates dopaminergic gene variants as modulators of cognitive functions. Neuroepigenetic studies demonstrate environmental factors also influence complex phenotypes by affecting gene expression regulation. To evaluate the mechanism of environmental influence on cognitive abilities, we examined if epigenetic regulation of dopaminergic genes plays a role in cognition. Using a DNA methylation profiling microarray, we used a monozygotic (MZ) twin difference design to evaluate if co-twin differences in methylation of CpG sites near six dopaminergic genes predicted differences in response inhibition and memory performance. Studying MZ twins allows us to assess if environmentally driven differences in methylation affect differences in phenotype while controlling for the influence of genotype and shared family environment. Response inhibition was assessed with the flanker task and short-term and working memory were assessed with digit span recall. We found MZ co-twin differences in DRD4 gene methylation predicted differences in short-term memory. MZ differences in COMT, DBH, DAT1, DRD1, and DRD2 gene methylation predicted differences in response inhibition. Taken together, findings suggest methylation status of dopaminergic genes may influence cognitive functions in a dissociable manner. Our results highlight the importance of the epigenome and environment, over and above the influence of genotype, in supporting complex cognitive functions. ARTICLE HISTORYORCID Candace R. Lewis http://orcid.org/0000-0001-5253-9989 Reagan S. Breitenstein http://orcid.org/0000-0001-9998-166X

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Section: Introductionmentioning

confidence: 99%

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

et al. 2019

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“…27 and TDRP [chr8:442616; A>G]) between monozygotic twins discordant for gender dysphoria. 30 Further investigations including functional analysis and epidemiological analysis are needed to confirm the significance of the mutations found in this study. Overall, these genetic studies are inconclusive and a role for genes in gender identity remains unsettled.…”

Section: Genesmentioning

confidence: 82%

“…There are also conflicting reports of associations between polymorphisms in the androgen receptor, oestrogen receptor β and CYP19 (ie, aromatase, the enzymes catalysing oestradiol synthesis) . A recent study using deep sequencing detected three low allele frequency gene mutants (i.e., FBXO38 [chr5:147774428; T>G], SMOC2 [chr6:169051385; A>G] and TDRP [chr8:442616; A>G]) between monozygotic twins discordant for gender dysphoria . Further investigations including functional analysis and epidemiological analysis are needed to confirm the significance of the mutations found in this study.…”

Section: Gender Identitymentioning

confidence: 99%

Neurobiology of gender identity and sexual orientation

Roselli

2018

J Neuroendocrinology

103

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Sexual identity and sexual orientation are independent components of a person's sexual identity. These dimensions are most often in harmony with each other and with an individual's genital sex, but not always. This review discusses the relationship of sexual identity and sexual orientation to prenatal factors that act to shape the development of the brain and the expression of sexual behaviors in animals and humans. One major influence discussed relates to organizational effects that the early hormone environment exerts on both gender identity and sexual orientation. Evidence that gender identity and sexual orientation are masculinized by prenatal exposure to testosterone and feminized in it absence is drawn from basic research in animals, correlations of biometric indices of androgen exposure and studies of clinical conditions associated with disorders in sexual development. There are, however, important exceptions to this theory that have yet to be resolved.Family and twin studies indicate that genes play a role, but no specific candidate genes have been identified. Evidence that relates to the number of older brothers implicates maternal immune responses as a contributing factor for male sexual orientation. It remains speculative how these influences might relate to each other and interact with postnatal socialization. Nonetheless, despite the many challenges to research in this area, existing empirical evidence makes it clear that there is a significant biological contribution to the development of an individual's sexual identity and sexual orientation.

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“…TDRP , the second gene in the microduplication, is known to be involved in sperm motility (Mao et al, ). A rare missense variant in TDRP has been reported in monozygotic twins with gender dysphoria (Morimoto et al, ). Otherwise, little is known about this gene up to now.…”

Section: Discussionmentioning

confidence: 99%

From man to fly – convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes

Harich

Klein

Ockeloen

et al. 2019

Child Psychology Psychiatry

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Background: Mental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD), have a complex etiology, and identification of underlying genetic risk factors is challenging. This study used a multistep approach to identify and validate a novel risk gene for ADHD and psychiatric comorbidity. Methods: In a single family, severely affected by ADHD and cooccurring disorders, we applied single nucleotide polymorphism (SNP)-array analysis to detect copynumber variations (CNVs) linked to disease. Genes present in the identified CNV were subsequently tested for their association with ADHD in the largest data set currently available (n = 55,374); this gene-set and gene-based association analyses were based on common genetic variants. Significant findings were taken forward for functional validation using Drosophila melanogaster as biological model system, altering gene expression using the GAL4-UAS system and a pan-neuronal driver, and subsequently characterizing locomotor activity and sleep as functional readouts. Results: We identified a copy number gain in 8p23.3, which segregated with psychiatric phenotypes in the family and was confirmed by quantitative RT-PCR. Common genetic variants in this locus were associated with ADHD, especially those in FBXO25 and TDRP. Overexpression of the FBXO25 orthologue in two Drosophila models consistently led to increased locomotor activity and reduced sleep compared with the genetic background control. Conclusions: We combine ADHD risk gene identification in an individual family with genetic association testing in a large case-control data set and functional validation in a model system, together providing an important illustration of an integrative approach suggesting that FBXO25 contributes to key features of ADHD and comorbid neuropsychiatric disorders. and Annette.Schenck@radboud umc.nl (A.S.) Key pointsIntegration of data across multiple levels can help in gene identification for psychiatric disorders. Microduplication cosegregated with different psychiatric phenotypes, ranging from learning difficulties to ADHD, psychosis, substance use, and aggressive behavior.First report providing evidence for FBXO25, a gene involved in ubiquitination, having a role in the nervous system.De novo variant in DUSP16 may have modifying role in early development of the patient's severe psychiatric phenotypes. Information about common variants may be used to support decisions about (clinical) relevance of rare genetic variants.

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Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease

Cited by 23 publications

References 37 publications

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

Neurobiology of gender identity and sexual orientation

From man to fly – convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes

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