Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

Tang, Jinsong; Fan, Yu; Li, Hong; Xiang, Qun; Zhang, Deng Feng; Li, Zongchang; He, Ying; Liao, Yanhui; Wang, Ya; He, Fan; Zhang, Fengyu; Shugart, Yin Yao; Liu, Chun Yu; Tang, Yanqing; Chan, Raymond C. K.; Wang, Chuanyue; Yao, Yong; Chen, Xiaogang

doi:10.1016/j.jgg.2017.05.005

Cited by 38 publications

(28 citation statements)

References 111 publications

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“…This might suggest that DNMs, inherited rare damaging variants and common risk alleles may lead schizophrenia susceptibility altogether. These results show that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size (48).…”

Section: Psychiatric Disordersmentioning

confidence: 75%

Epigenetic Basis of Twin Discordance in Diseases: Future Benefits

Demir

2018

Gynecol Obstet Reprod Med

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Monozygotic twins share the same genotype since they are derived from the same zygote. However, monozygotic twin siblings frequently present many phenotypic differences, such as their susceptibilities to diseases. These isogenic individuals are not entirely identical. They exhibit phenotypic incompatibility for many features, from birth weight to complex diseases. Recently, several studies have been published showing that phenotypic differences, especially in monozygotic twins, are being induced from prenatal period to life-long epigenetic differences. Epigenetic studies on twins have a great potential to contribute to our understanding of complex diseases, such as cancer, autoimmune disorders, psychiatric disorders and neurological diseases. Since monozygotic twins are genetic clones (genetically identical), they are considered as perfect models for studying the role of environmental factors as determinants of complex diseases and phenotypes. In this review, a number of intrauterine effects and genetic mechanisms that may affect phenotypic, genotypic, and epigenetic differences between monozygotic twins were described and effects of epigenetic mechanisms on complex diseases were mentioned. Further work on epigenetic changes in diseases using incompatible monozygotic twin models, would lead to new developments in medical therapies.

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Section: Psychiatric Disordersmentioning

confidence: 75%

Epigenetic Basis of Twin Discordance in Diseases: Future Benefits

Demir

2018

Gynecol Obstet Reprod Med

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“…DSCR3 : Down Syndrome Critical Region Gene 3 has previously been associated with neuroticism in a genome wide linkage study [4]. C14orf182 has been associated with schizophrenia in a Whole Genome Sequencing study done in discordant twins [66]. DGKZ is located within a schizophrenia GWAS loci and is further known to be dysregulated in schizophrenia patients [3, 49].…”

Section: Resultsmentioning

confidence: 99%

Finding associations in a heterogeneous setting: Statistical test for aberration enrichment

Mezlini

Das

Goldenberg

2020

Preprint

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Most two-group statistical tests are implicitly looking for a broad pattern such as an overall shift in mean, median or variance between the two groups. Therefore, they operate best in settings where the effect of interest is uniformly affecting everyone in one group versus the other. In real-world applications, there are many scenarios where the effect of interest is heterogeneous. For example, a drug that works very well on only a proportion of patients and is equivalent to a placebo on the remaining patients, or a disease associated gene expression dysregulation that only occurs in a proportion of cases whereas the remaining cases have expression levels indistinguishable from the controls for the considered gene. In these examples with heterogeneous effect, we believe that using classical two-group statistical tests may not be the most powerful way to detect the signal. In this paper, we developed a statistical test targeting heterogeneous effects and demonstrated its power in a controlled simulation setting compared to existing methods. We focused on the problem of finding meaningful associations in complex genetic diseases using omics data such as gene expression, miRNA expression, and DNA methylation. In simulated and real data, we showed that our test is complementary to the traditionally used statistical tests and is able to detect disease-relevant genes with heterogeneous effects which would not be detectable with previous approaches.

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“…At present, studies assessing monozygotic twins discordant for SLE by using WGS are rare. Due to the possibility of the existence of de novo variants and alterations of CNVs in monozygotic twins (13,15,18,30), the present study used WGS to explore the possible disease-causing variants which are responsible for the discordance in monozygotic twins regarding SLE. A total of 8 putative discordant variants in the DNA of leukocytes were selected out for validation by Sanger sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…They identified genetic differences in the IRF6 gene that are associated with the phenotype discordance for the monozygotic twin. In the present study, whole-genome sequencing (WGS), a widely used research tool for studying genetic disease (16)(17)(18), was applied to assess a monozygotic twin discordant for SLE to identify the possibly responsible mutation(s).…”

Section: Introductionmentioning

confidence: 99%

Whole‑genome sequencing of a monozygotic twin discordant for systemic lupus erythematosus

Chen

et al. 2018

Mol Med Report

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Systemic lupus erythematosus (SLE) is an autoimmune disease, and its genetic causes remain to be fully elucidated. Previous studies have identified several susceptibility genes for SLE, such as deoxyribonuclease 1‑like 3. In the present study, whole‑genome sequencing (30X coverage) was performed on the leukocytes of a monozygotic twin discordant for SLE to assess the potential association of de novo variants and copy number variations (CNVs) with the susceptibility to SLE. After analyzing the genomic data, 8 putative discordant exonic variants between the twins were selected. However, the 8 variants that were chosen for validation with Sanger sequencing exhibited no discrepancy in the leukocytes from the twins. Of note, CNV alterations in genes of SLE‑associated pathways were identified between the twins, which may be linked with the phenotype of the monozygotic twin discordant for SLE. The above results suggest that genomic sequences of leukocytes in the monozygotic twins may exhibit a rare difference, and that CNV changes may be associated with phenotype differences in the twin discordant for SLE.

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Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

Cited by 38 publications

References 111 publications

Epigenetic Basis of Twin Discordance in Diseases: Future Benefits

Epigenetic Basis of Twin Discordance in Diseases: Future Benefits

Finding associations in a heterogeneous setting: Statistical test for aberration enrichment

Whole‑genome sequencing of a monozygotic twin discordant for systemic lupus erythematosus

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