Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients

Li, M; Shen, Lu; Chen, Luan; Cong, Hui; Huang, Hailiang; Wu, Xi; Yang, Chao; Ma, Jianchao; Zhou, Wei; Du, Huihui; Fan, Lingzi; Wan, Chunling; Qin, Shengying

doi:10.1038/s41398-020-0708-y

Cited by 22 publications

(19 citation statements)

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“…The average age of parents is 52.8 ± 9.21, and the average age of probands are 26.8 ± 9.02.Diagnoses of SCZ in the participants were made by two independent qualified psychiatrists according to DSM-IV criteria. Identification of genetic relationship between each parents and children in all family trios were test by kinship analysis based on 18 short tandem repeats loci (including AMEX, D3S1358, D13S317, D7S820, D16S539, Penta E, TPOX, TH01, D2S1338, CSF1PO, D19S433, vWA, D5S818, FGA, D6S1043, D8S1179, D21S11, D18S51) or whole exome sequencing data by our previous study ( Li et al., 2020 ). The DNA sample of 75 controls (without mental disease, 36 males and 38 females) were previously collected and stored in Bio-X Institutes, Shanghai Jiao Tong University, without age records.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

Cong

Shen

et al. 2021

iScience

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Summary Schizophrenia (SCZ) is a severe neuropsychiatric disorder that affects 1% of the global population. Copy number variations (CNVs) have been shown to play a critical role in its pathophysiology; however, only case-control studies on SCZ susceptibility CNVs have been conducted in Han Chinese. Here, we performed an array comparative genomic hybridization-based genome-wide CNV analysis in 100 Chinese family trios with SCZ. Burden test suggested that the SCZ probands carried more duplications than their healthy parents and unrelated healthy controls. Besides, five CNV loci were firstly reported to be associated with SCZ here, including both unbalanced transmitted CNVs and enriched de novo CNVs. Moreover, two genes ( CTDSPL and MGAM ) in these CNVs showed significant SCZ relevance in the expression level. Our findings support the crucial role of CNVs in the etiology of SCZ and provide new insights into the underlying mechanism of SCZ pathogenesis.

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Section: Methodsmentioning

confidence: 99%

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

Cong

Shen

et al. 2021

iScience

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“…The first hit, i.e., the genetic predisposition, has recently been addressed by several genome-wide association studies (GWAS), copy number variation analyses, as well as exome sequencing approaches and hundreds of risk gene loci with variable effect sizes have been identified (Marshall et al, 2017 ; Pardiñas et al, 2018 ; Li et al, 2020 ). Among the best, repeatedly found, “cross-disorder” pleiotropic risk genes for neurodevelopmental psychiatric disorders is Transcription Factor 4 ( TCF4 ) that has been shown to be implicated in autism spectrum disorder, major depression, and schizophrenia (Forrest et al, 2018 ; Pardiñas et al, 2018 ; Amare et al, 2019 ; Calabrò et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

PsyCoP – A Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling Reveals Gene and Environment Dependent Impairments of Tcf4 Transgenic Mice Subjected to Social Defeat

Volkmann

Stephan

Krackow

et al. 2021

Front. Behav. Neurosci.

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Recently, hundreds of risk genes associated with psychiatric disorders have been identified. These are thought to interact with environmental stress factors in precipitating pathological behaviors. However, the individual phenotypes resulting from specific genotype by environment (G×E) interactions remain to be determined. Toward a more systematic approach, we developed a novel standardized and partially automatized platform for systematic behavioral and cognitive profiling (PsyCoP). Here, we assessed the behavioral and cognitive disturbances in Tcf4 transgenic mice (Tcf4tg) exposed to psychosocial stress by social defeat during adolescence using a “two-hit” G×E mouse model. Notably, TCF4 has been repeatedly identified as a candidate risk gene for different psychiatric diseases and Tcf4tg mice display behavioral endophenotypes such as fear memory impairment and hyperactivity. We use the Research Domain Criteria (RDoC) concept as framework to categorize phenotyping results in a translational approach. We propose two methods of dimension reduction, clustering, and visualization of behavioral phenotypes to retain statistical power and clarity of the overview. Taken together, our results reveal that sensorimotor gating is disturbed by Tcf4 overexpression whereas both negative and positive valence systems are primarily influenced by psychosocial stress. Moreover, we confirm previous reports showing that deficits in the cognitive domain are largely dependent on the interaction between Tcf4 and psychosocial stress. We recommend that the standardized analysis and visualization strategies described here should be applied to other two-hit mouse models of psychiatric diseases and anticipate that this will help directing future preclinical treatment trials.

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“…UniProtKB database reveals the occurrence of human SCO-spondin at transcriptomic level (A2VEC9) although the Human Genome Organization Gene Nomenclature Committee classifies human SCO-spondin as pseudogen (HGNC: 21998). The relevance of clarifying this aspect lies in the fact that anormal human SCO-spondin has been linked to several pathologies, including hydrocephaly [ 26 , 175 ], Parkinson’s disease [ 181 ], phenylketonuria [ 182 ], cancer [ 183 ], congenital midline cervical cleft [ 184 ], and schizophrenia [ 185 ]. In relation to schizophrenia, is interesting to highlight that this disease is related with cerebral aqueduct stenosis [ 186 ] and hydrocephaly [ 187 ], two pathologies also associated with SCO-spondin anomalies [ 26 , 175 ].…”

Section: Discussionmentioning

confidence: 99%

SCO-spondin, a giant matricellular protein that regulates cerebrospinal fluid activity

Sepúlveda

Maurelia

González

et al. 2021

Fluids Barriers CNS

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Cerebrospinal fluid is a clear fluid that occupies the ventricular and subarachnoid spaces within and around the brain and spinal cord. Cerebrospinal fluid is a dynamic signaling milieu that transports nutrients, waste materials and neuroactive substances that are crucial for the development, homeostasis and functionality of the central nervous system. The mechanisms that enable cerebrospinal fluid to simultaneously exert these homeostatic/dynamic functions are not fully understood. SCO-spondin is a large glycoprotein secreted since the early stages of development into the cerebrospinal fluid. Its domain architecture resembles a combination of a matricellular protein and the ligand-binding region of LDL receptor family. The matricellular proteins are a group of extracellular proteins with the capacity to interact with different molecules, such as growth factors, cytokines and cellular receptors; enabling the integration of information to modulate various physiological and pathological processes. In the same way, the LDL receptor family interacts with many ligands, including β-amyloid peptide and different growth factors. The domains similarity suggests that SCO-spondin is a matricellular protein enabled to bind, modulate, and transport different cerebrospinal fluid molecules. SCO-spondin can be found soluble or polymerized into a dynamic threadlike structure called the Reissner fiber, which extends from the diencephalon to the caudal tip of the spinal cord. Reissner fiber continuously moves caudally as new SCO-spondin molecules are added at the cephalic end and are disaggregated at the caudal end. This movement, like a conveyor belt, allows the transport of the bound molecules, thereby increasing their lifespan and action radius. The binding of SCO-spondin to some relevant molecules has already been reported; however, in this review we suggest more than 30 possible binding partners, including peptide β-amyloid and several growth factors. This new perspective characterizes SCO-spondin as a regulator of cerebrospinal fluid activity, explaining its high evolutionary conservation, its apparent multifunctionality, and the lethality or severe malformations, such as hydrocephalus and curved body axis, of knockout embryos. Understanding the regulation and identifying binding partners of SCO-spondin are crucial for better comprehension of cerebrospinal fluid physiology.

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Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients

Cited by 22 publications

References 68 publications

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

PsyCoP – A Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling Reveals Gene and Environment Dependent Impairments of Tcf4 Transgenic Mice Subjected to Social Defeat

SCO-spondin, a giant matricellular protein that regulates cerebrospinal fluid activity

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