Recent Advances in the Genetics of Schizophrenia

Avramopoulos, Dimitrios

doi:10.1159/000488679

Cited by 76 publications

(56 citation statements)

References 176 publications

(176 reference statements)

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“…This issue has become even more important with the revelation that the vast majority of neuropsychiatric disease-related single-nucleotide polymorphisms (SNPs) occur in non-coding regions (Avramopoulos, 2018). Due to chromosomal looping, the genes most linearly-proximal to a given variant are often not those directly affected (Mitchell et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Enhanced maturation of human stem cell derived interneurons by mTOR activation

Chu

Fitzgerald

Sehgal

et al. 2019

Preprint

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The use of stem cell derived neurons for cell-based therapies is limited by a protracted maturation. We present a novel? approach for accelerating the post-mitotic maturation of human stem cell derived interneurons via the activation of mTOR signaling. Lox sites were placed within PTEN, a key mTOR inhibitor, in a cortical interneuron (CIn) reporter line. Following directed differentiation and purification by FACS, the CIns were exposed to Cre-expressing lentivirus, then transplanted into mouse neocortex or plated onto cultured rat neocortex. Input synaptogenesis and dendritogenesis was greatly enhanced in the PTEN-deleted CIns. Whole-cell recording of the PTEN-deleted CIns in slices of transplanted neocortex revealed multiple indices of enhanced maturation. Finally, we observed similar effects using transient, doxycycline-inducible activation of AKT. We thus present an inducible, reversible approach for accelerating the maturation of human stem cell derived CIns, and to study the influences of this disease-related signaling system in human neurons.

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Section: Discussionmentioning

confidence: 99%

Enhanced maturation of human stem cell derived interneurons by mTOR activation

Chu

Fitzgerald

Sehgal

et al. 2019

Preprint

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“…0.37) [9, 10] and polygenic inheritance [11, 12]. However, promis ing genetic risk candidates for SCZ and MDD had not been well implicated until the emergence of recent large-scale genome-wide association studies (GWAS) [13-21]. GWAS is believed to be an ideal approach for studying common genetic variations across the genome, given its key feature that no a priori hypotheses are established [22].…”

Section: Introductionmentioning

confidence: 99%

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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“…Schizophrenia is a highly heritable disorder and it affected about 1% of the population worldwide ( Sullivan et al, 2003 , p. 20; Henriksen et al, 2017 ; Avramopoulos, 2018 ; Weinberger, 2019 ). Twins studies suggested the heritability is around 80% ( Sullivan et al, 2003 ; Henriksen et al, 2017 ; Avramopoulos, 2018 ) and common variants contributed to up to half of the genetic risk of schizophrenia ( International Schizophrenia Consortium et al, 2009 ; The Schizophrenia Psychiatric Genome-Wide Association Study (Gwas) Consortium, 2011 ). Genome-wide association studies (GWAS) identified more than 180 loci that were associated with the risk of schizophrenia ( Ripke et al, 2014 ; Li et al, 2017 ; Pardiñas et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets

et al. 2020

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In this study, we looked for potential gene-gene interaction in susceptibility to schizophrenia by an exhaustive searching for SNP–SNP interactions in 3 GWAS datasets (phs000021:phg000013, phs000021:phg000014, phs000167) using our recently published algorithm. The search space for SNP–SNP interaction was confined to 8 biologically plausible ways of interaction under dominant-dominant or recessive-recessive modes. First, we performed our search of all pair-wise combination of 729,454 SNPs after filtering by SNP genotype quality. All possible pairwise interactions of any 2 SNPs (5 × 10 11 ) were exhausted to search for significant interaction which was defined by p -value of chi-square tests. Nine out the top 10 interactions, protein coding genes were partnered with non-coding RNA (ncRNA) which suggested a new alternative insight into interaction biology other than the frequently sought-after protein–protein interaction. Therefore, we extended to look for replication among the top 10,000 interaction SNP pairs and high proportion of concurrent genes forming the interaction pairs were found. The results indicated that an enrichment of signals over noise was present in the top 10,000 interactions. Then, replications of SNP–SNP interaction were confirmed for 14 SNPs-pairs in both replication datasets. Biological insight was highlighted by a potential binding between FHIT (protein coding gene) and LINC00969 (lncRNA) which showed a replicable interaction between their SNPs. Both of them were reported to have expression in brain. Our study represented an early attempt of exhaustive interaction analysis of GWAS data which also yield replicated interaction and new insight into understanding of genetic interaction in schizophrenia.

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Recent Advances in the Genetics of Schizophrenia

Cited by 76 publications

References 176 publications

Enhanced maturation of human stem cell derived interneurons by mTOR activation

Enhanced maturation of human stem cell derived interneurons by mTOR activation

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets

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