Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype

Bustamante, M. Leonor; Herrera, Luisa; Gaspar, Pablo A.; Nieto, Rodrigo; Maturana, Alejandro; Villar, María José; Salinas, Valeria; Silva, Hernán

doi:10.1002/ajmg.b.32550

Cited by 12 publications

(7 citation statements)

References 92 publications

(101 reference statements)

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“…Consistently, SLC6A3, encoding DAT, has been a long-standing candidate gene in psychiatric diseases, such as bipolar disorder, schizophrenia, and ADHD (22,(58)(59)(60), but the reported effect sizes of associated common variants are small, as for most other genes, and this challenges deduction of potential disease relevant biological processes. Rare variants have been found to account for a significant component of the genetic architecture of several psychiatric disorders, and the association signal for both common and rare variants appears to be enriched in mutation intolerant genes (1,(61)(62)(63)(64). Indeed, DAT is classified as both 'loss of function intolerant' and 'missense constrained' (32).…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised. Here, we systematically characterized six rare genetic variants of DAT (I312F, T356M, D421N, A559V, E602G, and R615C) identified in patients with neuropsychiatric disorders. We evaluated dopamine uptake and ligand interactions, along with ion coordination and electrophysiological properties, to elucidate functional phenotypes, and applied Zn 2+ exposure and a substituted cysteineaccessibility approach to identify shared structural changes. Three variants (I312F, T356M, and D421N) exhibited impaired dopamine uptake associated with changes in ligand binding, ion coordination, and distinct conformational disturbances. Remarkably, we found that all three variants displayed gain-offunction electrophysiological phenotypes. I312F mediated an increased uncoupled anion conductance previously suggested to modulate neuronal excitability. T356M and D421N both mediated a cocaine-sensitive leakage of cations, which for T356M, was potentiated by Zn 2+ , concurrent with partial functional rescue. Collectively, our findings support that gain of disruptive functions due to missense mutations in SLC6A3 may be key to understanding how dopaminergic dyshomeostasis arises in heterozygous carriers.A substantial proportion of the disease etiology of common psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder, and schizophrenia is attributed genetic components (1). The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18). Despite progress, much of the genetic component remains unaccounted for, and we also have the challenge ahead of translating most of the comprehensive genetic information into an understanding of underlying biological processes, and subsequently into clinically applicable knowledge. Rare variants may provide a unique handle for obtaining new disease insights as they are expected to h...

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Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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“…The possible role of the product of gene loci associated with a higher risk of developing primary psychosis are described in Table 1 [17,18,22,42,43]. Genes were grouped according to the main function of their product.…”

Section: Sociodemographic Risk Factorsmentioning

confidence: 99%

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

et al. 2021

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Primary psychosis, which includes schizophrenia and other psychoses not caused by other psychic or physical conditions, has a strong impact worldwide in terms of disability, suffering and costs. Consequently, improvement of strategies to reduce the incidence and to improve the prognosis of this disorder is a current need. The purpose of this work is to review the current scientific literature on the main risk and protective factors of primary psychosis and to examine the main models of prevention, especially those related to the early detection of the onset. The conditions more strongly associated with primary psychosis are socio-demographic and economic factors such as male gender, birth in winter, ethnic minority, immigrant status, and difficult socio-economic conditions while the best-established preventive factors are elevated socio-economic status and an economic well-being. Risk and protective factors may be the targets for primordial, primary, and secondary preventive strategies. Acting on modifiable factors may reduce the incidence of the disorder or postpone its onset, while an early detection of the new cases enables a prompt treatment and a consequential better prognosis. According to this evidence, the study of the determinants of primary psychosis has a pivotal role in designing and promoting preventive policies aimed at reducing the burden of disability and suffering of the disorder.

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“…8 To reduce the ''noise'' that phenotypic heterogeneity brings to genetic studies, research efforts have been redirected to the recognition of endophenotypes, 9 i.e., biological traits that are disease-related but state-independent and closer to genetic determinants than the complete behavioral phenotype. 10,11 Cognitive deficits have been proposed as endophenotypes of schizophrenia. 12 These stable, persisting deficits strongly predict unfavorable functional outcomes, 13,14 are highly heritable, 14 and can be found in attenuated forms in first-degree healthy relatives.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls

Ferretjans

Souza

Panizzutti

et al. 2022

Braz. J. Psychiatry

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Objective: To test the hypothesis that genetic variations of cannabinoid receptors contribute to the pathophysiology of cognitive deficits in schizophrenia. Methods: In this genetic association case-control study, cannabinoid receptor polymorphisms CNR1 rs12720071 and CNR2 rs2229579 were tested for association with neurocognitive performance in 69 patients with schizophrenia and 45 healthy controls. Neurocognition was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS). Results: We found a consistent association between CNR1 rs12720071 polymorphism and the cognitive performance of patients in several cognitive domains. Patients with C/C polymorphism presented significantly worse performance in motor speed, verbal fluency, attention/processing speed and reasoning/problem solving. Conclusion: Although limited, our data support the hypothesis that CNR1 variations may be associated with the pathogenesis of cognitive deficits of schizophrenia.

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Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype

Cited by 12 publications

References 92 publications

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls

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