The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

Singh, Tarjinder; Walters, James; Johnstone, Mandy; Curtis, David; Suvisaari, Jaana; Torniainen, Minna; Rees, Elliott; Iyegbe, Conrad; Blackwood, Douglas; McIntosh, Andrew M.; Kirov, George; Geschwind, Daniel H.; Murray, Robin M.; Forti, Marta Di; Bramon, Elvira; Gandal, Michael J.; Hultman, Christina M.; Sklar, Pamela; Palotie, Aarno; Sullivan, Patrick F.; O'Donovan, Michael Conlon; Barrett, Jeffrey C.

doi:10.1038/ng.3903

Cited by 204 publications

(207 citation statements)

References 52 publications

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“…63 Schizophrenia patients with intellectual disability are particularly likely to show enrichment of rare damaging variants in developmental disorder genes, but a weaker but significant enrichment exists through-out the larger schizophrenia population. 64 Thus, many of the genetic variants associated with schizophrenia impact on brain development and in particular in cognitive development, 65 thus confirming an early article 27 entitled "The Genetics of Schizophrenia is the Genetics of Neurodevelopment. "…”

Section: Geneticsmentioning

confidence: 56%

30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis

Murray

Bhavsar

Tripoli

et al. 2017

Schizophrenia Bulletin

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244

140

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At its re-birth 30 years ago, the neurodevelopment hypothesis of schizophrenia focussed on aberrant genes and early neural hazards, but then it grew to include ideas concerning aberrant synaptic pruning in adolescence. The hypothesis had its own stormy development and it endured some difficult teenage years when a resurgence of interest in neurodegeneration threatened its survival. In early adult life, it overreached itself with some reductionists claiming that schizophrenia was simply a neurodevelopmental disease. However, by age 30, the hypothesis has matured sufficiently to incorporated childhood and adult adversity, urban living and migration, as well as heavy cannabis use, as important risk factors. Thus, it morphed into the developmental risk factor model of psychosis and integrated new evidence concerning dysregulated striatal dopamine as the final step on the pathway linking risk factors to psychotic symptoms.

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Section: Geneticsmentioning

confidence: 56%

30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis

Murray

Bhavsar

Tripoli

et al. 2017

Schizophrenia Bulletin

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244

140

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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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“…Gene sets that were tested included drug-related pathways 50,51 , as well as custom-curated neurodevelopmental and other brain-related gene sets that had gone through stringent quality control in a study originally designed to interrogate rare variants in schizophrenia 52 . In the latter, pathways with initially included.…”

Section: Magma Gene-based Analysis: Tissue Expression and Competitivementioning

confidence: 99%

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

Lam

Hill

Trampush

et al. 2019

Preprint

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Liability to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published GWAS in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results.Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("Concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants demonstrating the counterintuitive ("Discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education and/or schizophrenia at p<5x10 −8 . Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs, and many of these have been validated by larger, more recent single-phenotype GWAS.Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms: early neurodevelopmental pathways that characterize concordant allelic variation, and adulthood synaptic pruning pathways that were linked to the paradoxical positive genetic association between education and schizophrenia. Further, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia, but also to the broader biological dimensions that are implicated in both general health outcomes and psychiatric illness.

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The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

Cited by 204 publications

References 52 publications

30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis

30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis

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

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

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