Revisiting Schizophrenia from an Evolutionary Perspective: An Association Study of Recent Evolutionary Markers and Schizophrenia

Bhattacharyya, Upasana; Deshpande, Smita N.; Bhatia, Triptish; Thelma, B.K.

doi:10.1093/schbul/sbaa179

Cited by 14 publications

(10 citation statements)

References 86 publications

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“…Interestingly four HAR variants that showed association with schizophrenia in our previous study (Bhattacharyya et al 2020) also showed significant association in several cognitive function GWAS; with rs3800926 strongly associated (P-value 6.1E-06) in a meta general cognition GWAS (Supplementary Table 12). This particular SNP showed nominal association across all GWASs of related traits, namely neurocortism, intelligence, and educational attainment (Supplementary Table 12).…”

Section: Associated Hpo Phenotypes With the Mapped Genes And Transcription Factorsmentioning

confidence: 62%

“…FUMA-SNP2GENE module was used to map SNPs to genes using three approaches have been used for mapping: (i) Positional, (ii) eQTL and (iii) Chromatin interaction as previously described (Bhattacharyya et al 2020) (Supplementary Methods).…”

Section: ) (Supplementary Methods)mentioning

confidence: 99%

“…A consolidated list of all HARs (2737) reported in a recent study on role of HARs in autism (Doan et al 2016) has been used in this study. Selection criteria for HAR-SNPs to be genotyped, have been described by us previously (Bhattacharyya et al 2020…”

Section: Selection Of Variants From Harsmentioning

confidence: 99%

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Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

Bhattacharyya

Kukshal

Bhatia

et al. 2021

Preprint

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Cognition is believed to be a product of human evolution, while schizophrenia is ascribed as the by-product with cognitive impairment as it's genetically mediated endophenotype. Genomic loci associated with these traits are enriched with recent evolutionary markers such as Human accelerated regions (HARs). HARs are markedly different in humans since their divergence with chimpanzees and mostly regulate gene expression by binding to transcription factors and/or modulating chromatin interactions. We hypothesize that variants within HARs may alter such functions and thus contribute to disease pathogenesis. 49 systematically prioritized variants from 2737 genome-wide HARs were genotyped in a north-Indian schizophrenia cohort (331 cases, 235 controls). Six variants were significantly associated with cognitive impairment in schizophrenia, thirteen with general cognition in healthy individuals. These variants were mapped to 122 genes; predicted to alter 70 transcription factors binding sites and overlapped with promoters, enhancers and/or repressors. These genes and TFs are implicated in neurocognitive phenotypes, autism, schizophrenia and bipolar disorders; a few are targets of common or repurposable antipsychotics suggesting their draggability; and enriched for immune response and brain developmental pathways. Immune response has been more strongly targeted by natural selection during human evolution and has a prominent role in neurodevelopment. Thus, its disruption may have deleterious consequences for neuronal and cognitive functions. Importantly, among the 15 associated SNPs, 12 showed association in several independent GWASs of different neurocognitive functions. Further analysis of HARs may be valuable to understand their role in cognition biology and identify improved therapeutics for schizophrenia.

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Section: Associated Hpo Phenotypes With the Mapped Genes And Transcription Factorsmentioning

confidence: 62%

Section: ) (Supplementary Methods)mentioning

confidence: 99%

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Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

Bhattacharyya

Kukshal

Bhatia

et al. 2021

Preprint

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“…Lastly, the third topic comprises research on HARs’ involvement in psychiatric disorders. Most of the studies are focused on SCZ [ 66 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ], but there is also research on other neurodevelopmental psychiatric disorders and phenotypes, such as autism spectrum disorders (ASD) [ 52 , 58 , 66 ], bipolar disorder [ 76 ], and delirium syndrome [ 77 ] ( Table 4 ).…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge

Guardiola-Ripoll

Fatjó‐Vilas

2023

IJMS

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Schizophrenia is a psychiatric disorder that results from genetic and environmental factors interacting and disrupting neurodevelopmental trajectories. Human Accelerated Regions (HARs) are evolutionarily conserved genomic regions that have accumulated human-specific sequence changes. Thus, studies on the impact of HARs in the context of neurodevelopment, as well as with respect to adult brain phenotypes, have increased considerably in the last few years. Through a systematic approach, we aim to offer a comprehensive review of HARs’ role in terms of human brain development, configuration, and cognitive abilities, as well as whether HARs modulate the susceptibility to neurodevelopmental psychiatric disorders such as schizophrenia. First, the evidence in this review highlights HARs’ molecular functions in the context of the neurodevelopmental regulatory genetic machinery. Second, brain phenotypic analyses indicate that HAR genes’ expression spatially correlates with the regions that suffered human-specific cortical expansion, as well as with the regional interactions for synergistic information processing. Lastly, studies based on candidate HAR genes and the global “HARome” variability describe the involvement of these regions in the genetic background of schizophrenia, but also in other neurodevelopmental psychiatric disorders. Overall, the data considered in this review emphasise the crucial role of HARs in human-specific neurodevelopment processes and encourage future research on this evolutionary marker for a better understanding of the genetic basis of schizophrenia and other neurodevelopmental-related psychiatric disorders. Accordingly, HARs emerge as interesting genomic regions that require further study in order to bridge the neurodevelopmental and evolutionary hypotheses in schizophrenia and other related disorders and phenotypes.

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“…Human-accelerated regions (HAR) are genomic segments which have undergone accelerated nucleotide sequence change in humans relative to other primates. The most recent analyses suggest that there are 3,171 HARs in the human genome ( Pollard et al, 2006a , 2006b ; Prabhakar et al, 2006 ; Bird et al, 2007 ; Bush and Lahn, 2008 ; Lindblad-Toh et al, 2011 ; Hubisz and Pollard, 2014 ; Gittelman et al, 2015 ) HARs overlap regulatory elements important for brain development and are particularly related to elements active in the fetal brain ( Won et al, 2019 ; Bhattacharyya et al, 2021 , 2022 ; Cheung et al, 2022 ). Recently, massively parallel assay for regulatory element activity showed that 49% of HARs feature neurodevelopmental enhancer activity in human neural cells in vitro ( Girskis et al, 2021 ).…”

Section: Human Accelerated Cis -Regulatory Element...mentioning

confidence: 99%

Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia

Duński

Pękowska

2022

Front. Genet.

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The unique qualities of the human brain are a product of a complex evolutionary process. Evolution, famously described by François Jacob as a “tinkerer,” builds upon existing genetic elements by modifying and repurposing them for new functions. Genetic changes in DNA may lead to the emergence of new genes or cause altered gene expression patterns. Both gene and regulatory element mutations may lead to new functions. Yet, this process may lead to side-effects. An evolutionary trade-off occurs when an otherwise beneficial change, which is important for evolutionary success and is under strong positive selection, concurrently results in a detrimental change in another trait. Pleiotropy occurs when a gene affects multiple traits. Antagonistic pleiotropy is a phenomenon whereby a genetic variant leads to an increase in fitness at one life-stage or in a specific environment, but simultaneously decreases fitness in another respect. Therefore, it is conceivable that the molecular underpinnings of evolution of highly complex traits, including brain size or cognitive ability, under certain conditions could result in deleterious effects, which would increase the susceptibility to psychiatric or neurodevelopmental diseases. Here, we discuss possible trade-offs and antagonistic pleiotropies between evolutionary change in a gene sequence, dosage or activity and the susceptibility of individuals to autism spectrum disorders and schizophrenia. We present current knowledge about genes and alterations in gene regulatory landscapes, which have likely played a role in establishing human-specific traits and have been implicated in those diseases.

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Revisiting Schizophrenia from an Evolutionary Perspective: An Association Study of Recent Evolutionary Markers and Schizophrenia

Cited by 14 publications

References 86 publications

Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge

Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia

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