Interrogating the Evolutionary Paradox of Schizophrenia: A Novel Framework and Evidence Supporting Recent Negative Selection of Schizophrenia Risk Alleles

Liu, Chenxing; Everall, Ian; Pantelis, Christos; Bousman, Chad

doi:10.3389/fgene.2019.00389

Cited by 27 publications

(21 citation statements)

References 28 publications

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“…Thus, higher cognitive functions are regarded as one of the main distinctive traits of humans (Maclean 2016) and is considered to be a product of human evolution. On the contrary, schizophrenia has been hypothesized to be a by-product of recent evolution of the human genome from its closest ancestor, the chimpanzee (Liu et al 2019; Avila, Thaker, and Adami 2001; T. J. Crow 2000; Timothy J.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

Bhattacharyya

Kukshal

Bhatia

et al. 2021

Preprint

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“…The genetic architecture of schizophrenia has forced two separate lines of enquiry into its genetic aetiology. Genome wide associations studies (GWAS) have successfully targeted common variant with small individual effects 6, 11, 12 . Importantly, they have resulted in valuable leads for functional follow-up studies of individual loci.…”

Section: Introductionmentioning

confidence: 99%

Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia

Akingbuwa

Hammerschlag

Bartels

et al. 2021

Preprint

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Both common and rare genetic variants (minor allele frequency > 1% and < 0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene sets. Four types of gene sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene sets. We show that common as well as (ultra-)rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.

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“…Genome wide association study (GWAS) data and summary statistics have been most commonly used to investigate the contribution of natural selection on the genetic architecture of complex traits, such as psychiatric syndromes 6 . Findings from studies in mental illness have been ambiguous with a few implicating the role of positive selection [7][8][9] , while a number of others have shown either no evidence for selection or negative selection 4,10,11 .…”

Section: Introductionmentioning

confidence: 99%

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

Mahadevan

Pathak

Vemula

et al. 2021

Preprint

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Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 75 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimers disease and cognitive abilities in genome wide association studies. We then checked whether any of these 75 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 75 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

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Interrogating the Evolutionary Paradox of Schizophrenia: A Novel Framework and Evidence Supporting Recent Negative Selection of Schizophrenia Risk Alleles

Cited by 27 publications

References 28 publications

Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

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