Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGΒ4 gene in schizophrenia and bipolar disorder

O’Brien, Niamh; Fiorentino, Alessia; Curtis, David; Rayner, Christopher; Petrosellini, Chiara; Eissa, Mariam Al; Bass, Nick; McQuillin, Andrew; Sharp, Sally I.

doi:10.1016/j.schres.2018.03.001

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…Particular success in the search for rare variants has been achieved in psychiatric diseases including, for example, schizophrenia where several studies of family and unrelated samples have found a number of examples of relatively large-effect, lowfrequency variants (65)(66)(67)(68).…”

Section: Rare Variants With Large Effectsmentioning

confidence: 99%

Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants

Djm.

Bodmer

2020

Proc. Natl. Acad. Sci. U.S.A.

129

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The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher’s infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.

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Section: Rare Variants With Large Effectsmentioning

confidence: 99%

Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants

Djm.

Bodmer

2020

Proc. Natl. Acad. Sci. U.S.A.

129

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“…Gene based rare variant analysis of RFX7 in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort showed trending significance with entorhinal cortex thickness 76 . ITGB4, the index gene at the Aβ40TBS locus, encodes a transmembrane integrin involved in cell-to-cell adhesion, is differentially expressed in AD [77][78][79][80] with potential roles in the blood-brain barrier 81,82 , schizophrenia and bipolar disorder 83 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

Oatman

Reddy

Quicksall

et al. 2022

Preprint

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Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Main protein components of these hallmarks include Aβ40, Aβ42, tau, phospho-tau and APOE. With the exception of the APOE-ϵ4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

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“…ITGB4 encodes one component of a receptor for laminin, an extracellular matrix protein involved in cellular interaction, motility and signaling (Tarone et al, 2000). The gene has been associated to schizophrenia and bipolar disorder (O'Brien et al, 2018). Interestingly, ITGB4 binds NRG1 as part as Neuregulin-ERBB signaling, which plays a key role in neuronal migration and differentiation, synaptogenesis, neural myelination, neurotransmission, and synaptic plasticity (Mei and Nave, 2014;Kataria et al, 2019).…”

Section: Functional Characterization Of Genes Of Interestmentioning

confidence: 99%

Autism and Williams syndrome: dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood

Niego

Benítez‐Burraco

2020

Preprint

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Autism Spectrum Disorders (ASD) and Williams Syndrome (WS) are complex cognitive conditions exhibiting quite opposite features in the social domain: whereas people with ASD are mostly hyposocial, subjects with WS are usually reported as hypersocial. At the same time, ASD and WS share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this paper we adopted a comparative-molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of people with these conditions. We found a significant overlap between genes dysregulated in the blood of patients compared to neurotypical controls, with most of them being upregulated or, in some cases, downregulated. Still, genes with similar expression trends can exhibit quantitative differences between conditions, with most of them being more dysregulated in WS than in ASD. Differentially-expressed genes are involved in aspects of brain development and function (particularly, dendritogenesis) and are expressed in brain areas (particularly, the cerebellum, the thalamus and the striatum) of relevance for the ASD and the WS etiopathogenesis. Overall, these genes emerge as promising candidates for the similarities and differences between the ASD and the WS socio-cognitive profiles.

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Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGΒ4 gene in schizophrenia and bipolar disorder

Cited by 10 publications

References 45 publications

Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants

Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

Autism and Williams syndrome: dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood

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