Neuroimaging genetic associations between <i>SEMA6D</i>, brain structure, and reading skills

Thomas, Tina; Perdue, Meaghan V.; Khalaf, Shiva; Landi, Nicole; Hoeft, Fumiko; Pugh, Kenneth R.; Grigorenko, Elena L.

doi:10.1080/13803395.2021.1912300

Cited by 8 publications

(5 citation statements)

References 64 publications

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“…While our TWAS for general cognitive function did not show overlapping genes between the TWAS for AD and VaD, we identified genes associated with general cognitive function that were not explicitly identified by Davies et al (2018)(21) which were associated with pre-clinical AD and VaD risk factors including cardiovascular diseases, immunity and Alzheimer’s neuropathology. Our TWAS also identified genes previously associated with cognitive domains, neuropathology, and psychiatric illness including reading-related skills and neural structures ( SEMA6D (100) and SETBP1 (101)), working memory tasks ( CDH13 (102)) and Schizophrenia ( HP (103,104) , C18orf1 (105) and TMEM180 (106)). There are likely also distinct transcriptomic mechanisms that differentiate cognitive function and normal age-related brain changes from pathways related to dementia.…”

Section: Discussionmentioning

confidence: 71%

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Chaar,

Li,

Shang

et al. 2024

Preprint

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Genetic variants increase the risk of neurocognitive disorders in later life including Vascular Dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiology are not well understood. Transcriptome-wide association studies (TWAS) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWAS have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European (EA) and African ancestries (AA) to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha=P<2.9−10-6), some of which were previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, downregulation ofICA1Lwas associated with higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS of cognitive function and neurocognitive disorders that used expression mapping studies in multiple ancestries. This work may expand the benefits of TWAS studies beyond a single ancestry group and help to identify gene targets for pharmaceutical or preventative treatment for dementia.Author SummaryTranscriptome-wide association studies (TWAS) can be used to understand the mechanisms of gene expression that underly disease etiology. However, to date, TWAS methods have mostly been used in a single ancestry group, especially European ancestry (EA), and few TWAS have focused on cognitive function or structural brain measures. We used a newly developed TWAS method called the Multi-ancEstry TRanscriptOme-wide analysis (METRO) to incorproate gene expression data from 801 EA and 1,032 African ancestry (AA) adults to identify genes associated with general cognitive function, structural brain changes called white matter hyperintensities (WMH) that predispose people to vascular dementia, and another form of dementia called Alzheimer’s disease (AD). We found that reduced gene expression ofICA1Lwas associated with more WMH and with AD, indicating its potential contribution to overlapping AD and vascular dementia neuropathologies. To our knowledge, our study is the first TWAS of cognitive function and neurocognitive disorders using multiple ancestries. This work may expand the benefits of TWAS studies beyond a single ancestry group and help to identify gene targets for pharmaceutical or preventative treatment for dementia.

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Section: Discussionmentioning

confidence: 71%

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Chaar,

Li,

Shang

et al. 2024

Preprint

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“…In contrast, 19 independent loci were detected in the Neurodevelopmental GenomicSEM GWAS. The strongest SNP associations were near genes previously identified for neuronal development and neurodevelopmental disorders, including PAPPA2 (rs147036913) (33), SEMA6D (rs35175834) (34), PDE4B (rs10789205) (35), and CSMD1 (rs7830752) (36).…”

Section: Resultsmentioning

confidence: 95%

Enhancing the Discriminatory Power of ADHD and Autism Spectrum Disorder Polygenic Scores in Clinical and Non-Clinical Samples

Wang

et al. 2022

Preprint

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Objective: Polygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their impressive power to predict focal outcomes. However, they lack in discriminatory power, in part due to the high degree of genetic overlap between psychiatric disorders. The lack of prediction specificity limits the clinical utility of psychiatric PGS, particularly for diagnostic applications. The goal of the study was to enhance the discriminatory power of psychiatric PGS for two highly comorbid and genetically correlated neurodevelopmental disorders in ADHD and autism spectrum disorder (ASD). Methods: Genomic structural equation modeling (GenomicSEM) was used to generate novel PGS for ADHD and ASD by accounting for the genetic overlap between these disorders (and eight others) to achieve greater discriminatory power in non-focal outcome predictions. PGS associations were tested in two large independent samples, the Philadelphia Neurodevelopmental Cohort (N=4,789) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) ASD and sibling controls (N=5,045) cohort. Results: PGS from GenomicSEM achieved superior discriminatory power in terms of showing significantly attenuated associations with non-focal outcomes relative to traditionally computed PGS for these disorders. Additionally, genetic correlations between GenomicSEM PGS for ASD and ADHD were significantly attenuated in cross-trait associations with other psychiatric disorders and outcomes. Conclusions: Psychiatric PGS associations are likely inflated by the high degree of genetic overlap between the psychiatric disorders. Methods such as GenomicSEM can be used to refine PGS signals to be more disorder-specific, thereby enhancing their discriminatory power for future diagnostic applications.

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“…Among those M1 genes, aberrant expression of Il1a, Il1b, Il6, Il18 lead to cells or brain damage, 51 and Tmem47 plays an important role in M1 microglial migration and could increase the aggregation of M1 microglia at the inflammatory site. M2 genes, including sema6d and Igf1 play important roles in cell development, 52 , 53 C1qa is necessary for microglial phagocytosis, 54 fgd2 acts as a regulator in leukocyte signalling, 55 which indicates that Arid1a is involved in microglia/microphage polarization balance.…”

Section: Discussionmentioning

confidence: 99%

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

et al. 2022

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Objective: Microglia, the prototypical innate immune cells of the central nervous system (CNS), are highly plastic and assume their phenotypes dependent on intrinsically genetic, epigenetic regulation or extrinsically microenvironmental cues. Microglia has been recognized as key regulators of neural stem/progenitor cells (NSPCs) and brain functions. Chromatin accessibility is implicated in immune cell development and functional regulation. However, it is still unknown whether and how chromatin remodelling regulates the phenotypic plasticity of microglia and exerts what kind of effects on NSPCs. Methods:We investigated the role of chromatin accessibility in microglia by deleting chromatin remodelling gene Arid1a using microglia-specific Cx3cr1-cre and Cx3cr1-CreERT2 mice. RNA-seq and ATAC-seq were performed to dissect the molecular mechanisms. In addition, we examined postnatal M1/M2 microglia polarization and analysed neuronal differentiation of NSPCs. Finally, we tested the effects of microglial Arid1a deletion on mouse behaviours.Results: Increased chromatin accessibility upon Arid1a ablation resulted in enhanced M1 microglial polarization and weakened M2 polarization, which led to abnormal neurogenesis and anxiety-like behaviours. Switching the polarization state under IL4 stimulation could rescue abnormal neurogenesis, supporting an essential role for chromatin remodeler ARID1A in balancing microglial polarization and brain functions.Conclusions: Our study identifies ARID1A as a central regulator of microglia polarization, establishing a mechanistic link between chromatin remodelling, neurogenesis and mouse behaviours, and highlights the potential development of innovative therapeutics exploiting the innate regenerative capacity of the nervous system. | INTRODUCTIONMicroglia, the only resident immune cells that enduringly reside in the central nervous system (CNS), 1 play vital roles in regulating the homeostasis of CNS. 2 In the past years, studies on microglia have expanded from investigating their immunological functions as resident macrophages of brain and mediators of neuroinflammation, injury, neurodegeneration to understanding their origins and functions involved in complex neurodevelopmental programs in the CNS. [3][4][5][6] Evidence has shown that microglia modulate neurogenesis and synaptic pruning, during which they interact with neural stem/progenitor cells (NSPCs) or neurons to provide trophic support, respond to

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Neuroimaging genetic associations between SEMA6D, brain structure, and reading skills

Cited by 8 publications

References 64 publications

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Enhancing the Discriminatory Power of ADHD and Autism Spectrum Disorder Polygenic Scores in Clinical and Non-Clinical Samples

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

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