Chromatin accessibility mapping for functional GWAS risk variants of neuropsychiatric and neurodegenerative disorders in hiPSC-derived neural cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE263804 | GEO | 2024/09/05
REPOSITORIES: GEO
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Project description:Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) have identified 75 genetic risk loci 2-7, the disease causal mechanism underlying most GWAS risk loci remains largely unknown. A major challenge is how to identify a putative causal disease variant among multiple risk variants at individual GWAS risk locus and functionally link the risk allele to LOAD-relevant cellular phenotypes. Leveraging our recent approach for identifying functional noncoding GWAS risk variants that show allele-specific open chromatin (ASoC), we systematically identified putative causal LOAD risk variants in human iPSC-derived neurons and glia cells, and established a causal link between PICALM risk allele to unappreciated microglia (MG)-specific role of PICALM in lipid droplet (LD) accumulation and phagocytosis. Our ASoC mapping identified functional risk variants for 26 AD risk loci, most of which are MG-specific. At the PICALM locus, the LOAD risk allele of the ASoC SNP rs10792832 altered chromatin accessibility to PU.1 binding and reduced PICALM expression in MG, thereby leading to impaired phagocytosis of Amyloid beta (Aβ) and myelin debris. Interestingly, transcriptomic profiling of MG carrying PICALM risk allele not only supported abnormal phagocytosis but also revealed enrichment of gene pathways related to cholesterol synthesis and LD formation. Further genetic and pharmacological perturbations in MG established the causal link of the PICALM risk allele with PICALM reduction, LD accumulation and phagocytosis deficits. Our work elucidates an MG-specific role of PICALM in regulating lipid/cholesterol accumulation that is potentially linked to AD pathophysiology, providing a functional neurobiological basis for developing novel clinical interventions.
2025-01-30 | GSE263809 | GEO
Project description:Chromatin accessibility mapping for functional GWAS risk variants of neuropsychiatric and neurodegenerative disorders in hiPSC-derived neural cells
| PRJNA1099272 | ENA
Project description:Chromatin accessibility mapping for functional GWAS risk variants of neuropsychiatric and neurodegenerative disorders in hiPSC-derived neural cells
| PRJNA1099279 | ENA
Project description:Here, in NEUROG2-induced human neurons, we identified 31 credible risk SNPs in 26 schizophrenia (SZ) risk loci that displayed allele-specific open chromatin (ASoC) and were likely to be functional. For the VPS45 locus showing the strongest ASoC, CRISPR/Cas9 editing of ASoC SNP (rs2027349) altered the local expression of VPS45 and AC244033.2 (a lncRNA), and a distal gene, C1orf54. Notably, the global expression changes in neurons correlated with post-mortem brain expression signatures of neuropsychiatric disorders. Neurons carrying risk allele exhibited increased dendritic complexity, synaptic puncta density and hyperactivity, which were partially reversed by knocking-down each cis-regulated gene (VPS45, AC244033.2, or C1orf54), suggesting phenotypic contribution from all three genes.
2022-01-23 | GSE188491 | GEO
Project description:Abstract Background Neuropsychiatric disorders, including schizophrenia (SZ), afflict a significant fraction of the population. Recent genome-wide association studies (GWAS) under the framework of the Psychiatric Genomics Consortium (PGC), along with large-scale sequencing efforts, have identified a plethora of disease risk loci with common and/or rare risk variants. Translating these exciting genomic findings into causation and disease biology offers the promise of developing more tailored therapies in psychiatry. However, understanding the disease biology underlying most GWAS findings remains challenging: (1) The paucity of disease-relevant biological materials for assaying molecular and cellular phenotypes associated with risk loci; (2) Most disease variants lie within poorly-annotated noncoding parts of the genome for which functional interpretation is challenging; and (3) Each locus often contains many genes/variants equivalently associated with the disease due to linkage disequilibrium, and it is difficult to identify which are the likely causal gene/variant. Human neurons derived from induced pluripotent stem cells (iPSCs), both monolayer cultures (2D model) and the emerging brain organoids (3D model), provide a promising alternative to human brains for recapitulating cellular phenotypes relevant to psychiatric disorders. CRISPR/Cas9 editing further strengthens the utility of these models by enabling the generation of isogenic lines with essentially the same genetic background on which allelic effects of a risk variant can be directly compared, thus increasing the sensitivity to detect typically small effects of a GWAS variant. Methods To functionally assess the relevance of noncoding sequences in neuropsychiatric disorders, we hypothesized that disease-relevant noncoding sequences likely overlap with cell-specific open chromatin regions (OCRs). We have carried out a genome-wide OCR profiling of excitatory neuronal differentiation from human iPSCs using an Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq). Results We found that OCRs in neurons were enriched SZ risk variants in neural OCRs and can help prioritize putatively functional SZ risk variants that may impact OCRs and consequently, cellular development. At a leading SZ-risk locus flanking MIR137, we further examined the functional effects of a prioritized common GWAS SNP rs1198588 in CRISPR/Cas9-edited hiPSCs, and found that SZ-risk allele of rs1198588 altered MIR137 expression, OCR dynamics and dendrite arborization/synapse maturation. To systematically identify such disease risk variants that may affect OCR, we further carried out a proof-of-concept analysis of allele-specific open chromatin (ASoC) of in hIPSC-derived neurons. We found that Heterozygous SNPs showing ASoC are more prevalent in neurons than in hiPSCs. Out of the 12 schizophrenia GWAS-implicated SNPs that we found in neuronal OCRs of this single individual, two SNPs showed ASoC and are thus putatively functional: one lies within the 5’-UTR of CHRNA5 (cholinergic receptor, nicotinic, alpha 5) and the other is in the promoter region of VPS45, a Sec1 family gene involved in synaptic transmission. We are currently in the process of replicating the observed landscape of ASoC in iPSC-derived neurons from a larger sample pool. Discussion Our study suggests that OCR profiling in a human iPSC model of neuron differentiation can predict functional noncoding sequences that regulate neurodevelopment.
| S-EPMC5888490 | biostudies-literature
Project description:Putamen is enriched with dopamine and associated with dopamine-related phenotypes including many neuropsychiatric and neurodegenerative disorders that manifest with motor impairment, impulsive behavior, and cognitive deficits. The gray matter volume of the putamen is age-dependent and genetically controlled. In most neuropsychiatric and neurodegenerative disorders, including Parkinson's spectrum disorders, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, multiple sclerosis, attention deficit hyperactivity disorder, developmental dyslexia, and major depression, the putamen volume is significantly reduced. On the other hand, in individuals with bipolar disorder, schizophrenia spectrum disorders, especially neuroleptics-medicated patients with schizophrenia, autism spectrum disorders, obsessive-compulsive spectrum disorders, and cocaine/amphetamine dependence, the putamen volume is significantly enlarged. Therefore, the putamen volume may serve as a structural neural marker for many neuropsychiatric and neurodegenerative disorders and a predictor of treatment outcomes in individuals afflicted with these conditions. We provided an overview of the genetic bases of putamen volume and explored potential mechanisms whereby altered putamen volume manifests in these neuropsychiatric and neurodegenerative conditions, with a specific focus on dopaminergic processes.
| S-EPMC6641567 | biostudies-literature
Project description:Genetic dissection of neuropsychiatric disorders can potentially reveal novel therapeutic targets. While genome-wide association studies (GWAS) have tremendously advanced our understanding, we approach a sample size bottleneck (i.e., the number of cases needed to identify >90% of all loci is impractical). Therefore, computationally enhancing GWAS on existing samples may be particularly valuable. Here, we describe DeepGWAS, a deep neural network-based method to enhance GWAS by integrating GWAS results with linkage disequilibrium and brain-related functional annotations. DeepGWAS enhanced schizophrenia (SCZ) loci by ~3X when applied to the largest European GWAS, and 21.3% enhanced loci were validated by the latest multi-ancestry GWAS. Importantly, DeepGWAS models can be transferred to other neuropsychiatric disorders. Transferring SCZ-trained models to Alzheimer's disease and major depressive disorder, we observed 1.3-17.6X detected loci compared to standard GWAS, among which 27-40% were validated by other GWAS studies. We anticipate DeepGWAS to be a powerful tool in GWAS studies.
| S-EPMC9949268 | biostudies-literature
Project description:ObjectiveNeuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function.MethodsWe obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates.ResultsFrequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs.ConclusionsNPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.
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| S-EPMC9460021 | biostudies-literature