Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains

Hoffman, Gabriel E.; Hartley, Brigham J.; Flaherty, Erin; Ladran, Ian; Gochman, Peter; Ruderfer, Douglas M.; Stahl, Eli A.; Rapoport, Judith L.; Sklar, Pamela; Brennand, Kristen J.

doi:10.1038/s41467-017-02330-5

Cited by 150 publications

(191 citation statements)

References 88 publications

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“…Human induced pluripotent stem cells (iPSCs) were obtained from the Knight Alzheimer's Disease Research Center at Washington University 76 , the NIH Childhood-onset Schizophrenia study 77 , and the UCI ADRC (SI Methods Table 8). The Icahn School of Medicine at Mount Sinai IRB reviewed the relevant operating protocols as well as this specific study and determined it was exempt from approval.…”

Section: Cell Linesmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh

Liu

et al. 2019

Preprint

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Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PDassociated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

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Section: Cell Linesmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh

Liu

et al. 2019

Preprint

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“…Data for Timothy syndrome (20) was downloaded from GEO at GSE25542. Data for childhood onset schizophrenia (15) was downloaded from https: //www.synapse.org/#!Synapse:syn9907463.…”

Section: Resultsmentioning

confidence: 99%

“…Recent advances in the scale of transcriptomic and, more generally, functional genomic studies have enabled assaying individuals from multiple tissues (7,8), brain regions (9,10), cell types (11), time points (12,13,14) or induced pluripotent stem cell (iPSC) lines (15,16,17,18,19,20). These studies with multiple samples from each individual can test region-or context-specific effects, but can also increase the * To whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

dream: Powerful differential expression analysis for repeated measures designs

Hoffman

Roussos

2018

Preprint

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Large-scale transcriptome studies with multiple samples per individual are widely used to study disease biology. Yet current methods for differential expression are inadequate for cross-individual testing for these repeated measures designs. Most problematic, we observe across multiple datasets that current methods can give reproducible false positive findings that are driven by genetic regulation of gene expression, yet are unrelated to the trait of interest. Here we introduce a statistical software package, dream, that increases power, controls the false positive rate, enables multiple types of hypothesis tests, and integrates with standard workflows. In 12 analyses in 6 independent datasets, dream yields biological insight not found with existing software while addressing the issue of reproducible false positive findings. Dream is available within the variancePartition Bioconductor package (http://bioconductor.org/packages/ variancePartition).

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“…We used previously published data sets for several analyses. These comprise several cortical data sets in raw format (Affymetrix) from NCBI GEO: GSE35978 (Chen et al, 2013) (SCZ & BD), GSE53987 (Iwamoto et al, 2005) (SCZ & BD), GSE12649 (Lanz et al, 2015) (SCZ & BD), GSE17612 (Maycox et al, 2009) (SCZ), GSE21138 (Narayan et al, 2008) (SCZ), GSE5392 (Ryan et al, 2006) (BD); next-generation sequencing from NCBI GEO: GSE80655 (Ramaker et al, 2017), GSE106589 (Hoffman et al, 2017), GSE68559 (Webb et al, 2015), GSE96659 (Fontenot et al, 2017), GSE45642 (Li et al, 2013); data of DLPFC sequencing of 600 SCZ patients and controls was obtained from the Common Mind Consortium (http:// www.synapse.org/CMC).…”

Section: Human Patient Datamentioning

confidence: 99%

Integrative transcriptomics reveals sexually dimorphic microRNA control of the cholinergic/neurokine interface in schizophrenia and bipolar disorder

Lobentanzer

Hanin

Klein

et al. 2019

Preprint

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135 words): RNA-sequencing analyses are often limited to identifying lowest p-value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA-sequencing of human male-and female-originated cell lines, and connectomics of transcription factor-and microRNA-interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. While these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method explicates the differences between afflicted men and women, and identifies diseaseaffected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function, interlinked by microRNAs. This approach may open new perspectives for seeking biomarkers and therapeutic targets, also in other transmitter systems and diseases.Manuscript (Erta et al., 2012): the gp130 co-receptor (also known as IL6ST, IL-6 signal transducer), and the LIF-receptor. Gp130-family neurokines unite properties of neurotrophic (e.g. on dopaminergic neurons) and immunogenic nature, both prominent facets in the molecular etiology of SCZ and BD (Harrison, 2015) and in cholinergic signaling (Stanke et al., 2006). Neurokines can activate JAK1/2, TYK2 and STAT1/3/5A/5B (Rawlings, 2004), affecting neurotransmission as well as immunity. However, to the best of our knowledge, their roles in SCZ/BD were not yet studied.SCZ/BD hallmarks also involve circadian perturbations. The cholinergic-catecholaminergic imbalance in BD (Van Enkhuizen et al., 2015) follows variable transcriptionally-regulated rhythms (e.g. CLOCK, ARNTL, RORA), and affected individuals exhibit decreased REM latency (the duration from onset of sleep to the first rapid eye movement phase) and increased vulnerability for disease that can be modulated by muscarinic agonists/antagonists (Ising et al., 2005). Correspondingly, the muscarinic M1/M3 receptor genes are essential for REM sleep (Niwa et al., 2018), and sleep deprivation exerts short-term antidepressant effects (Wu and Bunney, 1990), reduced cortical ACh levels (Boonstra et al., 2007), and vast transcriptional changes in basal forebrain cholinergic neurons (Nikonova et al., 2017).The quantitative measurement of disease-relevance of individual perturbed genes is a common methodological problem in transcriptomic analyses. To reduce complexity, transcripts are often filtered by their p-values, leading to bias towards few highly expressed and differentially regulated genes. This does not agree with a polygenic model where each component contributes a small effect. To alleviate this bias while still attempting the necessary complexity reduction, we developed an integrative approach of multiple perspectives. Jerusalem and Andreas Meisel, Berlin and to Dr. Ester Bennett, Jerusalem ...

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Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains

Cited by 150 publications

References 88 publications

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

dream: Powerful differential expression analysis for repeated measures designs

Integrative transcriptomics reveals sexually dimorphic microRNA control of the cholinergic/neurokine interface in schizophrenia and bipolar disorder

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