Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

In the paper

“In accordance with previous results (1), we observed pervasive differential gene expression (DGE) in ASD, SCZ, and BD (n=1611, 4821, and 1119 genes at FDR<0.05, respectively; Fig 1A; Table S1).”

What the sources say

• Not checked yetcites [1] Gandal MJ, Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 359, 693– 697 (2018). 29439242 PMC5898828 source

In the paper

“Expanding these analyses to the transcript isoform-level, we observe widespread differential transcript expression (DTE) across ASD, SCZ, and BD (n=767, 3803, and 248 isoforms at FDR<0.05, respectively; Table S1).”

In the paper

“There was substantial cross-disorder sharing of this DE signal and a gradient of transcriptomic severity with the largest changes in ASD compared with SCZ or BD (ASD vs SCZ, mean |log2FC| 0.26 vs 0.10, P<2×10−16, Kolmogorov-Smirnov (K-S) test; ASD vs BD, mean |log2FC| 0.26 vs 0.15, P<2×10−16, K-S test), as observed previously (1).”

What the sources say

• Not checked yetcites [1] Gandal MJ, Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 359, 693– 697 (2018). 29439242 PMC5898828 source

In the paper

“Furthermore, although isoform and gene-level changes exhibited similar pathway and cell type enrichments (e.g. Fig 1D-E), isoform-level analysis identified DE transcripts that did not show DGE (‘isoform-only DE’), including 811 in SCZ, 294 in ASD, and 60 in BD.”

In the paper

“Based on Gencode annotations, we identify 944 ncRNAs exhibiting gene- or isoform-level DE in at least one disorder (herein referred to as ‘neuropsychiatric (NP) ncRNAs’ (21)), 693 of which were DE in SCZ, 178 in ASD, and 174 in BD, of which 208, 60, and 52 are annotated as intergenic long non-coding RNAs (lincRNAs), in each disorder, respectively.”

What the sources say

• ?Not matched

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  cites [21] See supplemental methods.

In the paper

“DS genes overlapped significantly with DTE results for ASD and SCZ (Fig S8B), but not BD, which likely still remains underpowered.”

In the paper

“and subsequently, overlap among DS genes (Fig 2A-B), although the majority of splicing changes still are disorder specific.”

In the paper

“Of 4821 DE genes in SCZ, only 143 showed even nominal association between effect size magnitude and age. Similar associations were seen in 29 of 1119 DE genes in BD and 85 of 1611 DE genes in ASD.”

In the paper

“We identified 18 genes or isoforms whose expression was significantly associated with PRS ((21); Bonferroni-corrected P < 0.05), 16 in ASD, 2 in SCZ, with none in BD (Fig 3C; Table S4).”

What the sources say

• ?Not matched

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  cites [21] See supplemental methods.

In the paper

“and LINC00634, an unstudied brain enriched lincRNA downregulated in SCZ (log2FC −0.06, FDR 0.027) with a genome-wide significant SCZ TWAS association as described below.”

In the paper

“Significant associations with PRS were observed for DGE and DTE signal in SCZ, with greater polygenic association at the isoform level in accordance with the larger transcript isoform effect sizes observed.”

In the paper

“We identified 515 DS intron clusters in 472 genes across all disorders (FDR<0.1), 117 of which (25%) contained one or more novel exons (Table S3; Fig 2A).”

In the paper

“The most commonly observed local splicing change was exon skipping (41–60%), followed by alternative 5’ exon inclusion (e.g. due to alternative promoter usage; 11–21%) and alternative 3’ splice site usage (5–18%) (Table S3; Fig S8A).”

In the paper

“Another example is CADPS, which is located within an ASD GWAS risk locus and supported by Hi-C defined chromatin interactions as a putative target gene (38) and manifests multiple isoform and splice alterations in ASD (Fig S9; Tables S1 and S3).”

What the sources say

• Not checked yetcites [38] Grove J, Common risk variants identified in autism spectrum disorder. bioRxiv (2017), p. 224774. source

In the paper

“We identify 74 NPncRNAs (~8%) under purifying selection in humans, with average exon-level context-dependent tolerance scores (CDTS) below the 10th percentile (21).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [21] See supplemental methods.

In the paper

“Over 200 NPncRNAs exhibited broad and non-specific expression patterns across cell types, whereas 66 were expressed within a specific cell type class (Table S2).”

In the paper

“Notable examples are: LINC00996, which is downregulated in SCZ (log2FC −0.71, FDR<5×10−11) and BD (log2FC −0.45, FDR=0.02) and restricted to microglia in brain (Fig S6)”

In the paper

“GRIN1 encodes the obligatory subunit of the NMDA-type glutamate ionotropic receptors, is upregulated in SCZ and BD and shows increased skipping of exon 4 in both ASD and SCZ that impacts its extracellular ligand-binding domain (Fig 2E-G).”

In the paper

“LINC00343, expressed in excitatory neurons, and downregulated in BD (log2FC −0.33, FDR=0.012) with a trend in SCZ (log2FC −0.15, FDR 0.065)”

In the paper

“Notably, 48 DS genes (10%; FDR=8.8×10−4) encode RNA binding proteins or splicing factors (34), with at least six splicing factors also showing DTE in ASD (MATR3), SCZ (QKI, RBM3, SRRM2, U2AF1) or both (SRSF11).”

What the sources say

• Not checked yetcites [34] Sebestyén E, Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 26, 732– 744 (2016). 27197215 PMC4889968 source

In the paper

“The second most abundant RBFOX1 isoform is in another module, isoM17, which is downregulated in both ASD and SCZ (Fig 6B).”

In the paper

“Moreover, the two modules show differential association with common genetic risk (Fig 6E), with isoM2 exhibiting GWAS enrichment across SCZ, BD, and MDD.”

In the paper

“Of the 107 conditionally significant genes prioritized by TWAS, 62 were further supported by SMR (PSMR<0.05, PHEIDI>0.05) and 11 were also concordantly DE in SCZ brain in the same direction as predicted by TWAS.”

In the paper

“isoM13 showed the greatest overall significance of enrichment for SCZ and educational attainment GWAS, and was also enriched in BD GWAS to a lesser degree,”

In the paper

“Most genes identified in this analysis show disease-specific effects, as only four genes (MCHR1, VPS45, SNAP91, DCLK3) showed overlap between SCZ and BD TWAS, and none overlapped with ASD.”

In the paper

“This includes the 17q21.31 region, which showed multiple PRS associations as described above, but did not reach genome-wide significance in the largest GWAS to date (38).”

What the sources say

• Not checked yetcites [38] Grove J, Common risk variants identified in autism spectrum disorder. bioRxiv (2017), p. 224774. source

In the paper

“In SCZ, TWAS identifies 193 genes of which 107 remain significant following conditional analysis at each gene within multi-hit loci.”

In the paper

“The module pair geneM1/isoM2, downregulated only in ASD (Fig 6B), contains the predominant brain-expressed RBFOX1 isoform and includes several cation channels (e.g., HCN1, SCN8A).”

In the paper

“Concordantly, we find a strong positive correlation between C4A expression and genetically imputed C4A copy number (R=0.36, P=6×10−21) and imputed number of C4-HERV elements (R=0.35, P=4×10−20), but a slight negative association with C4B copy number (R=−0.087, P=0.03; ref (21)).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [21] See supplemental methods.

In the paper

“Five modules are shared across all three disorders, 3 up and two downregulated; 22 modules are shared by 2 of the 3 disorders, and 36 demonstrate more specific patterns of dysregulation in either ASD, SCZ or BD (Fig 5; Table S5).”

In the paper

“The third biological process, geneM26/isoM22 (Fig 5C), is downregulated, and enriched for endothelial and pericyte genes, with hubs that represent markers of the blood-brain barrier, including ITIH5, SLC38A5, ABCB1, and GPR124, a critical regulator of brain-specific angiogenesis (53, 54).”

What the sources say

• Not checked yetcites [53] Daneman R, The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One. 5, e13741 (2010). 21060791 PMC2966423 source
• Not checked yetcites [54] Obermeier B, Daneman R, Ransohoff RM, Development, maintenance and disruption of the blood-brain barrier. Nat. Med 19, 1584– 1596 (2013). 24309662 PMC4080800 source

In the paper

“We do observe neuronal modules broadly dysregulated across multiple disorders, including a neuronal/synaptic module (isoM18) with multiple isoforms of the known ASD risk gene, ANK2, as hubs.”

In the paper

“Consistent with expectations, modules showed enrichment for gene ontology pathways and we identified modules strongly and selectively enriched for markers of all major CNS cell types (Fig 5A-B; Fig S12)”

In the paper

“Altogether, 64 genes were consistently prioritized across multiple methods, including 10 ncRNAs (Table S4; (21)).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [21] See supplemental methods.

In the paper

“However, the isoform-level networks captured greater detail and a larger proportion were associated with disease GWAS than gene-level networks (61% vs 41% with nominal GWAS enrichment, P=0.07, χ2; Fig 5A).”

In the paper

“Of the seven TWAS-significant genes at this locus, conditional analysis prioritizes one – LRRC37A, which is further supported by SMR and Hi-C interaction in fetal brain (38).”

What the sources say

• Not checked yetcites [38] Grove J, Common risk variants identified in autism spectrum disorder. bioRxiv (2017), p. 224774. source

In the paper

“A previous TWAS study in SCZ primarily based on non-neural tissue prioritized 157 genes, 37 of which are identified here, a significant overlap (OR 61, p<10−42, Fisher’s exact test).”

In the paper

“These included a number of intriguing novel candidates for SCZ: two downregulated lysine methyltransferayjec9vses (SETD6, SETD8); RERE, a downregulated, mutationally intolerant nuclear receptor co-regulator of retinoic acid signaling associated with a rare neurodevelopmental genetic syndrome; LINC00634, a downregulated poorly annotated brain-enriched lincRNA; and SLC12A5, encoding a mitochondrial”

In the paper

“A notable example is geneM2/isoM13, which is enriched for oligodendrocyte markers and neuron projection developmental pathways and is downregulated in ASD and SCZ, with a trend in BD (Fig 5C).”

In the paper

“Here, we find that isoM17 shows greater enrichment for nuclear RBFOX1 targets (Fig 6C), whereas isoM2 shows stronger overlap with cytoplasmic targets (32).”

What the sources say

• Not checked yetcites [32] Lee J-A, Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes. Neuron. 89, 113– 128 (2016). 26687839 PMC4858412 source

In the paper

“In BD, TWAS prioritizes 17 genes across 14 distinct loci (Bonferroni-corrected P<0.05; Fig 4; Table S4), none of which exhibited DE.”

In the paper

“The interferon response module (geneM32) contains critical components of the IFN-stimulated gene factor 3 (ISGF3) complex”

What the sources say

• Not checked yetcites [71] Rusinova I, Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res. 41, D1040– 6 (2013). 23203888 PMC3531205 source

In the paper

“all preserved in the signed networks with strong cell type and GWAS enrichments”

In the paper

“This module pair contained as hubs the two major GABA synthesizing enzymes (GAD1, GAD2), multiple GABA transporters (SLC6A1, SLC24A3), many other known interneuron markers (RELN, VIP), as well as DLX1 and the lncRNA DLX6-AS1, both critical known regulators of inhibitory neuron development (62).”

What the sources say

• Not checked yetcites [62] Bond AM, Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat. Neurosci 12, 1020– 1027 (2009). 19620975 PMC3203213 source

In the paper

“Indeed, geneM21/isoM30 was associated with genes downregulated by chronic high-doses (but not low-doses) of haloperidol, as well as genes upregulated by the antidepressant fluoxetine (Fig S11A).”

In the paper

“This pattern is clearly distinct from ASD, which shows a dynamic trajectory, but remains upregulated throughout (Fig 7F).”

In the paper

“We provide a table of putative mRNA targets for these brain expressed lncRNAs, including 209 exhibiting DE in ASD, 122 in BD and 241 in SCZ (Table S6).”

In the paper

“including geneM7, enriched for synaptic and metabolic processes with the splicing regulator NOVA2 (Fig 5C).”

In the paper

“The increased resolution here allowed us to identify several modules enriched in inhibitory interneuron markers (Fig 5B), including geneM23/isoM19, which is downregulated in ASD and SCZ, with a trend toward downregulation observed in BD;”

In the paper

“Several neuronal modules that distinguish between the disorders differentiate BD and SCZ from ASD, including the module pair geneM21/isoM30 (Fig 5C), which captures known elements of activity-dependent neuronal gene regulation, whose hubs include classic early-response (ARC, EGR1, NPAS4, NR4A1) and late-response genes (BDNF, HOMER1) (40).”

What the sources say

• Not checked yetcites [40] West AE, Greenberg ME, Neuronal activity-regulated gene transcription in synapse development and cognitive function. Cold Spring Harb. Perspect. Biol 3 (2011), doi: 10.1101/cshperspect.a005744. PMC3098681 21555405 source

In the paper

“A large proportion of disease-associated co-expression modules are enriched for cell type specific markers, as is overall disease DE signal”

In the paper

“These switch isoforms show markedly different expression patterns, belonging to different co-expression modules, geneM3/isoM1 (Fig 7C) and isoM18”

In the paper

“are down and upregulated in ASD and SCZ, respectively (Fig S17).”

In the paper

“are up and downregulated in ASD and SCZ, respectively (Fig S17).”

In the paper

“present both in the cell nucleus and cytoplasm (Fig 8A; Fig S16)”

In the paper

“Genes with switch isoforms are also enriched for the regulatory targets of two ASD risk genes, CHD8 and FMRP, as well as highly mutationally constrained genes (pLI>0.99), syndromic ASD genes, and in genes with de novo exonic mutations in ASD, SCZ and BD (Fig 8F; Table S7; (21)).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [21] See supplemental methods.

In the paper

“whereas LINC01166 is significantly downregulated in BD (log2FC −0.17, FDR<0.05) with trends in ASD and SCZ (FDR’s < 0.1).”

In the paper

“which are enriched in astrocyte and neuronal cell types, respectively (Fig 5A; Fig S12).”

In the paper

“most of these ncRNAs show significant CNS enrichment, but until now, have limited functional annotation.”

In the paper

“A module enriched for microglial-associated genes, for example, shows a clear distinction between disorders, with strong upregulation observed on ASD and significant downregulation in SCZ and BD.”

In the paper

“Such regulatory relationships show substantial heterogeneity across human cell types, tissues, and developmental stages (10), and are often highly species-specific (11).”

What the sources say

• Not checked yetcites [10] GTEx Consortium, Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 348, 648– 660 (2015). 25954001 PMC4547484 source
• Not checked yetcites [11] Reilly SK, Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science. 347, 1155– 1159 (2015). 25745175 PMC4426903 source

In the paper

“Data was generated across eight studies (2, 19, 20), uniformly processed, and combined through a consolidated genomic data processing pipeline ((21); Fig S1), yielding a total of 2188 samples passing quality control (QC) for this analysis, representing frontal and temporal cerebral cortex from 1695 unique subjects across the lifespan, including 279 technical replicates (Fig S2).”

What the sources say

• Not checked yetcites [2] Fromer M, Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat. Neurosci 19, 1442– 1453 (2016). 27668389 PMC5083142 source
• Not checked yetcites [19] Parikshak NN, Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature. 540, 423– 427 (2016). 27919067 PMC7102905 source
• Not checked yetcites [20] Kang HJ, Spatio-temporal transcriptome of the human brain. Nature. 478, 483– 489 (2011). 22031440 PMC3566780 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [21] See supplemental methods.

In the paper

“Studies have identified hundreds of causal genetic variants robustly associated with these disorders, and thousands more that likely contribute to their pathogenesis (4).”

What the sources say

• Not checked yetcites [4] Gandal MJ, Leppa V, Won H, Parikshak NN, Geschwind DH, The road to precision psychiatry: translating genetics into disease mechanisms. Nat. Neurosci 19, 1397– 1407 (2016). 27786179 PMC9012265 source

In the paper

“Extensive quality control steps were taken within and across individual studies resulting in the detection of 16,541 protein-coding and 9,233 non-coding genes with the Gencode v19 annotations ((21); Fig S3).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [21] See supplemental methods.

In the paper

“Previous studies have identified alterations in local splicing events in ASD (19, 30) and in smaller cohorts in SCZ (2, 24) and BD (31).”

What the sources say

• Not checked yetcites [19] Parikshak NN, Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature. 540, 423– 427 (2016). 27919067 PMC7102905 source
• Not checked yetcites [30] Irimia M, A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell. 159, 1511– 1523 (2014). 25525873 PMC4390143 source
• Not checked yetcites [2] Fromer M, Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat. Neurosci 19, 1442– 1453 (2016). 27668389 PMC5083142 source
• Not checked yetcites [24] Jaffe AE, Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat. Neurosci 21, 1117– 1125 (2018). 30050107 PMC6438700 source
• Not checked yetcites [31] Akula N, RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Mol. Psychiatry 19, 1179– 1185 (2014). 24393808 PMC5560442 source

In the paper

“We used surrogate variable correction in our analyses to account for such unmeasured confounders (43), which is a standard approach (44).”

What the sources say

• Not checked yetcites [43] Leek JT, Storey JD, Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 3, 1724– 1735 (2007). 17907809 PMC1994707 source
• Not checked yetcites [44] GTEx Consortium, Genetic effects on gene expression across human tissues. Nature. 550, 204 (2017). 29022597 PMC5776756 source

In the paper

“Notably, DS exhibited greatest overlap with the ncRNA signal, suggesting a role for non-coding genes in regulating local splicing events.”

In the paper

“We used LeafCutter (29) to assess local differential splicing (DS) differences in ASD, SCZ and BD using de novo aligned RNA-seq reads, controlling for the same covariates as DGE/DTE (Fig S7).”

What the sources say

• Not checked yetcites [29] Li YI, Annotation-free quantification of RNA splicing using LeafCutter. Nat. Genet 50, 151– 158 (2018). 29229983 PMC5742080 source

In the paper

“Experiments in mouse indicate that RBFOX1 has distinct nuclear and cytoplasmic isoforms with differing functions, the nuclear isoform primarily regulating pre-mRNA alternative splicing, and the cytoplasmic isoform binding to the 3’ UTR to stabilize target transcripts involved in regulation of neuronal excitability (28, 32, 58, 60).”

What the sources say

• Not checked yetcites [28] Vuong CK, Black DL, Zheng S, The neurogenetics of alternative splicing. Nat. Rev. Neurosci 17, 265– 281 (2016). 27094079 PMC4861142 source
• Not checked yetcites [32] Lee J-A, Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes. Neuron. 89, 113– 128 (2016). 26687839 PMC4858412 source
• Not checked yetcites [58] Vuong CK, Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1. Neuron. 98, 127– 141.e7 (2018). 29621484 PMC5890944 source
• Not checked yetcites [60] Gehman LT, The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nat. Genet 43, 706– 711 (2011). 21623373 PMC3125461 source

In the paper

“However, expression of all three was also significantly (P<0.05) correlated with imputed C4A copy number, suggesting pleiotropic effects.”

In the paper

“The two isoforms with PRS associations in BD (NCALD, SNF8) were non-significant in TWAS, perhaps due to lack of a nearby genome-wide significant locus or isoform-specific regulation, suggesting those expression changes may be driven by trans-acting factors.”

In the paper

“However, the large sample size, coupled with the specificity of isoform-level qualifications, enabled us to identify synaptic modules containing unique isoforms with distinct disease associations and to separate signals from excitatory and inhibitory neurons (Fig 5B).”

In the paper

“Overall, this analysis provides a core set of strong candidate genes implicated by risk loci, and provides a mechanistic basis for the composite activity of disease risk variants.”

In the paper

“Previous work has identified downregulated neuronal modules in ASD and SCZ containing RBFOX1 as a hub (1, 16).”

What the sources say

• Not checked yetcites [1] Gandal MJ, Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 359, 693– 697 (2018). 29439242 PMC5898828 source
• Not checked yetcites [16] Voineagu I, Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 474, 380– 384 (2011). 21614001 PMC3607626 source

In the paper

“Previous work has identified differential activation of glial and neural-immune processes in brain from patients with psychiatric disorders (16, 52, 57, 66–69)”

What the sources say

• Not checked yetcites [16] Voineagu I, Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 474, 380– 384 (2011). 21614001 PMC3607626 source
• Not checked yetcites [52] Chen C, Two gene co-expression modules differentiate psychotics and controls. Mol. Psychiatry 18, 1308– 1314 (2013). 23147385 PMC4018461 source
• Not checked yetcites [57] Ramaker RC, Post-mortem molecular profiling of three psychiatric disorders. Genome Med. 9, 72 (2017). 28754123 PMC5534072 source
• Not checked yetcites [66] Birnbaum R, Investigating the neuroimmunogenic architecture of schizophrenia. Mol. Psychiatry 23, 1251– 1260 (2018). 28485405 source
• Not checked yetcites [67] Fillman SG, Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 18, 206– 214 (2013). 22869038 source
• Not checked yetcites [68] Pacifico R, Davis RL, Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Mol. Psychiatry 22, 441– 449 (2017). 27350034 source
• Not checked yetcites [69] Rao JS, Harry GJ, Rapoport SI, Kim HW, Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol. Psychiatry 15, 384– 392 (2010). 19488045 PMC2844920 source

In the paper

“Although these modules were not significantly downregulated in ASD, subsampling indicates that the differences between disorders could be driven by sample size (Fig S14).”

In the paper

“the lncRNA DLX6-AS1, a known development regulator of interneuron specification (62)”

What the sources say

• Not checked yetcites [62] Bond AM, Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat. Neurosci 12, 1020– 1027 (2009). 19620975 PMC3203213 source

In the paper

“and both microglia and astrocytes in ASD (19, 70).”

What the sources say

• Not checked yetcites [19] Parikshak NN, Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature. 540, 423– 427 (2016). 27919067 PMC7102905 source
• Not checked yetcites [70] Gupta S, Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun 5, 5748 (2014). 25494366 PMC4270294 source

In the paper

“Two additional immune-related modules appear to represent more broadly expressed signaling pathways: interferon response (geneM32) and NFkB (geneM5/isoM5).”

In the paper

“Remarkably, a nearly identical module was recently identified as a sex-specific transcriptional signature of major depression and stress susceptibility (64).”

What the sources say

• Not checked yetcites [64] Labonté B, Sex-specific transcriptional signatures in human depression. Nat. Med 23, 1102– 1111 (2017). 28825715 PMC5734943 source

In the paper

“As a subset of lncRNAs are thought to function by repressing mRNA targets (72)”

What the sources say

• Not checked yetcites [72] Necsulea A, The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature. 505, 635– 640 (2014). 24463510 source

In the paper

“maximally diverges from controls during early adulthood, coincident with typical disease onset in SCZ and BD (~25).”

In the paper

“including upregulation of astrocytes in SCZ and BD (1, 57)”

What the sources say

• Not checked yetcites [1] Gandal MJ, Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 359, 693– 697 (2018). 29439242 PMC5898828 source
• Not checked yetcites [57] Ramaker RC, Post-mortem molecular profiling of three psychiatric disorders. Genome Med. 9, 72 (2017). 28754123 PMC5534072 source

In the paper

“the top GWAS-supported, and strongly upregulated, risk gene for SCZ (5).”

What the sources say

• Not checked yetcites [5] Sekar A, Schizophrenia risk from complex variation of complement component 4. Nature. 530, 177– 183 (2016). 26814963 PMC4752392 source

In the paper

“LINC00473 is regulated by synaptic activity and downregulates immediate early gene expression (74)”

What the sources say

• Not checked yetcites [74] Pruunsild P, Bengtson CP, Bading H, Networks of Cultured iPSC-Derived Neurons Reveal the Human Synaptic Activity-Regulated Adaptive Gene Program. Cell Rep. 18, 122– 135 (2017). 28052243 PMC5236011 source

In the paper

“peaking during early development, coincident with clinical onset.”

In the paper

“Evidence supports hyperactive complement-mediated synaptic pruning in SCZ pathophysiology, presumably through microglia (5)”

What the sources say

• Not checked yetcites [5] Sekar A, Schizophrenia risk from complex variation of complement component 4. Nature. 530, 177– 183 (2016). 26814963 PMC4752392 source

In the paper

“These genes play critical roles in regulating synaptic plasticity and the balance of excitatory and inhibitory synapses (40).”

What the sources say

• Not checked yetcites [40] West AE, Greenberg ME, Neuronal activity-regulated gene transcription in synapse development and cognitive function. Cold Spring Harb. Perspect. Biol 3 (2011), doi: 10.1101/cshperspect.a005744. PMC3098681 21555405 source

In the paper

“NIPBL, a gene associated with Cornelia de Lange Syndrome (80)”

What the sources say

• Not checked yetcites [80] Krantz ID, Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat. Genet 36, 631– 635 (2004). 15146186 PMC4902017 source

In the paper

“These data confirm the importance of microexon regulation in neuropsychiatric disorders beyond ASD, and their potential role in distinguishing among biological pathways differentially affected across conditions.”

In the paper

“alternative splicing patterns are more distinct than in other organ systems (82).”

What the sources say

• Not checked yetcites [82] Melé M, Human genomics. The human transcriptome across tissues and individuals. Science. 348, 660– 665 (2015). 25954002 PMC4547472 source

In the paper

“At each step of analysis, we have attempted to mitigate the contribution of these factors through known and hidden covariate correction, assessment of age trajectories, and via enrichment for causal genetic variation.”

In the paper

“several studies have demonstrated that genes carrying microexons are preferentially expressed in brain and their splicing is dysregulated in ASD (30, 82, 83).”

What the sources say

• Not checked yetcites [30] Irimia M, A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell. 159, 1511– 1523 (2014). 25525873 PMC4390143 source
• Not checked yetcites [82] Melé M, Human genomics. The human transcriptome across tissues and individuals. Science. 348, 660– 665 (2015). 25954002 PMC4547472 source
• Not checked yetcites [83] Quesnel-Vallières M, Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders. Mol. Cell 64, 1023– 1034 (2016). 27984743 source

In the paper

“SOX2-OT is a heavily spliced, evolutionarily-conserved lncRNA exhibiting predominant brain expression and a hub of these oligodendrocyte modules, without previous mechanistic links to myelination (75, 76).”

What the sources say

• Not checked yetcites [75] Amaral PP, Complex architecture and regulated expression of the Sox2ot locus during vertebrate development. RNA. 15, 2013– 2027 (2009). 19767420 PMC2764477 source
• Not checked yetcites [76] Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS, Specific expression of long noncoding RNAs in the mouse brain. Proc. Natl. Acad. Sci. U. S. A 105, 716– 721 (2008). 18184812 PMC2206602 source

In the paper

“This likely varies by transcript class, and some of the modest correlations are likely due to low abundance genes, such as ncRNAs”

In the paper

“Several broad shared patterns of gene expression dysregulation have been observed in post mortem brain in previous studies, most prominently, a gradient of downregulation of neuronal and synaptic signaling genes, and upregulation of glial-immune or neuroinflammatory signals.”

In the paper

“SMARCA2, a member of the BAF-complex strongly implicated in several neurodevelopmental disorders including ASD (79)”

What the sources say

• Not checked yetcites [79] Koga M, Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia. Hum. Mol. Genet 18, 2483– 2494 (2009). 19363039 source

In the paper

“by performing a well-powered brain-relevant TWAS in SCZ, and to a lesser extent in BD and ASD”

In the paper

“the ASD risk gene ANK2 (81)”

What the sources say

• Not checked yetcites [81] Sanders SJ, Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 87, 1215– 1233 (2015). 26402605 PMC4624267 source

In the paper

“an established regulator of oligodendrocyte-gene splicing also located in this module (77, 78).”

What the sources say

• Not checked yetcites [77] Aberg K, Saetre P, Jareborg N, Jazin E, Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc. Natl. Acad. Sci. U. S. A 103, 7482– 7487 (2006). 16641098 PMC1464365 source
• Not checked yetcites [78] Barry G, The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol. Psychiatry 19, 486– 494 (2014). 23628989 source

In the paper

“These analyses predict critical roles for these or these often overlooked non-coding genes in oligodendrocyte function (77, 78) and potentially in psychiatric conditions.”

What the sources say

• Not checked yetcites [77] Aberg K, Saetre P, Jareborg N, Jazin E, Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc. Natl. Acad. Sci. U. S. A 103, 7482– 7487 (2006). 16641098 PMC1464365 source
• Not checked yetcites [78] Barry G, The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol. Psychiatry 19, 486– 494 (2014). 23628989 source

In the paper

“likely cell type specific interactions that suggest distinct functions of the isoforms of this gene in different neural cell types and diseases.”