Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion.

paper Cited Public

Authors: Lin, Mingyan; Pedrosa, Erika; Hrabovsky, Anastasia; Chen, Jian; Puliafito, Benjamin R; Gilbert, Stephanie R; Zheng, Deyou; Lachman, Herbert M
Year: 2016
Journal: BMC systems biology
PMID: 27846841
DOI: 10.1186/s12918-016-0366-0
PMCID: PMC5111260

BACKGROUND: Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in early differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients. METHODS: Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subjected to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. Lastly, we related our findings from in vitro neuronal cultures to brain development by mapping differentially expressed genes to BrainSpan transcriptomes. RESULTS: We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p < 0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples. By leveraging transcriptome profiles of normal human brain tissues across human development into adulthood, we showed that the differentially expressed genes converge on a sub-network mediated by CDC45 and the cell cycle, which would be disrupted by the 22q11.2 deletion during embryonic brain development, and another sub-network modulated by PRODH, which could contribute to disruption of brain function during adolescence. CONCLUSIONS: This study has provided evidence for disruption of potential molecular events in SZ patient with 22q11.2 deletion and related our findings from in vitro neuronal cultures to functional perturbations that can occur during brain development in SZ.

Fig. 1

Differentially expressed genes in 22q11.2 SZ neurons and their enriched functions. a Heat map showing relative expression of 782 genes that exhibited significant change between control and SZ at p-value < 0.05 (503 increased in SZ; 279 decreased). b Bar plot presenting batch-corrected expression values of 22q11.2 genes in control and SZ samples. Three genes flanking the deleted region at either side were also included. Asterisks (*) indicate significant differential expression at the genome-wide level (FDR < 0.05). c Enriched GO terms of the DEGs as determined by the software David. d Enriched pathways for the DEGs as determined by the software Toppgene

Fig. 2

qPCR validation and NPC proliferation assay. a qPCR analysis of six DEGs using neuronal RNAs from 4–5 controls and 4–5 patients. Relative expression values were determined and pooled by phenotype. Error bars show standard error of the mean; Two-tailed t-test p-value <0.01 (**) and <0.05 (*) are indicated. b Proliferation rates of NPCs derived from control (n = 4) and 22q.11.2 (n = 4) iPSCs. An equal number of cells were plated for each sample (10,000) on day 0. Fold changes were calculated by normalizing the day 1 controls to 1.00, and the control and patient samples were pooled. Statistical significance was determined using a two-tailed Student’s t-test. The asterisk denotes statistically significant difference in proliferation at p < 0.05

Fig. 3

WGCNA modules and function enrichment. a Module preservation Z-summary statistics of 15 modules identified by WGCNA. b Barplot showing the –log10 (p-value) (y-axis) of expression differences between SZ samples and controls for 13 modules whose module structures were well preserved between SZ and control samples (Z > 10, A). c Network of top pathways in the differentially expressed pink module. Each node represents a term and an edge between two nodes indicates that the two terms share genes. d The top pathways in the pink module as determined by the software Enrichr

Fig. 4

Enrichment of DEGs in a region of chromosome 6 predicted to interact with 22q11.2. Scatterplot presenting the –log10 (p-values) (y-axis) of changes in gene expression for each gene along chromosome 6. The heat map below shows the reported Hi-C correlation between each section of chromosome 6 and the 22q11.2 region. Note that the 6p21 region, which is highlighted by a yellow box in the heat map, was enriched for differentially expressed genes, and it displayed the strongest physical interaction with 22q11.2

Fig. 5

Highest co-expression of DEGs in specific brain regions. a Interconnectedness of transcriptional coexpression networks at various developmental stages and in different brain regions based on DEGs or randomly selected genes were evaluated using RNA-seq data from the BrainSpan Atlas. A pair of genes was defined as coexpressed if their expression correlation coefficient |R| was ≥ 0.9, across all tissues from a given brain region and a given developmental stage (Table 1). Dotted lines indicate numbers of connections (i.e., edges) in networks actually observed for DEGs, while the histograms represent distributions of the numbers of edges in 10,000 simulated networks derived from randomly picked genes. b Multiple testing adjusted –log10(P-value) for the significance of difference between the numbers of observed and simulated network edges

Fig. 6

ClueGO network for top correlating DEGs and co-expressed non-DEGs in frontal cortex during the embryonic stage. The size of the nodes reflects the statistical significance of the terms. Only terms with p-values < 0.05 are shown. For grouping terms, the initial group size was set to 3 and the percentage for merging groups was set to 50%. A term can be included in more than one group. Different groups were colored differently. The group leading term (in bold) is the most significant term of the group

Fig. 7

ClueGO network for top correlating DEGs and co-expressed non-DEGs in frontal cortex during the adolescence stage. See annotation in Fig. 6

#	Section	Preview
0	Background	SZ is a very complex disorder caused by multivariate genetic and environmental factors. Apart from…
1	Background	Thus, it is valuable to search for SZ-specific changes in early neural development of individuals…
2	Background	In this study, we performed a global and unbiased transcriptome analysis of iPSC-derived neurons…
3	Background	are consistent with a number of previous reports showing abnormal apoptotic function in the…
4	Methods — Development of iPSCs from skin fibroblasts	Controls and patients with 22q11.2 del diagnosed with a psychotic disorder (SZ, childhood onset…
5	Methods — Development of iPSCs from skin fibroblasts	The iPSC lines were generated from fibroblasts obtained from skin biopsies performed by…
6	Methods — Characterizing iPSC lines	Pluripotency for all iPSC lines was confirmed by immunocytochemistry using antibodies (Ab) against…
7	Methods — Neuronal differentiation	Neurons were generated from iPSC-derived neural progenitor cells (NPCs) as described by Marchetto et…
8	Methods — Quantitative real-time PCR (qPCR)	qPCR was carried out on reverse transcribed cDNA from the same RNA samples used for the RNA-seq by…
9	Methods — Proliferation assay	Cell proliferation was assayed using the Vybrant MTT cell proliferation assay kit (Invitrogen)…
10	Methods — RNA-seq data acquisition	Paired-end RNA-seq was carried out on an Illumina HiSeq 2000. We obtained 101-bp mate-paired reads…
11	Methods — Sample clustering and “Batch” correction	RNA-seq samples were clustered based on all expressed transcripts (average FPKM > 1, n = 17,669,…
12	Methods — Sample clustering and “Batch” correction	stem cell and neural progenitor markers (e.g., VIM, SMAD2 and NOTCH2). These suggest that variation…
13	Methods — Characterization of neuronal fate and maturity	To characterize the neuronal fate and maturity of our differential neurons, we compared gene…
14	Methods — Characterization of neuronal fate and maturity	expression data set encompassing cerebral cortical development from human embryonic stem cells [51],…
15	Methods — Identifying differentially expressed genes (DEGs)	Although we have biological replicates for a few iPSC lines, we found that intra-individual…
16	Methods — Identifying differentially expressed genes (DEGs)	We used DESeq2 [52] to determine differential expression from the corrected RNA-seq read count…
17	Methods — Identifying differentially expressed gene modules	We used Weighted Gene Coexpression Network Analysis (WGCNA) [60] to identify co-expressed gene…
18	Methods — Function enrichment analysis	We identified enriched pathways in the REACTOME databases with Toppgene [61] and enriched Gene…
19	Methods — Mapping differentially expressed genes to BrainSpan transcriptomes	To evaluate gene coexpression across brain regions at different developmental periods for the DEGs…

Citation	PMID	DOI	Status
Agalliu, D et al., Neural Dev, 2009, Heterogeneity in the developmental potential of motor neuron progenitors revealed by clonal analysis of single cells in vitro	19123929	10.1186/1749-8104-4-2	Cited
Andreassen, O et al., Mol Psychiatry, 2015, Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci	24468824	10.1038/mp.2013.195	Cited
Archinti, M et al., CNS Neurol Disord Drug Targets, 2011, The urokinase receptor in the central nervous system	20874700	10.2174/187152711794480393	Cited
Arinami, T, J Hum Genet, 2006, Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia	16969581	10.1007/s10038-006-0058-5	Cited
Arion, D et al., Biol Psychiatry, 2007, Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia	17568569	10.1016/j.biopsych.2006.12.021	Cited
Aston, C et al., J Neurosci Res, 2004, Microarray analysis of postmortem temporal cortex from patients with schizophrenia	15334603	10.1002/jnr.20208	Cited
Barabasi, A-L et al., Nat Rev Genet, 2004, Network biology: understanding the cell's functional organization	14735121	10.1038/nrg1272	Cited
Barge‐Schaapveld, DQ et al., Am J Med Genet A, 2011, The atypical 16p11. 2 deletion: a not so atypical microdeletion syndrome?	21465664	10.1002/ajmg.a.33991	Cited
Bassett, AS et al., Curr Psychiatry Rep, 2008, Schizophrenia and 22q11. 2 deletion syndrome	18474208	10.1007/s11920-008-0026-1	Cited
Benes, F et al., Mol Psychiatry, 2005, The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia	16288314	10.1038/sj.mp.4001758	Cited
Benes, FM, Schizophr Res, 2015, Building models for postmortem abnormalities in hippocampus of schizophrenics	25749020	10.1016/j.schres.2015.01.014	Cited
Beneyto M, Abbott A, Hashimoto T, Lewis DA. Lamina-specific alterations in cortical GABAA receptor subunit expression in schizophrenia. Cereb Cortex. 2011;21(5):999-1011. doi: 10.1093/cercor/bhq169.10.1093/cercor/bhq169PMC307742720843900	—	—	—
Benjamini, Y et al., J Roy Stat Soc Ser B (Stat Method), 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing	—	—	—
Beveridge, N et al., Mol Psychiatry, 2010, Schizophrenia is associated with an increase in cortical microRNA biogenesis	19721432	10.1038/mp.2009.84	Cited
Bindea, G et al., Bioinformatics, 2009, ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks	19237447	10.1093/bioinformatics/btp101	Cited
Blumenthal, I et al., Am J Hum Genet, 2014, Transcriptional Consequences of 16p11. 2 Deletion and Duplication in Mouse Cortex and Multiplex Autism Families	24906019	10.1016/j.ajhg.2014.05.004	Cited
Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, et al. Protein kinases and phosphatases in the control of cell fate. Enzyme Res. 2011;2011:329098. doi: 10.4061/2011/329098.10.4061/2011/329098PMC316677821904669	—	—	—
Boulanger, LM, Neuron Glia Biol, 2004, MHC class I in activity-dependent structural and functional plasticity	18185853	10.1017/S1740925X05000128	Cited
Boyajyan, A et al., Mol Biol, 2013, Markers of apoptotic dysfunctions in schizophrenia	24466757	10.1134/S002689331304002X	Cited
Brennand, KJ et al., Nature, 2011, Modelling schizophrenia using human induced pluripotent stem cells	21490598	10.1038/nature09915	Cited
Brown, AS et al., Arch Gen Psychiatry, 2004, Serologic evidence of prenatal influenza in the etiology of schizophrenia	15289276	10.1001/archpsyc.61.8.774	Cited
Carter, C, Schizophr Bull, 2009, Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii	18552348	10.1093/schbul/sbn054	Cited
Catts, VS et al., Schizophr Res, 2006, Apoptosis and schizophrenia: a pilot study based on dermal fibroblast cell lines	16626937	10.1016/j.schres.2006.03.016	Cited
Chen, C et al., Mol Psychiatry, 2012, Two gene co-expression modules differentiate psychotics and controls	23147385	10.1038/mp.2012.146	Cited
Chen, EY et al., BMC Bioinformatics, 2013, Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool	23586463	10.1186/1471-2105-14-128	Cited
Chen, J et al., Nucleic Acids Res, 2009, ToppGene Suite for gene list enrichment analysis and candidate gene prioritization	19465376	10.1093/nar/gkp427	Cited
Chen, J et al., PLoS One, 2013, Transcriptome comparison of human neurons generated using induced pluripotent stem cells derived from dental pulp and skin fibroblasts	24098394	10.1371/journal.pone.0075682	Cited
Chen, Z et al., J Biol Chem, 2012, DiGeorge syndrome critical region 8 (DGCR8) protein-mediated microRNA biogenesis is essential for vascular smooth muscle cell development in mice	22511778	10.1074/jbc.M112.351791	Cited
Cheung, EC et al., Sci Signal, 2004, Emerging role for ERK as a key regulator of neuronal apoptosis	15383672	10.1126/stke.2512004pe45	Cited
Cinque, P et al., Ann Neurol, 2004, The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations	15122709	10.1002/ana.20076	Cited
Consortium ISG, 2 WTCCC, Biol Psychiatry, 2012, Genome-wide association study implicates HLA-C* 01: 02 as a risk factor at the major histocompatibility complex locus in schizophrenia	22883433	10.1016/j.biopsych.2012.05.035	Cited
Consortium SWGotPG, Nature, 2014, Biological insights from 108 schizophrenia-associated genetic loci	25056061	10.1038/nature13595	Cited
Corriveau, RA et al., Neuron, 1998, Regulation of class I MHC gene expression in the developing and mature CNS by neural activity	9768838	10.1016/S0896-6273(00)80562-0	Cited
Cremer, T et al., Nat Rev Genet, 2001, Chromosome territories, nuclear architecture and gene regulation in mammalian cells	11283701	10.1038/35066075	Cited
Cunningham, O et al., Glia, 2009, Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation	19459212	10.1002/glia.20892	Cited
Da Wei Huang, BTS et al., Nat Protoc, 2008, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources	19131956	10.1038/nprot.2008.211	Cited
Darmanis, S et al., Proc Natl Acad Sci U S A, 2015, A survey of human brain transcriptome diversity at the single cell level	26060301	10.1073/pnas.1507125112	Cited
Dekker, J, Science, 2008, Gene regulation in the third dimension	18369139	10.1126/science.1152850	Cited
Dimos, JT et al., Science, 2008, Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons	18669821	10.1126/science.1158799	Cited
Dolmetsch, R et al., Cell, 2011, The human brain in a dish: the promise of iPSC-derived neurons	21663789	10.1016/j.cell.2011.05.034	Cited
Driscoll, D et al., Am J Hum Genet, 1992, A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11	1349199	—	Cited
Everitt, AR et al., Nature, 2012, IFITM3 restricts the morbidity and mortality associated with influenza	22446628	10.1038/nature10921	Cited
Eyo, UB et al., J Neuroimmune Pharmacol, 2013, Microglia: key elements in neural development, plasticity, and pathology	23354784	10.1007/s11481-013-9434-z	Cited
Fan, Y et al., Biol Psychiatry, 2012, Altered cell cycle dynamics in schizophrenia	22074612	10.1016/j.biopsych.2011.10.004	Cited
Fatemi, SH et al., Schizophr Bull, 2009, The neurodevelopmental hypothesis of schizophrenia, revisited	19223657	10.1093/schbul/sbn187	Cited
Funk, AJ et al., Neuropsychopharmacology, 2011, Abnormal activity of the MAPK-and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia	22048463	10.1038/npp.2011.267	Cited
Gassó, P et al., J Psychiatr Res, 2014, Increased susceptibility to apoptosis in cultured fibroblasts from antipsychotic-naïve first-episode schizophrenia patients	24128664	10.1016/j.jpsychires.2013.09.017	Cited
Glantz, LA et al., Schizophr Res, 2006, Apoptotic mechanisms and the synaptic pathology of schizophrenia	16226876	10.1016/j.schres.2005.08.014	Cited
Goddard, CA et al., Proc Natl Acad Sci U S A, 2007, Regulation of CNS synapses by neuronal MHC class I	17420446	10.1073/pnas.0702023104	Cited
Gogos, J et al., Nat Genet, 1999, The gene encoding proline dehydrogenase modulates sensorimotor gating in mice	10192398	10.1038/7777	Cited
Gondi, CS et al., Int J Oncol, 2007, Downregulation of uPAR and uPA activates caspase mediated apoptosis, inhibits the PI3k/AKT pathway	17549401	—	Cited
Gulsuner, S et al., Cell, 2013, Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network	23911319	10.1016/j.cell.2013.06.049	Cited
Hakak, Y et al., Proc Natl Acad Sci U S A, 2001, Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia	11296301	10.1073/pnas.081071198	Cited
Haroutunian, V et al., Int J Neuropsychopharmacol, 2007, Variations in oligodendrocyte-related gene expression across multiple cortical regions: implications for the pathophysiology of schizophrenia	17291370	10.1017/S1461145706007310	Cited
Harrow, J et al., Genome Res, 2012, GENCODE: the reference human genome annotation for The ENCODE Project	22955987	10.1101/gr.135350.111	Cited
Heckers, S et al., Schizophr Res, 2015, GABAergic mechanisms of hippocampal hyperactivity in schizophrenia	25449711	10.1016/j.schres.2014.09.041	Cited
Huang, DW et al., Nucleic Acids Res, 2009, Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists	19033363	10.1093/nar/gkn923	Cited
Huttenlocher, PR, Brain Res, 1979, Synaptic density in human frontal cortex-developmental changes and effects of aging	427544	10.1016/0006-8993(79)90349-4	Cited
Jacquet, H et al., Hum Mol Genet, 2002, PRODH mutations and hyperprolinemia in a subset of schizophrenic patients	12217952	10.1093/hmg/11.19.2243	Cited
Jalbrzikowski M, Lazaro MT, Gao F, Huang A, Chow C, Geschwind DH, et al. Transcriptome profiling of peripheral blood in 22q11.2 deletion syndrome reveals functional pathways related to psychosis and autism spectrum disorder. PLoS One. 2015;10(7):e0132542. doi:10.1371/journal.pone.0132542.10.1371/journal.pone.0132542PMC451176626201030	—	—	—
Jarskog, LF et al., Am J Psychiatry, 2004, Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation	14702258	10.1176/appi.ajp.161.1.109	Cited
Jarskog, LF et al., Biol Psychiatry, 2000, Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia	11032975	10.1016/S0006-3223(00)00988-4	Cited
Jarskog, LF et al., Prog Neuro-Psychopharmacol Biol Psychiatry, 2005, Apoptotic mechanisms in the pathophysiology of schizophrenia	15908096	10.1016/j.pnpbp.2005.03.010	Cited
Juraeva, D et al., PLoS Genet, 2014, Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia	24901509	10.1371/journal.pgen.1004345	Cited
Kalla, C et al., Eur J Cancer, 2007, Analysis of 11q22–q23 deletion target genes in B-cell chronic lymphocytic leukaemia: Evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B	17449237	10.1016/j.ejca.2007.02.005	Cited
Kang, W et al., J Neurosci, 2009, The transition from radial glial to intermediate progenitor cell is inhibited by FGF signaling during corticogenesis	19923290	10.1523/JNEUROSCI.3844-09.2009	Cited
Karayiorgou, M et al., Mol Brain Res, 2004, The molecular genetics of the 22q11-associated schizophrenia	15582150	10.1016/j.molbrainres.2004.09.029	Cited
Karayiorgou, M et al., Nat Rev Neurosci, 2010, 22q11. 2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia	20485365	10.1038/nrn2841	Cited
Katsel, P et al., Neuropsychopharmacology, 2008, Abnormal indices of cell cycle activity in schizophrenia and their potential association with oligodendrocytes	18322470	10.1038/npp.2008.19	Cited
Kazama, H et al., Neuroscience, 2008, Innervation and activity dependent dynamics of postsynaptic oxidative metabolism	18242000	10.1016/j.neuroscience.2007.12.020	Cited
Kempf, L et al., PLoS Genet, 2008, Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function	18989458	10.1371/journal.pgen.1000252	Cited
Kim, D et al., Genome Biol, 2013, TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions	23618408	10.1186/gb-2013-14-4-r36	Cited
Kornfeld, SJ et al., J Allergy Clin Immunol, 2000, DiGeorge anomaly: a comparative study of the clinical and immunologic characteristics of patients positive and negative by fluorescence in situ hybridization	10808180	10.1067/mai.2000.105527	Cited
Kosak, ST et al., Genes Dev, 2004, Form follows function: The genomic organization of cellular differentiation	15198979	10.1101/gad.1209304	Cited
Kyosseva, SV et al., Biol Psychiatry, 1999, Mitogen-activated protein kinases in schizophrenia	10472421	10.1016/S0006-3223(99)00104-3	Cited
Kyosseva, SV, Int Rev Neurobiol, 2004, Mitogen-activated protein kinase signaling	15006489	10.1016/S0074-7742(04)59008-6	Cited
Lachman, HM et al., Pharmacogenet Genomics, 1996, Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders	8807664	10.1097/00008571-199606000-00007	Cited
Lake, BB et al., Science, 2016, Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain	27339989	10.1126/science.aaf1204	Cited
Langfelder, P et al., BMC Bioinformatics, 2008, WGCNA: an R package for weighted correlation network analysis	19114008	10.1186/1471-2105-9-559	Cited
Lee, G et al., Nature, 2009, Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs	19693009	10.1038/nature08320	Cited
Leek JT JW, Parker HS, Fertig EJ, Jaffe AE, Storey JD. sva: Surrogate Variable Analysis. R package version 3120. 2016.	—	—	—
Li, T et al., Am J Med Genet B Neuropsychiatr Genet, 2004, Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population	15274030	10.1002/ajmg.b.30049	Cited
Lieberman-Aiden, E et al., Science, 2009, Comprehensive mapping of long-range interactions reveals folding principles of the human genome	19815776	10.1126/science.1181369	Cited
Lin M, Lachman HM, Zheng D. Transcriptomics analysis of iPSC-derived neurons and modeling of neuropsychiatric disorders. Mol Cell Neurosci. 2016; In press.10.1016/j.mcn.2015.11.009PMC486725026631648	—	—	—
Lin, M et al., PLoS One, 2011, RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders	21915259	10.1371/journal.pone.0023356	Cited
Lin, M et al., PLoS One, 2012, Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders	22952857	10.1371/journal.pone.0044017	Cited
Lin, M et al., PLoS One, 2014, Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon	24736721	10.1371/journal.pone.0094968	Cited
Liu, H et al., Proc Natl Acad Sci U S A, 2002, Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia	11891283	10.1073/pnas.042700699	Cited
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2. Genome Biology. 2014;15:550. doi: 10.1186/s13059-014-0550-810.1186/s13059-014-0550-8PMC430204925516281	—	—	—
Lu, Z et al., IUBMB Life, 2006, ERK1/2 MAP kinases in cell survival and apoptosis	17085381	10.1080/15216540600957438	Cited
Marchetto, MC et al., Cell, 2010, A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells	21074045	10.1016/j.cell.2010.10.016	Cited
Maycox, PR et al., Mol Psychiatry, 2009, Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function	19255580	10.1038/mp.2009.18	Cited
Maynard, T et al., Proc Natl Acad Sci U S A, 2003, A comprehensive analysis of 22q11 gene expression in the developing and adult brain	14614146	10.1073/pnas.2235651100	Cited
Meechan, D et al., Gene Expr, 2006, When half is not enough: gene expression and dosage in the 22q11 deletion syndrome	17708416	10.3727/000000006781510697	Cited
Meechan, D et al., Mol Cell Neurosci, 2006, Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome	17097888	10.1016/j.mcn.2006.09.001	Cited
Meechan, DW et al., Proc Natl Acad Sci U S A, 2009, Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome	19805316	10.1073/pnas.0905696106	Cited
Misteli, T, Cell, 2007, Beyond the sequence: cellular organization of genome function	17320514	10.1016/j.cell.2007.01.028	Cited
Muenthaisong, S et al., Exp Cell Res, 2012, Generation of mouse induced pluripotent stem cells from different genetic backgrounds using Sleeping beauty transposon mediated gene transfer	22846649	10.1016/j.yexcr.2012.07.014	Cited
Murphy, KC et al., Arch Gen Psychiatry, 1999, High rates of schizophrenia in adults with velo-cardio-facial syndrome	10530637	10.1001/archpsyc.56.10.940	Cited
Nadri, C et al., Schizophr Res, 2004, GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients	15474909	10.1016/j.schres.2004.02.020	Cited
Obulesu, M et al., Neurochem Res, 2014, Apoptosis in Alzheimer’s disease: an understanding of the physiology, pathology and therapeutic avenues	25322820	10.1007/s11064-014-1454-4	Cited
Okita, K et al., Nat Methods, 2011, A more efficient method to generate integration-free human iPS cells	21460823	10.1038/nmeth.1591	Cited
Ouchi, Y et al., J Neurosci, 2013, Reduced adult hippocampal neurogenesis and working memory deficits in the Dgcr8-deficient mouse model of 22q11. 2 deletion-associated schizophrenia can be rescued by IGF2	23719809	10.1523/JNEUROSCI.2700-12.2013	Cited
Pal, R et al., J Biosci Bioeng, 2013, Comparative analysis of cardiomyocyte differentiation from human embryonic stem cells under 3-D and 2-D culture conditions	23040993	10.1016/j.jbiosc.2012.08.018	Cited
Paterlini, M et al., Nat Neurosci, 2005, Transcriptional and behavioral interaction between 22q11. 2 orthologs modulates schizophrenia-related phenotypes in mice	16234811	10.1038/nn1562	Cited
Prilutsky, D et al., Trends Mol Med, 2014, iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls	24374161	10.1016/j.molmed.2013.11.004	Cited
Rakic, P et al., Science, 1986, Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex	3952506	10.1126/science.3952506	Cited
Raux, G et al., Hum Mol Genet, 2007, Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome	17135275	10.1093/hmg/ddl443	Cited
Sahara, S et al., Neuron, 2009, Fgf10 regulates transition period of cortical stem cell differentiation to radial glia controlling generation of neurons and basal progenitors	19607792	10.1016/j.neuron.2009.06.006	Cited
Samuels, IS et al., J Neurosci, 2008, Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function	18596172	10.1523/JNEUROSCI.0679-08.2008	Cited
Scambler, P et al., Lancet, 1992, Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus	1349369	10.1016/0140-6736(92)90734-K	Cited
Schapira, AH et al., Lancet, 2014, Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives	24954676	10.1016/S0140-6736(14)61010-2	Cited
Sexton, T et al., Nat Struct Mol Biol, 2007, Gene regulation through nuclear organization	17984967	10.1038/nsmb1324	Cited
Shannon, P et al., Genome Res, 2003, Cytoscape: a software environment for integrated models of biomolecular interaction networks	14597658	10.1101/gr.1239303	Cited
Shatz, CJ, Neuron, 2009, MHC class I: an unexpected role in neuronal plasticity	19840547	10.1016/j.neuron.2009.09.044	Cited
Shprintzen, R et al., Cleft Palate J, 1978, A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome	272242	—	Cited
Sivagnanasundaram, S et al., Brain Res, 2007, Differential gene expression in the hippocampus of the Df1/+ mice: a model for 22q11. 2 deletion syndrome and schizophrenia	17292336	10.1016/j.brainres.2007.01.014	Cited
Stark, KL et al., Nat Genet, 2008, Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model	18469815	10.1038/ng.138	Cited
Sullivan, KE, Immunol Allergy Clin North Am, 2008, Chromosome 22q11. 2 deletion syndrome: DiGeorge syndrome/velocardiofacial syndrome	18424337	10.1016/j.iac.2008.01.003	Cited
Sundram F, Murphy KC. Schizophrenia and 22q11. 2 Deletion Syndrome. eLS. Chichester: John Wiley & Sons Ltd. 2011. DOI: 10.1002/9780470015902.a0005229.pub2.	—	—	—
Suslov, ON et al., Proc Natl Acad Sci U S A, 2002, Neural stem cell heterogeneity demonstrated by molecular phenotyping of clonal neurospheres	12381788	10.1073/pnas.212525299	Cited
Sweatt, JD, J Neurochem, 2001, The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory	11145972	10.1046/j.1471-4159.2001.00054.x	Cited
Takahashi, K et al., Cell, 2006, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors	16904174	10.1016/j.cell.2006.07.024	Cited
Topol, A et al., Cell Rep, 2016, Dysregulation of miRNA-9 in a subset of schizophrenia patient-derived neural progenitor cells	27117414	10.1016/j.celrep.2016.03.090	Cited
Torkamani, A et al., Genome Res, 2010, Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia	20197298	10.1101/gr.101956.109	Cited
van Amelsvoort, T et al., Arch Gen Psychiatry, 2004, Brain anatomy in adults with velocardiofacial syndrome with and without Schizophrenia: preliminary results of a structural magnetic resonance imaging study	15520356	10.1001/archpsyc.61.11.1085	Cited
van Beveren, NJ et al., PLoS One, 2012, Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome	22457764	10.1371/journal.pone.0033473	Cited
van de Leemput, J et al., Neuron, 2014, CORTECON: a temporal transcriptome analysis of in vitro human cerebral cortex development from human embryonic stem cells	24991954	10.1016/j.neuron.2014.05.013	Cited
Volk, DW et al., Schizophr Bull, 2014, Early developmental disturbances of cortical inhibitory neurons: contribution to cognitive deficits in schizophrenia	25053651	10.1093/schbul/sbu111	Cited
Wakim, LM et al., Nat Immunol, 2013, Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3	23354485	10.1038/ni.2525	Cited
Wang, P et al., Mol Autism, 2015, CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment	26491539	10.1186/s13229-015-0048-6	Cited
Wernig, M et al., Proc Natl Acad Sci U S A, 2008, Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease	18391196	10.1073/pnas.0801677105	Cited
Williams, NM et al., Hum Mol Genet, 2008, Strong evidence that GNB1L is associated with schizophrenia	18003636	10.1093/hmg/ddm330	Cited
Willsey, AJ et al., Cell, 2013, Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism	24267886	10.1016/j.cell.2013.10.020	Cited
Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol. 2005;4:Article17. doi:10.2202/1544-6115.1128.10.2202/1544-6115.112816646834	—	—	—
Zhang, Y-H et al., Nat Commun, 2013, Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals	23361009	10.1038/ncomms2433	Cited
Zhao D, Lin M, Chen J, Pedrosa E, Hrabovsky A, Fourcade HM, et al. MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and schizoaffective disorder, and 22q11. 2 Del. PLoS One. 2015;10(7):e0132387.10.1371/journal.pone.0132387PMC450182026173148	—	—	—
Zohar, O et al., J Immunol, 2008, Cutting edge: MHC class I–Ly49 interaction regulates neuronal function	18453559	10.4049/jimmunol.180.10.6447	Cited

In this knowledge base

Title	Year	PMID
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	2018	29897633
Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes.	2017	28757163

External

Title	Authors	Journal	Year	Link
Control of retrotransposon-driven activation of the interferon response by the double-stranded RNA binding protein DGCR8.	Gázquez-Gutiérrez A et al.	—	2026	→
Developmental convergence and divergence in human stem cell models of autism.	Gordon A et al.	—	2026	→
Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome-associated schizophrenia.	Rao SB et al.	—	2025	→
An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome.	Thakur P et al.	—	2025	→
A systematic review of miRNA expression in schizophrenia spectrum disorders across the blood and the brain.	Kotas M et al.	—	2025	→
Five differentially expressed proteins identified to serve as potential blood biomarkers for schizophrenia screening based on proteomics.	Li R et al.	—	2025	→
Peering into the mind: unraveling schizophrenia's secrets using models.	Nani JV et al.	—	2025	→
Rare Copy Number Variants Reveal Critical Cell Types and Periods of Brain Development in Neurodevelopmental Disorders.	Malwade S et al.	—	2025	→
Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models.	Perrottelli A et al.	—	2024	→
Developmental convergence and divergence in human stem cell models of autism spectrum disorder	Gordon A et al.	—	2024	—
Lymphoblast transcriptome analysis in 22q11.2 deletion syndrome individuals with schizophrenia-spectrum disorder.	Michaelovsky E et al.	—	2024	→
NACC2, a molecular effector of miR-132 regulation at the interface between adult neurogenesis and Alzheimer's disease.	Penning A et al.	—	2024	→
Parkinson's disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes.	Karunakaran KB et al.	—	2024	→
Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.	Shin D et al.	—	2024	→
A CRISPR-engineered isogenic model of the 22q11.2 A-B syndromic deletion.	Paranjape N et al.	—	2023	→
A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome.	Fiksinski AM et al.	—	2023	→
Coexisting Conditions Modifying Phenotypes of Patients with 22q11.2 Deletion Syndrome.	Smyk M et al.	—	2023	→
Deciphering the Molecular Mechanisms of Autonomic Nervous System Neuron Induction through Integrative Bioinformatics Analysis.	Takayama Y et al.	—	2023	→
Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.	Parker DA et al.	—	2023	→
Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood-Brain Barriers.	Li Y et al.	—	2023	→
The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research.	Nakamura T et al.	—	2023	→
Unlocking Neural Function with 3D In Vitro Models: A Technical Review of Self-Assembled, Guided, and Bioprinted Brain Organoids and Their Applications in the Study of Neurodevelopmental and Neurodegenerative Disorders.	D'Antoni C et al.	—	2023	→
Current advancements of modelling schizophrenia using patient-derived induced pluripotent stem cells.	Dubonyte U et al.	—	2022	→
Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance.	Page SC et al.	—	2022	→
Establishment of fishing cat cell biobanking for sustainable conservation.	Sukparangsi W et al.	—	2022	→
High abundance of CDC45 inhibits cell proliferation through elevation of HSPA6.	Fu Y et al.	—	2022	→
Impact of COMT, PRODH and DISC1 Genetic Variants on Cognitive Performance of Patients with Schizophrenia.	Fricke-Galindo I et al.	—	2022	→
Modelling the Human Blood-Brain Barrier in Huntington Disease.	Vignone D et al.	—	2022	→
T Cell Transcriptome in Chromosome 22q11.2 Deletion Syndrome.	Raje NR et al.	—	2022	→
The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.	Nehme R et al.	—	2022	→
What genes are differentially expressed in individuals with schizophrenia? A systematic review.	Merikangas AK et al.	—	2022	→
A Novel Balanced Chromosomal Translocation in an Azoospermic Male: A Case Report.	Chakraborty A et al.	—	2021	→
Cellular Models in Schizophrenia Research.	Abashkin DA et al.	—	2021	→
Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome.	Sefik E et al.	—	2021	→
Directional Persistence of Cell Migration in Schizophrenia Patient-Derived Olfactory Cells.	Tee JY et al.	—	2021	→
ERK/MAPK signalling in the developing brain: Perturbations and consequences.	Iroegbu JD et al.	—	2021	→
Investigation of Neurodevelopmental Deficits of 22 q11.2 Deletion Syndrome with a Patient-iPSC-Derived Blood-Brain Barrier Model.	Li Y et al.	—	2021	→
Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets.	Pintacuda G et al.	—	2021	→
Network Effects of the 15q13.3 Microdeletion on the Transcriptome and Epigenome in Human-Induced Neurons.	Zhang S et al.	—	2021	→
Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics.	Forsyth JK et al.	—	2021	→
Strategies to identify candidate repurposable drugs: COVID-19 treatment as a case example.	Imami AS et al.	—	2021	→
The Perspectives of Early Diagnosis of Schizophrenia Through the Detection of Epigenomics-Based Biomarkers in iPSC-Derived Neurons.	Lee D et al.	—	2021	→
Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations.	Gordon A et al.	—	2021	→
Unveiling the Pathogenesis of Psychiatric Disorders Using Network Models.	Zuo Y et al.	—	2021	→
Comparative Transcriptomic Analysis of Cerebral Organoids and Cortical Neuron Cultures Derived from Human Induced Pluripotent Stem Cells.	Kathuria A et al.	—	2020	→
Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs.	Burke EE et al.	—	2020	→
Human in vitro models for understanding mechanisms of autism spectrum disorder.	Gordon A et al.	—	2020	→
Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells.	Powell SK et al.	—	2020	→
Mental health dished up-the use of iPSC models in neuropsychiatric research.	McNeill RV et al.	—	2020	→
Negative Symptoms of Schizophrenia and Dopaminergic Transmission: Translational Models and Perspectives Opened by iPSC Techniques.	Collo G et al.	—	2020	→
Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.	Khan TA et al.	—	2020	→
Studying Abnormal Chromosomal Diseases Using Patient-Derived Induced Pluripotent Stem Cells.	Hayashi Y et al.	—	2020	→
Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell-Derived Cerebral Organoids in Schizophrenia.	Kathuria A et al.	—	2020	→
Can Animal Models of Copy Number Variants That Predispose to Schizophrenia Elucidate Underlying Biology?	Forsingdal A et al.	—	2019	→
Contribution of induced pluripotent stem cell technologies to the understanding of cellular phenotypes in schizophrenia.	Balan S et al.	—	2019	→
Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome.	Dantas AG et al.	—	2019	→
Epigenome-wide DNA methylation in placentas from preterm infants: association with maternal socioeconomic status.	Santos HP et al.	—	2019	→
Mitochondrial deficits in human iPSC-derived neurons from patients with 22q11.2 deletion syndrome and schizophrenia.	Li J et al.	—	2019	→
New considerations for hiPSC-based models of neuropsychiatric disorders.	Hoffman GE et al.	—	2019	→
Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells.	Hoffmann A et al.	—	2018	→
Genetic and clinical features of social cognition in 22q11.2 deletion syndrome.	Lattanzi GM et al.	—	2018	→
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	Prytkova I et al.	—	2018	→
Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.	LaMarca EA et al.	—	2018	→
Newfound sex differences in axonal structure underlie differential outcomes from in vitro traumatic axonal injury.	Dollé JP et al.	—	2018	→
CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells.	Wang P et al.	—	2017	→
Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes.	Ho SM et al.	—	2017	→
Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs).	Noh H et al.	—	2017	→
Prospects for Modeling Abnormal Neuronal Function in Schizophrenia Using Human Induced Pluripotent Stem Cells.	Prytkova I et al.	—	2017	→
Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains.	Hoffman GE et al.	—	2017	→
Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress.	Zhao D et al.	—	2017	→
Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia.	Van L et al.	—	2017	→