Table 1.
hiPSC models of neuropsychiatric risk variants (only studies with clearly defined disease risk variants and cellular phenotypes are listed).
| Author/year | Ref | Disease | Risk variant/gene | Perturbation | Sample size | Brain cell type | Cellular phenotypes |
|---|---|---|---|---|---|---|---|
| Urresti 2021 | 34433918 | ASD | 16p11.2 CNV | Comparative | 3 × DEL & 3 × DUP + 3 ctrls | Organoids | Excess of neurons and depletion of NPCs in DELs; Organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients. |
| Roth 2020 | 33169669 | ASD | 16p11.2 CNV | Comparative | 10 DEL/3 DUP + 4 ctrls | Cortical neurons | Significant correlation between transcription modules and clinical phenotypes in 16pDS patients. |
| Deshpande 2017 | 29212016 | ASD | 16p11.2 CNV | Comparative | 3 × DEL & 3 × DUP + 4 ctrls | Neurons | Increased soma size and dendrite length in 16p DEL, which were decreased in 16p DUP neurons. Both exhibited reduced synaptic density. |
| Deneault 2019 | 30747104 | ASD | 16p11.2 DEL, NRXN1Δ/+ | Comparative; CRISPR/Cas9 | 14 ASD + 11 ctrls | Glutamatergic neurons | Consistent spontaneous network hyperactivity for CNTN5--deficient or EHMT2/UBE2I-variant. |
| Carbonell 2019 | 31388001 | ASD | ANKS1B | Comparative | 2 cases + 2 ctrls | Neurons | Loss of ANKS1B led to altered synaptogenesis and neurodevelopment. |
| Deneault 2018 | 30392976 | ASD | FF2/FMR2, ANOS1, ASTN2, etc. | CRISPR/Cas9; isogenic | 10 isogenic hiPSC lines | Excitatory neurons | Electrophysiological deficits were distinct for different mutations. Consistent reduction of synaptic activity and reduced sEPSC frequencies. |
| Avazzadeh 2021 | 34525970 | ASD | NRXN1α | Comparative | 3 NRXN1α+/− + 5 ctrls | Cortical neurons | Higher sodium currents and action potential, and accelerated depolarization time. |
| Zaslavsky 2019 | 30911184 | ASD | SHANK2 DEL (R841X) | CRISPR/Cas9 | 2–4 isogenic lines | Cortical neurons | Increased synapse numbers and longer dendrites. Hyperconnectivity and increased sEPSC frequency. |
| Wang 2021 | bioRxiv | ASD | SHANK3 | CRISPR/Cas9; isogenic | 3 mutants + 3 ctrls | Cortico-striatal organoids | Smaller organoids with fewer and smaller neurons. Fewer synapsin1/SHANK3-containing excitatory synaptic puncta and high excitability. |
| Gouder 2019 | 30643170 | ASD | SHANK3 (E809X, Q1243X, G1271Afs*15, L1142Vfs*153) | Comparative | 4 SHANK3-het ASD + 3 ctrls | Pyramidal cortical neurons | Significant reduction in dendritic spine densities and whole spine and spine head volumes. |
| Chiola 2021 | 33558651 | ASD | SHANK3 hemizygosity | CRISPR/Cas9; xenografting | 4 PSC lines + 4 ctrls | Astrocytes & glut neurons | Impaired AMPA-mediated synaptic transmission, dendritic arbors, and spines in the mouse cortex. |
| Fink 2021 | 34538422 | ASD (AS) | 15q11-q13 DUP | Comparative | 4 Dup + 6 ctrls | Excitatory & inhibitory neurons | Increased excitatory synaptic activity, dendritic density, and action potential. Decreased inhibitory synaptic transmission. |
| Utami 2020 | 32653109 | ASD (FXS) | FMR1 | CRISPR/Cas9 | 4 FXS + 3 ctrls (1 isogenic) | GABAergic & glutamatergic | Abnormal FXS neural rosette formation. Overall impairment of electrophysiological network activities. |
| Das Sharma 2020 | 32560741 | ASD (FXS) | FMR1 | CRISPR/Cas9; comparative | 3 FXS + 3 ctrls (1 isogenic) | Cortical neurons | No observed differences in the intrinsic properties of FXS neurons. Shorter and more frequent spontaneous action potential firing in FXS neurons. |
| Achuta 2017 | 27411166 | ASD (FXS) | FMR1 | Comparative | 4 FXS + 3 ctrls | NPCs and neurospheres | Intracellular calcium response to the mGluR agonist DHPG was augmented in FXS NPCs. |
| Lutz 2020 | 32522805 | ASD (PMS) | SHANK3 deficiency | Comparative | 5 PMS + 3 ctrls | Neurons/myotubes | Shortened Z-discs and severe impairment of acetylcholine receptor clustering in PMS myotubes. |
| Roessler 2018 | 30456368 | ASD (PMS) | 22q13.3 DEL | CRISPR/Cas9; comparative | 3 DEL & 2 CRISPR + 1 ctrl | NPCs & cortical neurons | Impairment of neuronal maturation and reduced overall activity in 22q DEL. reduced protein levels of SHANK3, JIP2, DCX, and NeuN. |
| Trujillo 2021 | 33501759 | ASD (RTT) | MECP2 LoF (Q83X, K82 frameshift) | CRISPR/Cas9; drug screening | 2 mutants + 2 ctrls | Neurons & organoids | Nefiracetam and PHA 543613 reversed the cytologic neuropathology in MECP2-KO neurons, increased calcium activity in mosaic neurospheres. |
| Chen 2021 | 32851591 | ASD (RTT) | MECP2 | CRISPR/Cas9 mutagenesis | 2 mutants + 3 isogenic ctrls | Cortical neurons | RTT neurons lack electrophysiological maturation. Spine density is impaired. Synaptic transmission abnormalities were observed in MECP2 KD neurons. |
| Gomes 2020 | 33363173 | ASD (RTT) | MeCP2: R255X(XX), MeCP2:Q83X(XY) | Comparative | 2 MeCP2 RTT + 4 ctrls | Forebrain organoids | Premature development of the deep-cortical layer neurons, low NPCs, and altered calcium dynamics. Impaired interneuron migration in RTT forebrain organoids. |
| Xiang 2020 | 32526163 | ASD (RTT) | BRD4, MECP2 (c.397C > T, C.808C > T, c.916C > T) | CRISPR/Cas9 | 5 RTT + 2 ctrls (1 isogenic) | Interneurons and brain organoids | Abnormal increases in BRD4 binding cause the abnormal transcription of mutant MeCP2 in RTT interneurons.) |
| Nott 2016 | 27428650 | ASD (RTT) | MECP2 (R306C) | CR1SPR/Cas9; comparative | 1 mutant + 1 isogenic ctrl | NPCs | Deficits in HDAC3 and FOXO recruitment and gene expression. CRISPR editing rescued the impaired HDAC3-FOXO-mediated phenotype in NPCs. |
| Williams 2014 | 24419315 | ASD (RTT) | MECP2 | Comparative | 3 RTT + 3 ctrls | Astrocyte & neuron | Mutant astrocytes had adverse effects on the morphology and function of wild-type neurons. |
| Ananiev 2011 | 21966470 | ASD (RTT) | MECP2 (R306C, T158M, R294X, V247X) | CRISPR/Cas9; comparative | 4 MeCP2 + 4 ctrls | Neurons | RTT neurons were smaller than their isogenic controls. |
| Kim 2011 | 21807996 | ASD (RTT) | MECP2 (T158M, Q244X, E235fs, R306C, X487W) | Comparative | 5 RTT + 5 ctrls | NPCs & neurons | Neuronal maturation deficits. |
| Marchetto 2010 | 21074045 | ASD (RTT) | MECP2 (1155del32, R306C, Q244X, T158M) | Comparative | 4 RTT + 5 ctrls | NPCs & neurons | RTT NPCs had normal proliferation. RTT neurons had reduced glutamatergic synapse numbers and abnormal morphologies. |
| Panagiotakos 2019 | 31868578 | ASD (TS) | CACNA1C | Comparative | 3 TS + 3 ctrls | NPCs & neurons | SATB2+ neurons were less abundant while CTIP2+ neurons were more abundant. |
| Paşca 2011 | 22120178 | ASD (TS) | CACNA1C | Comparative | 2 TS + 3 ctrls | NPCs & neurons | Deficient Ca2+ signaling, decreased lower cortical layers, abnormal tyrosine hydroxylase expression, and increased production of norepinephrine and dopamine. |
| Nadadhur 2019 | 30581017 | ASD (TSC) | TSC1 (2249G > A), TSC2 (1563dupA/H522T) | Comparative | 2 TSC + 3 ctrls | Neurons & oligodendrocytes | Increased dendritic branching and network activity. Oligodendrocytes had increased proliferation and decreased maturation. |
| Becker 2020 | 32929080 | ASD, MICPCH | CASK (c. 1296 + 1 G > T), CASK (Xp11.4 DUP) | Comparative | 2 mutants + 2 ctrls | Neurons | Altered presynaptic development and affecting their excitatory/inhibitory balance. |
| Jiang 2019 | 30135510 | BP | TRANK1 (rs9834970T > C, rs906482G > A) | Comparative; drug treatment | 2 BP + 8 ctrls | NPCs & neurons & astrocytes | The NPCs with the risk allele of rs9834970 had lower baseline TRANK1 expression. |
| Yoshimizu 2015 | 25403839 | MDD, BP, SZ | CACNA1C (rs1006737 G > A) | Comparative | 10 BP + 4 SZ + 2 MDD + 8 unaffected | Neurons | L-type VGCC current density, as well as mRNA expression of CACNA1C, were increased. |
| Wen 2014 | 25132547 | MDD, SZ | DISC1 | Comparative | 4 DISC1-het (2 isogenic) + 4 ctrls | NPCs & cortical neurons | Synaptic vesicle release deficits in forebrain neurons. Dysregulated expression of many synaptic genes associated with psychiatric disorders. |
| Sundberg 2021 | 34006844 | SZ | 16p11.2 CNV | CRISPR/Cas9; isogenic | 3 isogenic lines & 1 x 16p11.2 ctrl | Dopaminergic neurons (DA) | 16p DUP showed deficits in neuronal differentiation. 16p DEL had increased soma size and hyperactivity, which can be rescued by RHOA inhibition (Rhosin). |
| de Vrij 2018 | 29302076 | SZ | CSPG4 (c.391G > A [p.A131T]) | Comparative | 3 SZ + 3 related ctrls | OPCs | Aberrant cellular morphology, and myelination potential. |
| Srikanth 2018 | 30410030 | SZ | DISC1, UNC5D | CRISPR/dCas9-VPR for KD | 2 mutants + 2 isogenic ctrls | Neurons | DISC1 mutations did not seem to alter cell fate, presynaptic protein expression, or electrophysiological activity. Reduced neurite outgrowth. |
| Shrode 2019 | 31548722 | SZ | FURIN (rs4702), SNAP91, TSNARE1 | CRISPR/Cas9; CRISPRa/i | 4 CRISPR-edited + 4 ctrls | NPCs, glut & GABAergic | Reduced neurite length and firing rates in rs4702 GG neurons. sEPSCs frequency/amplitude increased in SNAP91 CRISPRa (decreased with CRISPRi). |
| Forrest 2017 | 28803920 | SZ | MIR137 (rs1198588) | CRISPR/Cas9 | 1 isogenic pair (2 clones) | Glutamatergic neurons | The Risk allele is associated with lower MIR137 expression, increased dendritic complexity, and synaptic puncta positive for GluA1 and PSD95. |
| Pak 2021 | 34035170 | SZ | NRXN1 | Patient-specific & TALENs | 3 patients + 3 ctrls; 3 edited | Neurons | A deficit in spontaneous & evoked synaptic events responses, synaptic paired-pulse depression. Impaired synaptic function regardless of genetic background. |
| Zhang 2021 | bioRxiv | SZ | VPS45, AC244033.2, or C1orf54 (rs2027349) | CRISPR/Cas9; isogenic | 2 isogenic pairs (2–3 clones) | Excitatory neurons | Risk allele A is associated with increased dendritic complexity, synaptic puncta density, and hyperactivity; cis-regulated all three genes with synergistic effects. |
| Li 2021c | 34009292 | SZ (DGS) | 22q11.2 DEL | Comparative | 8 × DEL + 6 ctrls | Neurons | Reduced OXPHOS activity and ATP levels. |
| Li 2019 | 31740674 | SZ (DGS) | 22q11.2 DEL, MRPL40 | CRISPR/Cas9; comparative | 4 × DEL & 1 KO + 5 ctrls | Neurons | Reduced levels of mitochondrial-encoded proteins, ATP, and electron transport chain activity. |
| Khan 2020 | 32989314 | SZ (DGS), ASD | 22q11.2 DEL, DGCR8 | CRISPR/Cas9; comparative | 12 × 22q11DS + 11 ctrls | Cerebral cortical organoids | Defects in spontaneous neuronal activity and calcium signaling. DGCR8+/− neurons show similar neuronal dysfunction and behavior to 22q11DS neurons. |
| Flaherty 2019 | 31784728 | SZ (psychotic) | NRXNα | Comparative | 4 NRXN1α+/− + 4 ctrls | Glutamatergic & GABAergic | Aberrant and differentially-expressed NRXN1 isoforms. Deficits in neuronal activity depending on expressed NRXN1α isoforms in a genotype-dependent manner. |
| Li 2021d | 33833053 | SZ, ASD | 16p11.2 CNV, CD47 | Comparative | 11 SZ and ASD lines + 3 ctrls | NPCs & OPCs | CD47 is overexpressed in 16p11.2 DEL contributing to reduced phagocytosis. |
| Johnstone 2018 | 30401811 | SZ, GAD/MDD | 16p13.11 DUP, TSC2 (16:2115634:C/T) | Comparative | 3 × 16p13.11 DUP + 5 ctrls | NPC & organoids | 16p13.11 DUP NPCs had proliferation deficits and cerebral organoids were smaller and had altered radial glial progenitor cell division fates. |