Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models

Tai, Derek J.C.; Razaz, Parisa; Erdin, Serkan; Gao, Dadi; Wang, Jennifer; Nuttle, Xander; Esch, Celine E. de; Collins, Ryan L.; Currall, Benjamin; O’Keefe, Kathryn; Burt, Nicholas D.; Yadav, Rachita; Wang, Lily; Mohajeri, Kiana; Aneichyk, Tatsiana; Ragavendran, Ashok; Stortchevoi, Alexei; Morini, Elisabetta; Ma, Wen-Ya; Lucente, Diane; Hastie, Alex; Kelleher, Raymond J.; Perlis, Roy H.; Talkowski, Michael E.; Gusella, James F.

doi:10.1016/j.ajhg.2022.08.012

Cited by 20 publications

(17 citation statements)

References 114 publications

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“…In line with the findings in etiologically valid mouse models, molecular profiling of these cellular models generally supports dysregulation of genes related to neural transmission, especially synaptic genes [95-97, 100, 101, 106], transcriptional regulators including microRNAs [94,104], and schizophrenia-associated genes discovered by human genetics studies [96,97,104]. Also, morphological alteration of soma and dendrite were common except for iPS cell-derived neurons with NRXN1 deletion [94,98,101,102,106]. Abnormal neural activities are identified in multiple patient-derived or genetically engineered iPS cellderived neurons, however, the directions of the abnormalities are sometimes inconsistent across models manipulating different genes [97,[101][102][103][104][105][106].…”

Section: Cellular Modelssupporting

confidence: 54%

“…Recent technological advances have enabled the reproduction of pathological conditions in vitro by creating patient-derived or mutation-carrying induced pluripotent stem (iPS) cells and then differentiating them into central nervous system cells or miniature brains. Studies of etiologically valid cellular models of schizophrenia produced with this technology, including those with 22q11.2 deletion, 16p11.2 deletion/duplication, SETD1A LOF/PTV, and NRXN LOF/PTV, have been conducted and reported [94][95][96][97][98][99][100][101][102][103][104][105][106] (Table 3).…”

Section: Cellular Modelsmentioning

confidence: 99%

“…Also, morphological alteration of soma and dendrite were common except for iPS cell-derived neurons with NRXN1 deletion [94,98,101,102,106]. Abnormal neural activities are identified in multiple patient-derived or genetically engineered iPS cellderived neurons, however, the directions of the abnormalities are sometimes inconsistent across models manipulating different genes [97,[101][102][103][104][105][106]. Though it may be due to artifacts depending on the differences in the experimental designs, another possibility is that imbalanced excitatory/inhibitory activities themselves [107], regardless of the direction of abnormality, are important in schizophrenia pathology.…”

Section: Cellular Modelsmentioning

confidence: 99%

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The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

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Despite enormous efforts employing various approaches, the molecular pathology in the schizophrenia brain remains elusive. On the other hand, the knowledge of the association between the disease risk and changes in the DNA sequences, in other words, our understanding of the genetic pathology of schizophrenia, has dramatically improved over the past two decades. As the consequence, now we can explain more than 20% of the liability to schizophrenia by considering all analyzable common genetic variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase the risk for schizophrenia, of which six genes (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, and RB1CC1) showed odds ratios larger than ten. Based on these findings together with the preceding discovery of copy number variants (CNVs) with similarly large effect sizes, multiple disease models with high etiological validity have been generated and analyzed. Studies of the brains of these models, as well as transcriptomic and epigenomic analyses of patient postmortem tissues, have provided new insights into the molecular pathology of schizophrenia. In this review, we overview the current knowledge acquired from these studies, their limitations, and directions for future research that may redefine schizophrenia based on biological alterations in the responsible organ rather than operationalized criteria.

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Section: Cellular Modelssupporting

confidence: 54%

Section: Cellular Modelsmentioning

confidence: 99%

Section: Cellular Modelsmentioning

confidence: 99%

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The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Nakamura

Takata

2023

Mol Psychiatry

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“…heterozygous for DNAJC30) were also found to have impaired mitochondrial function and reduced ATP production (Tebbenkamp et al, 2018). In addition, a recent study of reciprocal CNVs at the neurodevelopmental disorder associated locus 16p11.2 also found a strong signal for enrichment of DEGs related to energy metabolism and mitochondrial function in both mouse brain and cultured human neural cell lines (Tai et al, 2022). Another study of convergent biology in mouse models of the neurodevelopmental CNVs 1q21.…”

Section: Discussionmentioning

confidence: 99%

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Purcell

Sefik

Werner

et al. 2023

Preprint

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Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R. > 40). Understanding the impact of the 3q29 deletion (3q29Del) on the developing CNS may therefore lead to insights about the pathobiology of schizophrenia. To gain clues about the molecular and cellular perturbations caused by the 3q29 deletion, we interrogated transcriptomic effects in two experimental model systems with complementary advantages: isogenic human forebrain cortical organoids and isocortex from the 3q29Del mouse model. We first created isogenic lines by engineering the full 3q29Del into an induced pluripotent stem cell line from a neurotypical individual. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 months and 12 months, as well as day p7 perinatal mouse isocortex, all at single cell resolution. Differential expression analysis by genotype in each cell-type cluster revealed that more than half of the differentially expressed genes identified in mouse cortex were also differentially expressed in human cortical organoids, and strong correlations were observed in mouse-human differential gene expression across most major cell-types. We systematically filtered differentially expressed genes to identify changes occurring in both model systems. Pathway analysis on this filtered gene set implicated dysregulation of mitochondrial function and energy metabolism, although the direction of the effect was dependent on developmental timepoint. Transcriptomic changes were validated at the protein level by analysis of oxidative phosphorylation protein complexes in mouse brain tissue. Assays of mitochondrial function in human heterologous cells further confirmed robust mitochondrial dysregulation in 3q29Del cells, and these effects are partially recapitulated by ablation of the 3q29Del gene PAK2. Taken together these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species. These results converge with data from other rare SCZ-associated variants as well as idiopathic schizophrenia, suggesting that mitochondrial dysfunction may be a significant but overlooked contributing factor to the development of psychotic disorders. This cross-species scRNA-seq analysis of the SCZ-associated 3q29 deletion reveals that this copy number variant may produce early and persistent changes in cellular metabolism that are relevant to human neurodevelopment.

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“…We included noncoding genes, as they have not received significant attention in studies of these regions, despite some evidence of miRNA contribution to 22q11.2 phenotypes. In addition, we considered flanking genes within 200kb of the region, as there is suggestive evidence of broader transcriptional effects in CNV carriers, and because we previously found evidence of flanking gene involvement in psychosis [22,27]. Supplementary tables 1 and 2 contain single and pairwise CNV genes used in analysis.…”

Section: Methodsmentioning

confidence: 99%

Combinations of genes at the 16p11.2 and 22q11.2 CNVs contribute to neurobehavioral traits

Vysotskiy

Weiss

2022

Preprint

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The 16p11.2 and 22q11.2 copy number variants (CNVs) are associated with neurobehavioral traits including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, obesity, and intellectual disability. Identifying specific genes contributing to each disorder and dissecting the architecture of CNV-trait association has been difficult, inspiring hypotheses of more complex models, such as the effects of pairs of genes. We generated pairwise expression imputation models for CNV genes and then applied these models to GWAS for: ASD, bipolar disorder, schizophrenia, BMI (obesity), and IQ (intellectual disability). We compared the trait variance explained by pairs with the variance explained with single genes and with traditional interaction models. We also modeled polygene region-wide effects using summed ranks across all genes in the region. In all CNV-trait pairs except for bipolar disorder at 22q11.2, pairwise effects explain more variance than single genes, which was specific to the CNV region for all 16p11.2 traits and ASD at 22q11.2. We identified individual genes over-represented in top pairs that did not show single-gene signal. We also found that BMI and IQ have a significant association with a regionwide score. Genetic architecture differs by trait and region, but 9/10 CNV-trait combinations showed evidence for multigene contribution, and for most of these, the importance of combinatorial models appeared unique to CNV regions. Our findings suggest that mechanistic insights for CNV pathology may require combinational models.

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Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models

Cited by 20 publications

References 114 publications

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Combinations of genes at the 16p11.2 and 22q11.2 CNVs contribute to neurobehavioral traits

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