About

Stewart A Anderson, MD, is a Professor of Psychiatry and the Research Director of Child and Adolescent Psychiatry at The Children's Hospital of Philadelphia. His educational background includes a BA in Neuroscience and Psychology from Amherst College and an MD from the University of Connecticut. Since July 2012, he has been based at the University of Pennsylvania and The Children's Hospital of Philadelphia, focusing on laboratory research into the causes of neuropsychiatric illnesses, moving away from clinical patient care. His laboratory research centers on the molecular and cellular mechanisms that govern the development of the mammalian forebrain. He employs techniques such as mouse genetics, forebrain slice and dissociated culture methods, and uses mouse and human pluripotent stem cells in cell culture and transplantation experiments. His work aims to understand the fate determination of interneurons in the cerebral cortex, particularly subclasses of GABAergic interneurons implicated in autism and schizophrenia. Additionally, he investigates the use of stem cell-derived interneurons in animal models for cell-based therapies targeting seizures and psychosis, as well as studying gene-gene and gene-environment interactions in neuropsychiatric diseases. His research also includes studying mitochondria in stem cell-derived neurons from individuals with 22q11.2 deletion syndrome and schizophrenia, and examining human stem cell-derived microglia infected with HIV.

Research topics

• Medicine
• Psychiatry
• Neuroscience
• Immunology
• Biology

Selected publications

• Author response: 3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity

  2025-01-15

  peer-reviewOpen access
  PublisherDOI

• Charting Brain Structure in 22q11.2 Deletion Syndrome with Clinical Neuroimaging

  medRxiv · 2025-11-27 · 1 citations

  preprintOpen access

  Background: 22q11.2 deletion syndrome (22q11DS) is a common microdeletion associated with widespread brain alterations and elevated risk for schizophrenia and other neuropsychiatric conditions. Prospective research studies often exclude individuals with severe cognitive impairment, medical comorbidities, or inability to tolerate research MRI without sedation, features common in 22q11DS. This limits both the generalizability of neuroimaging findings and our understanding of the full phenotypic spectrum. Moreover, while standard brain growth charts quantify deviation from typical development, they cannot identify patients who are disproportionately affected relative to their genetic peers, limiting clinical utility for risk stratification. Leveraging clinical MRI data offers a scalable approach to address these gaps. Methods: We analyzed 92 patients with 22q11DS (age 0.5-21 years, 49% female) and 252 matched clinical controls. Using normative modeling derived from 1,995 reference clinical scans, we quantified individual-level brain deviations from population norms. We validated clinical findings against the independent ENIGMA-22q research consortium, characterized rates of extreme structural deviations to assess within-syndrome heterogeneity, correlated spatial patterns of brain alterations with gene expression from the Allen Human Brain Atlas, and generated syndrome-specific growth charts to test whether deviations from syndrome-specific norms predicted cognitive and language outcomes. Results: Patients with 22q11DS showed widespread reductions in brain volumes (max Cohen's d=-1.31) and cortical surface area (d=-0.71) with increased cortical thickness (d=0.39). These findings were highly convergent with the ENIGMA-22q research cohort (r=0.61-0.87). Forty percent of patients showed at least one global brain measure below the 2.5th percentile. Spatial patterns of cortical volume and surface area correlated with the expression of genes within the 22q11.2 locus. Critically, syndrome-specific growth charts revealed that smaller cerebellar volume relative to 22q11DS peers predicted lower language scores across two independent assessment methods (p<0.03), demonstrating potential prognostic utility. Conclusions: This study provides a critical proof of principle for using heterogeneous clinical imaging to robustly characterize brain structure in rare genetic disorders. Syndrome-specific growth charts provide a novel framework to quantify within-syndrome variability and demonstrate potential prognostic value by linking individual brain structure to cognitive outcomes.

  PublisherOA PDFDOI

• Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors

  Cell Death and Disease · 2025-12-15 · 1 citations

  articleOpen access

  AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the SLC25A12 gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.

  PublisherOA PDFDOI

• 3D genomic features across &gt;50 diverse cell types reveal insights into the genomic architecture of childhood obesity

  eLife · 2025-01-15 · 2 citations

  articleOpen access

  The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF , ADCY3 , TMEM18, and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 – an inflammation-responsive gene in nerve nociceptors – was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

  PublisherDOI

• Control of striatal circuit development by the chromatin regulator <i>Zswim6</i>

  Science Advances · 2025-01-17 · 4 citations

  articleOpen access

  The pathophysiology of neurodevelopmental disorders involves vulnerable neural populations, including striatal circuitry, and convergent molecular nodes, including chromatin regulation and synapse function. Despite this, how epigenetic regulation regulates striatal development is understudied. Recurrent de novo mutations in Zswim6 are associated with intellectual disability and autism. We demonstrate that ZSWIM6 localizes to the nucleus where it associates with repressive chromatin regulators. Disruption of Zswim6 in ventral telencephalic progenitors leads to increased chromatin accessibility and transcriptional dysregulation. Ablating Zswim6 in either striatal direct or indirect pathway spiny projection neurons resulted in similar cell-autonomous changes in excitatory but not inhibitory synaptic transmission. Specifically, Zswim6 disruption altered the desensitization properties of AMPA receptors, leading to enhanced synaptic recruitment of SPNs, explaining SPN-subtype specific effects on activity and behavioral sub-structure. Last, adult deletion of Zswim6 identified a continuing role in the maintenance of mature striatal synapses. Together, we describe a mechanistic role for Zswim6 in the epigenetic control of striatal synaptic development.

  PublisherDOI

• Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome

  Science Translational Medicine · 2025-08-20 · 3 citations

  articleCorresponding

  Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared with peripheral endothelial cells, although the functional implications of this phenomenon are unclear. Here, we studied BBB mitochondrial function in the context of 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. Because the 22q11.2 deletion includes six mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and affect behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (iBMECs) from people with 22qDS and in BBB endothelial cells from a mouse model of 22qDS. We found that treatment with bezafibrate, an activator of mitochondrial biogenesis, attenuates mitochondrial deficits and enhances BBB function in both the iBMECs and a mouse model of 22qDS. This treatment also corrects social memory in the mouse model, a deficit previously associated with BBB dysfunction. Given that BBB integrity correlated with social memory performance, our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior.

  PublisherDOI

• HGG-27. High-grade gliomas chemoattract migratory interneuron precursors modified to deliver therapeutic proteins

  Neuro-Oncology Pediatrics · 2025-08-01

  articleOpen access

  Abstract High-grade gliomas (HGG) represent the most common cause of cancer-related mortality in the pediatric population due to a lack of curative therapies. Limitations for cellular-based therapies include the lack of unique tumor antigens, down regulation of surface antigens being targeted, marked tumor heterogeneity, and the immune suppressive tumor microenvironment. Here we describe a cellular delivery system using derived from post-mitotic migratory inhibitory interneuron precursors (MIPs) which are chemoattracted to tumors in an independent manner and are capable of delivering a therapeutic payload. During normal fetal development, MIPs migrate long distances from the medial ganglionic eminence to the cortex driven by several chemoattractants such as CXCL12. Notably, HGGs secrete these same factors, leading us to postulate that transplanted MIPs could migrate in a targeted manner to these tumors. Using transwell migration assays, we observed robust migration to conditioned media. This migration was recapitulated in vivo using orthotopic xenograft models transplanted in nude mice. MIPs were equipped with an EGFR or CD19 control bispecific T-cell engager (BITE) then co-cultured with HGG cells and CD8 T-cells at an effector to target ratio of 4:1. EGFR-BiTE secreting MIPs, but not CD19 control BiTEs, kill HGG cells. Results were validated in vivo via orthotopic xenografts of HGG in nude mice. CD8 T-cells were either administer as a single dose or weekly via interventricular cannula. Mice treated with EGFR-expressing MIPs had extended survival compared to CD19 BiTE expressing controls. Collectively, these data suggest that MIPs may be a viable cellular delivery system with flexibility to be equipped with a wide range of agents targeting HGG. MIPs can be engineered to modulate this migration, could also play a role in treating tumor-related epilepsy, and could be differentiated from induced pluripotent stem cells that are HLA-matched to avoid need for immunosuppression in humans.

  PublisherDOI

• Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection

  Stem Cell Reports · 2025-06-04

  erratumOpen access
  PublisherOA PDFDOI

• 3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

  Genome biology · 2025-12-08 · 1 citations

  articleOpen access

  Abstract Background Insight into the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but this alone does not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. Results Here, we generate 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrate this data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. The majority of variants implicated by these cis-regulatory architectures are trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, leading to enrichment of similar biological networks. While this suggests a high level of genetic diversity and complexity that converges at the level of target gene and cell type, some trait-specific pathways representing potential areas for disease-specific intervention were identified. We pharmacologically validate squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach and supported by prior eQTL data in multiple sclerosis and systemic lupus erythematosus, as a novel immunomodulatory drug target controlling T cell inflammatory cytokine production and aiding B cell antibody production in a human lymphoid organoid model. Conclusions These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types. Graphical Abstract

  PublisherDOI

• Author response: 3D genomic features across &gt;50 diverse cell types reveal insights into the genomic architecture of childhood obesity

  2024-08-05 · 1 citations

  peer-reviewOpen access

  The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 – an inflammation-responsive gene in nerve nociceptors – was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.What are the causal variants and corresponding effector genes conferring pediatric obesity susceptibility in different cellular contexts?Our method of assessing 3D genomic data across a range of cell types revealed heritability enrichment of childhood obesity variants, particularly within pancreatic alpha cells. The mapping of putative causal variants to cis-regulatory elements revealed candidate effector genes for cell types spanning metabolic, neural, and immune systems.We gain a systemic view of childhood obesity genomics by leveraging 3D techniques that implicate regulatory regions harboring causal variants, providing insights into the disease pathogenesis across different cellular systems.

  PublisherDOI

Recent grants

• NIH Grant R21NS054866

  NIH · $390k · 2009

• NIH Grant K02MH070031

  NIH · $1.2M · 2013

• NIH Grant RC1MH089690

  NIH · $999k · 2011

• NIH Grant P01NS048120

  NIH · $25.9M · 2016

• NIH Grant K08MH001620

  NIH · $768k · 2003

Frequent coauthors

• Jennifer A. Tyson

  Philadelphia University

  36 shared

• David J. Tischfield

  35 shared

• Andrew D. Wells

  34 shared

• Joan M. O’Brien

  University of Pennsylvania Health System

  30 shared

• Struan F.A. Grant

  28 shared

• Alessandra Chesi

  Children's Hospital of Philadelphia

  26 shared

• Douglas C. Wallace

  Children's Hospital of Philadelphia

  26 shared

• Theodore H. Schwartz

  25 shared