About

Michael J. Gandal, MD, Ph.D., is the William & Noreen Hetznecker Associate Professor in Psychiatry at the University of Pennsylvania's Perelman School of Medicine. He is a Faculty Investigator at the Lifespan Brain Institute (LIBI) at Penn Med and the Children’s Hospital Philadelphia (CHOP). His research integrates computational biology and functional genomics to understand the genetic mechanisms contributing to neurodevelopmental and psychiatric disorders, with a focus on identifying novel therapeutic targets. Dr. Gandal's expertise encompasses psychiatric genetics, functional genomics, transcriptomics, and human brain development. His work involves leveraging genome-wide association studies (GWAS), whole genome sequencing, and gene network biology to study conditions such as Autism Spectrum Disorder (ASD), ADHD, bipolar disorder, and schizophrenia. He is actively involved in investigating the genetic landscape across multiple psychiatric disorders and translating these findings into biological understanding, contributing significantly to the field of neurogenomics.

Research topics

• Biology
• Genetics
• Neuroscience
• Medicine
• Psychology
• Psychiatry
• Clinical psychology
• Computer Science
• Computational biology
• Immunology
• Physiology
• Evolutionary biology
• Medical emergency

Selected publications

• Can psychiatric genetics advance without incorporating a lifecourse perspective?

  Biological Psychiatry · 2026-04-01

  articleOpen access
  PublisherOA PDFDOI

• Leveraging genomic and transcriptomic data of diverse ancestry to uncover mechanisms of psychiatric risk in the adult and developing brain

  Research Square · 2025-02-20

  preprintOpen access
  PublisherOA PDFDOI

• AUTISM GENETICS: TRANSLATING ASSOCIATION TO BIOLOGICAL UNDERSTANDING

  European Neuropsychopharmacology · 2025-10-01

  articleSenior author
  PublisherDOI

• The overlapping genetic architecture of psychiatric disorders and cortical brain structure

  Nature Mental Health · 2025-08-11 · 3 citations

  article
  PublisherDOI

• Genetic prediction of early adolescent chronotype: effects of sex and pubertal status

  SLEEP · 2025-04-11 · 3 citations

  articleOpen access

  STUDY OBJECTIVES: Adolescence is characterized by later sleep onset and wake times, indicating a shift to an evening chronotype. Genome-wide association studies (GWAS) in adults show chronotype is polygenic and causally linked to depression, schizophrenia, and cognitive function. Yet, the impact of genetics on adolescent chronotype remains largely unexplored, and biological factors influencing the predictive relationship between genetics and chronotype have not been well-defined. This study aims to assess the utility of polygenic scores (PGS) derived from adult GWAS in predicting adolescent chronotype, mental health, and cognition while considering sex- and puberty-dependent effects. METHODS: Generalized linear models were used to assess the relationship between PGS for chronotype and self-reported chronotype, mental health, and cognition in 2411 youths of European ancestry aged 10-13 years. Interaction terms assessed whether the genotype-phenotype relationships varied by sex or pubertal development. Statistical significance was determined using a likelihood ratio test. RESULTS: Significant sex- and puberty-dependent effects were observed. Higher PGS for morningness concordantly predicted earlier self-reported chronotype, but in female youth only. Follow-up analyses showed that sex-specific effects were mediated by the interaction between PGS and pubertal status. Greater genetic predisposition for morningness was negatively associated with somnolence and cognition in males and negatively associated with psychotic-like experiences in females. CONCLUSIONS: The influence of genetic predisposition for early versus late chronotype on adolescent sleep-wake behavior emerges as puberty progresses. These findings suggest puberty is a critical transition when genetic variants associated with chronotype in adults become relevant to pediatric cohorts.

  PublisherDOI

• Morphogen-guided neocortical organoids recapitulate regional areal identity and model neurodevelopmental disorder pathology

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-03 · 2 citations

  preprintOpen access

  The human neocortex exhibits characteristic regional patterning (arealization) critical for higher-order cognitive function. Disrupted arealization is strongly implicated in neurodevelopmental disorders (NDDs), but current neocortical organoid models largely fail to recapitulate this patterning, limiting mechanistic understanding. Here, we establish a straightforward method for generating arealized organoids through short-term early exposure to anterior (FGF8) or posterior (BMP4/CHIR-99021) morphogens. These treatments created distinct anterior and posterior signaling centers, supporting long-lasting polarization, which we validated with single-cell RNA sequencing that revealed area-specific molecular signatures matching prenatal human cortex. To demonstrate the utility of this platform, we modeled Fragile X Syndrome (FXS) in organoids with distinct anterior and posterior regional identities. FXS organoids showed highly disrupted SOX4/SOX11 expression gradients along the anterior-posterior axis, consistent with alterations found in autism spectrum disorder (ASD) and demonstrate how regional patterning defects may contribute to NDD pathology. Together, our study provides a robust platform for generating neocortical organoids with anterior-posterior molecular signatures and highlights the importance of modeling NDDs using experimental platforms with neuroanatomic specificity.

  PublisherOA PDFDOI

• A single cell multi-omic analysis identifies molecular and gene-regulatory mechanisms dysregulated in the developing Down syndrome neocortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-04 · 6 citations

  preprintOpen access

  Down syndrome is the most common genetic cause of intellectual disability, presenting with cognitive, learning, memory, and language deficits. The cellular and molecular mechanisms driving this disorder remain unclear, limited by a lack of systematic studies in the developing human brain. Here, we leveraged single-nucleus multi-omics to profile the mid-gestation neocortex in a cohort of 26 donors. We observed a reduction in neural progenitors and corticothalamic neurons and concomitant increase of intratelencephalic neurons, accompanied by accelerated time to neuronal specification. We uncovered widespread changes in gene expression, chromatin accessibility and cell interaction networks impacting neurogenesis, specification and maturation and gene-regulatory networks directing these processes, including those downstream of transcription factors encoded in chromosome 21. Finally, we identified cell-specific molecular pathways shared with other neurodevelopmental disorders as well as heritability enrichment of GWAS signals in altered chromatin. Together, our data revealed a cascade of molecular dysregulation outlining the earliest steps in Down syndrome, providing a foundation for future therapeutic targets.

  PublisherOA PDFDOI

• Mapping the genetic landscape across 14 psychiatric disorders

  Nature · 2025-12-10 · 44 citations

  articleOpen access

  Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations. Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

  PublisherOA PDFDOI

• Leveraging genomic and transcriptomic data of diverse ancestry to uncover mechanisms of psychiatric risk in the adult and developing brain

  Nature Communications · 2025-12-29

  articleOpen access

  We explore strategies to harness ancestral diversity in PsychENCODE Consortium Genotype-Expression (GEx) reference panels (adult and developing brain) and Psychiatric Genomics Consortium GWAS data to improve genetically regulated expression (GReX) models and their use for Transcriptome-wide association study (TWAS) discoveries, uncovering previously unknown aspects of psychiatric functional genomics. We trained multiple GReX models on rigorously constructed GEx panel subsets, generated by downsampling, segregating, and/or mixing samples of Admixed African and European ancestries, and based on disease status. Ancestry-specific GReX genes were enriched in pathways involving mitochondrial functions, organelle structure, and metabolism. These models were integrated with ancestry-specific GWASs to conduct bipolar disorder, major depressive disorder, posttraumatic stress disorder, and schizophrenia TWAS. TWAS signals obtained by applying AA- and EUR-specific GReX models to an ancestry-specific GWAS were largely concordant, and mismatched-TWAS (e.g. AA-GReX applied to EUR-GWAS) revealed biologically meaningful signals missed by matched-TWAS. Shared signals across the four disorders were more prominent in the developing brain, involving genes such as H4C13, ZSCAN12P1, and FLOT1, and pathways related to megakaryocyte and muscle development, and neurotransmitter regulation. Overall, we demonstrate concordance in shared TWAS signals across GReX models and provide insight into GReX-specific detectable genes and pathways.

  PublisherOA PDFDOI

• Copy Number Variant Architecture of Child Psychopathology and Cognitive Development in the ABCD Study

  American Journal of Psychiatry · 2025-06-11 · 4 citations

  article

  OBJECTIVE: Late childhood is a crucial period for individuals with psychiatric disorders. While common single-nucleotide polymorphisms explain a large proportion of inherited risk, structural variations including copy number variants (CNVs) play a significant role in the genetic architecture of neurodevelopmental disorders. The relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored. The authors conducted a comprehensive exploration of the CNV architecture underlying dimensions of psychopathology and cognitive phenotypes within the Adolescent Brain Cognitive Development (ABCD) Study. METHODS: Using two algorithms for CNV detection, the authors identified duplications and deletions across 11,876 individuals from the ABCD Study. Quality control procedures considered array log R ratio and B allele frequency profiles, CNV size, agreement between the two algorithms, and genomic location of CNVs. CNVs that passed quality control were used to identify regions associated with quantitative measures of broad psychiatric symptom domains and cognitive functioning. Additionally, CNV risk scores, reflecting the aggregated burden of genetic intolerance to inactivation and dosage sensitivity, were calculated to assess cumulative impact on overall and dimensional psychiatric and cognitive phenotypes. RESULTS: Across 8,564 individuals whose data passed quality control, 4,111 carried 5,760 autosomal CNVs. Although no CNV regions reached significance after strict multiple testing correction was applied, 16 regions were associated with psychopathology and cognitive development at an uncorrected genome-wide significance level. A duplication at 14q11.2 showed the strongest association with attentional psychopathology. Moreover, individuals carrying CNVs previously associated with neurodevelopmental disorders exhibited greater impairment in social functioning and cognitive performance across fluid intelligence, working memory, and processing speed. Notably, higher CNV risk scores were significantly correlated with greater attention problems and cognitive impairment across multiple domains (fluid intelligence, attention, working memory, flexible thinking, and processing speed). CONCLUSIONS: These findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology.

  PublisherDOI

Recent grants

• Population-level and mechanistic dissection of 17q21 structural variant association with psychiatric traits

  NIH · $3.1M · 2023–2026

• Isoform-level probabilistic transcriptome-wide association to undercover neurogenetic mechanisms underlying complex psychiatric traits

  NIH · $3.4M · 2020–2025

• NIH Grant F30MH087071

  NIH · $13k · 2011

Frequent coauthors

• Daniel H. Geschwind

  Center for Autism and Related Disorders

  184 shared

• Chunyu Liu

  Changchun Institute of Optics, Fine Mechanics and Physics

  130 shared

• Daniel Vo

  Center for Autism and Related Disorders

  125 shared

• Andrew E. Jaffe

  Johns Hopkins Medicine

  81 shared

• Hyejung Won

  Lieber Institute for Brain Development

  77 shared

• Thomas G. Schulze

  National Institute of Mental Health

  74 shared

• Thomas M. Hyde

  Johns Hopkins University

  71 shared

• Thomas Werge

  69 shared

Labs

• Gandal LabPI

Education

• Residency, Adult Psychiatry

  University of California, Los Angeles

  2017

• MD

  University of Pennsylvania

  2013

• PhD, Bioengineering

  University of Pennsylvania

  2011