Biomedical subjects

Michael J Gandal

Publications and source records attributed to Michael J Gandal.

3 recordsLinked to original sources

PubMed2026

Beyond the gene: isoform diversity as a key contributor to human brain disorders.

The human brain exhibits exceptional transcriptomic complexity, with alternative splicing, promoter usage, and polyadenylation generating extensive transcript-isoform diversity. Isoform dysregulation is increasingly implicated in neurodevelopmental and psychiatric disorders (NPDs), yet the landscape, function, and genetic regulation of brain isoforms remain poorly understood due to limitations of short-read RNA sequencing. Advances in long-read sequencing (LR-seq) enable scalable full-length transcriptome profiling with single-cell and spatial resolution across developmental stages. Here, we review recent progress in isoform discovery, quantification, functional annotation, and genetic regulation, highlighting emerging links to human neurodevelopment and disease. LR-seq studies have uncovered tens of thousands of previously unannotated brain isoforms, with neuronal maturation characterized by increased exon inclusion and progressive 3' untranslated region (3' UTR) lengthening. Isoform-resolved genetic mapping outperforms gene-level analyses for NPD gene discovery and mechanistic interpretation. We argue that a shift from gene-centric to isoform-centric frameworks is essential to fully capture regulatory complexity in human neurogenetics. Together, these advances establish isoform diversity as a fundamental yet underappreciated axis of brain gene regulation and a key entry point for dissecting NPD biology.

Humans↗

PubMed2026

Can Psychiatric Genetics Advance Without Incorporating a Life Course Perspective?

Psychiatric disorders unfold over the life course; however, genomic studies of these conditions overwhelmingly rely on phenotypes collected at a single time point, often in adulthood. Therefore, genome-wide association studies (GWASs) of psychiatric conditions may miss genetic variants with time-varying relevance to etiology, prevention, and treatment, such as those that influence trajectories of symptoms and behaviors, age at onset, course of treatment response, and the co-evolution of comorbidities. With recent advances in longitudinal biobanks and analytic tools, we posit that incorporating a life course perspective in psychiatric genetics will enable critically relevant insights into each of these areas of investigation. We propose that the current inconsistent portability of polygenic scores across age groups can be reconciled through the design of carefully considered longitudinal GWASs in age-diverse samples. Pioneering longitudinal GWASs in psychiatry have revealed novel genomic signals associated with time-dependent phenotypes that are distinct from those influencing lifetime diagnosis, suggesting that the study of longitudinal phenotypes will complement cross-sectional approaches and empower biological and therapeutic discoveries. Advances in post-GWAS functional annotation resources and analytic approaches now enable us to contextualize the genetic contributions to psychiatric disorders as dynamic age- and exposure-dependent processes. Although longitudinal GWASs pose unique challenges with regard to data availability, selection bias, and missing data, integrating temporality into psychiatric genetics at scale is now attainable and promises to reveal novel biology and therapeutic opportunities for psychiatric conditions.

Cohort study↗

PubMed2025

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

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.

Humans↗