This study investigated differences in lifetime substance use among individuals diagnosed with obsessive-compulsive disorder (OCD), comparing those without body dysmorphic disorder (BDD) to those with comorbid probable BDD (OCD + pBDD). The sample included 1475 participants meeting diagnostic criteria for OCD (OCD without pBDD: n = 770; OCD + pBDD: n = 705). OCD was assessed using the Florida Obsessive-Compulsive Inventory (FOCI), and symptom severity was measured with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Alcohol and tobacco use severity were evaluated using a modified CAGE questionnaire, while lifetime marijuana and illicit drug use were assessed via a yes/no question. Chi-square (χ²) analyses examined group differences in substance use prevalence, and regression analyses evaluated the association between pBDD and alcohol/tobacco use severity. Results indicated significantly higher rates of lifetime alcohol use, tobacco use, marijuana use, and illicit drug use among individuals with OCD + pBDD compared to those with OCD alone. The OCD + pBDD group also demonstrated greater severity of alcohol and tobacco use and reported significantly higher rates of alcohol use to manage anxiety. Clinical implications and future research are discussed.
Anxiety disorders affect roughly 40%–50% of people with Alzheimer's disease (AD), highlighting the need for treatments that address both cognition and emotional health. Cog-201, a gene therapy targeting the 5-HT2A receptor, has been shown in preclinical studies to improve memory and reduce anxiety. Analyses from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were used to develop an unbiased, translational rationale for deploying Cog-201 to treat AD holistically, targeting cognition and anxiety together. Global cognition (MMSE), anxiety (NPI-A), overall neuropsychiatric symptom burden (NPI Total), amyloid PET burden, and serotonergic genotypes ( HTR2A rs6313; SLC6A4 rs25531) were analyzed using group comparisons and correlations, with visit-adjusted models for combined month-12 and month-24 observations. Across the whole ADNI cohort at month 12, higher NPI Total scores were significantly correlated with lower MMSE scores (r = −0.32), indicating that worsening neuropsychiatric symptoms, including anxiety and psychosis, accompany cognitive decline in AD. Higher neuropsychiatric symptom burden demonstrated a modest but statistically significant positive association with cortical amyloid burden measured using standardized ADNI UC Berkeley SUMMARY_SUVR values. Genotype-restricted analyses suggested that a serotonergic background may influence these relationships: the HTR2A rs6313 SNP (CT) showed a modest inverse association between MMSE and anxiety, and the SLC6A4 rs25531 (CC; within 5-HTTLPR) displayed a steeper negative slope. Taken with Cog-201’s preclinical profile, these results justify clinical evaluation of Cog-201 for AD with clinically relevant anxiety, advancing a holistic strategy that targets both cognition and neuropsychiatric symptoms. Exploratory genotype-stratified analyses suggested that serotonergic genetic background may influence these relationships; however, subgroup sizes were limited, and these findings should be interpreted cautiously. This study investigated whether anxiety severity is linked to poorer cognition, whether neuropsychiatric symptom burden is associated with cortical amyloid burden measured using standardized ADNI amyloid PET SUVR metrics, and whether common serotonergic variants influence these effects.
Common epilepsies are heterogeneous neurological disorders with significant heritability. Recent large-scale molecular genetic studies have identified both common and rare genetic variants affecting the risk of common epilepsies, suggesting the involvement of thousands of genetic variants. Most of these are common and individually have minuscule effects on disease risk. To date, more than 20 genomic loci with genome-wide significant common variant associations have been identified for genetic generalized epilepsies, implicating genes related to excitatory and GABAergic neurons, intracellular signal transduction, and synaptic excitability. While only a few common variant associations have reached genome-wide significance for focal epilepsies, exome-wide sequencing studies have robustly implicated protein-truncating ultrarare variants in genes encoding parts of the GATOR1 complex. Emerging data suggest a partly convergent genetic signal across subtypes of epilepsy and across common and rare variants. Furthermore, the genetic associations for common epilepsies overlap with a wide range of clinically related phenotypes, including cognitive ability and comorbid psychiatric and neurological disorders. Presently, genetic risk prediction tools that summarize an individual's common variant risk burden have limited clinical utility, but may eventually improve as statistical power increases. This review describes recent advances in the genetics of common epilepsies and outlines clinical implications and remaining challenges.
Individuals affected with a psychiatric disorder typically have elevated genetic risks for other mental disorders beyond the one from which they are currently suffering. From this observation it is possible to develop the concept of genetic specificity , defined in a cohort of affected individuals, as the proportion of the genetic risk for a set of psychiatric conditions due specifically to the disorder from which they are affected. To investigate this phenomenon, we studied all Swedish individuals born 1950 to 1995 with one of nine disorders ascertained from national registers: schizophrenia (SZ), bipolar disorder (BD), alcohol use disorder (AUD), ADHD, Autism spectrum disorder (ASD), PTSD, major depression (MD), anxiety disorder (AD) and drug use disorder (DUD). Genetic liabilities were calculated from family genetic risk scores. Specificity of genetic risk was defined as the proportion of genetic risk to all nine disorders due to genetic risk to the diagnosed disorder. The specificity of genetic risk varied from 29.5% for DUD to 73.1% for SZ. With increasing age at onset (AAO), genetic specificity decreased for BD and increased for PTSD. Higher levels of recurrence increased genetic specificity for all disorders with the largest effects on BD and ADHD. Genetic specificity was highest with hospitalized cases for BD while for PTSD, AD and MD, specificity was highest in primary care cases. Common psychiatric disorders differ widely in their degrees of genetic specificity. The genetic specificity for many disorders can vary substantially as a function of AAO, level of recurrence, and site of treatment.
Dr. Dilek Colak is an Associate Professor of Neuroscience at the Feil Family Brain and Mind Research Institute and Associate Professor of Pediatrics at the Gale and Ira Drukier Institute for Children's Health, both at Weill Cornell Medicine in New York City. Her scientific training began in Germany, where she pursued doctoral work at the Max Planck Institute of Neurobiology and the Helmholtz Center's Stem Cell Institute in Munich under the mentorship of Dr. Magdalena Götz, laying the foundation for her enduring interest in the cellular logic of brain development. She relocated to New York in 2009 for postdoctoral research in the laboratory of Dr. Samie Jaffrey in the Department of Pharmacology at Weill Cornell Medicine, where she uncovered an RNA-directed silencing mechanism implicated in Fragile X Syndrome, a discovery that reshaped her thinking about translational opportunities in neuropsychiatric disease and prompted her transition to an independent faculty position in 2015. Now promoted to Associate Professor, she leads a research program that integrates genetically engineered mouse models and human stem cell-derived brain organoids to investigate how glial cell dysfunction and RNA regulation shape the cellular and molecular pathology of neurodevelopmental and neuropsychiatric disorders, with particular attention to autism and schizophrenia. Her dual appointment positions her at the interface of molecular neuroscience and pediatric medicine, where she champions rigorous methodology, collaborative integrity, and the scrutiny of long-standing dogmas. In this Genomic Press Interview, Dr. Colak is happy to share reflections on her life and career with our readers.
The investigational drug davunetide is a small active fragment of activity-dependent neuroprotective protein (ADNP), regulating and being regulated by sex hormones. Mutations in ADNP sex-dependently dysregulate microtubules/mitochondria/unfolded protein response/autophagy/neurogenesis, leading to tauopathy, and are corrected by the microtubule-protecting, davunetide. The striking sex differences discovered in mice, coupled with multiple failures of clinical trials mixing the sexes in devastating tauopathies, emphasize the need for a paradigm-shifting approach towards sex-specific brain medicine. Indeed, the Tau-targeting davunetide has previously demonstrated sex-dependent clinical efficacy across diverse populations of neurodegenerative tauopathies and neuronal decline (e.g., Alzheimer's disease, progressive supranuclear palsy, and post-coronary artery bypass grafting [CABG] surgery), suggesting differences in drug bioavailability. Here, performing fluorescent davunetide bioavailability experiments via in vivo imaging in mice, we discovered sex-specific estrous-cycle-dependent brain bioavailability. Thus, females showed significantly greater head/body bioavailability than their male counterparts, especially during proestrus and estrus, corresponding to the highest estrogen levels, and extended to comparisons in females within the estrous cycle. In a human population of healthy adults, analysis of plasma pharmacokinetics following intranasal davunetide administration trended toward higher peak plasma concentrations in women and longer half-life in men, consistent with the preclinical findings and previous clinical trials. In the broader context, while considering our study limitation and the fact that davunetide is an investigational drug, we maintain that sex-specific brain medicine should become a central focus of precision medical investigation required for maintaining better health.
This review focuses on the function of HuD (ELAVL4) from the perspective of the mRNA targets and biological pathways it regulates from early brain development to the adult nervous system. HuD is a member of the Hu family of RNA-binding proteins (RBPs), which are critical post-transcriptional regulators and one of the earliest neuronal markers. HuD knockout (KO) mice exhibit deficits in motoneuron development and learning and memory, and multiple studies demonstrate HuD is essential for neuronal differentiation, nerve regeneration, and synaptic plasticity. In previous studies, we identified the repertoire of mRNAs bound to HuD in both embryonic and adult mouse brain tissues. Of the close to 4000 HuD-bound mRNAs, half are expressed in both developing and mature neurons. These shared mRNA targets are enriched in several networks and biological pathways, including proliferation of neural cell progenitors, quantity of synapses, and regeneration of the nervous system. Common target mRNAs are also involved in signaling from GABA, opioid, and ephrin receptors. Targets expressed only in embryonic brains contribute to several developmental pathways, including RHO GTPase activation, WNT/β-catenin signaling, and semaphorin interactions, while those expressed exclusively in adult tissues participate in synaptogenesis, JAK-STAT signaling, regulation of stress-induced responses, and hypoxia signaling. Comparative analyses of HuD-regulated pathways across the E18, adult, and common sets of targets reveal that, despite differences in specific mRNA components, these sets share 15 canonical pathways and 31 diseases and functions. Shared functional networks include axon guidance, neuritogenesis, and netrin signaling. These findings underscore that HuD-mediated target regulation in mature neurons often recapitulates processes used for neurite remodeling in early neuronal differentiation.
Professor Maria Margarita Behrens is a faculty member in the Computational Neurobiology Laboratory at the Salk Institute for Biological Studies and an Adjunct Professor in the Department of Psychiatry at the University of California, San Diego. Born in Uruguay and raised in Chile, she trained in biochemistry and molecular biology in Brazil and Spain before transitioning into neuroscience in the United States. She joined the Salk Institute in 2009 after positions at Washington University School of Medicine, The Scripps Research Institute, and the Department of Medicine at UCSD. Her laboratory investigates the epigenomic basis of brain development and maturation, with particular emphasis on understanding how neural circuits form in the prefrontal cortex during the perinatal period. As a principal investigator in the NIH BRAIN Initiative Cell Atlas Network (BICAN), she has contributed to generating comprehensive single-cell epigenomic atlases of the mouse and human brain and to identifying cell types through their DNA methylation signatures. Her work aims to elucidate how disruptions during critical developmental windows may lead to neurodevelopmental and neuropsychiatric disorders. In this Genomic Press Interview, Professor Behrens reflects on her unconventional path to neuroscience, her passion for collaborative research, and the questions that continue to drive her scientific curiosity.
Trace amine-associated receptor 1 (TAAR1) is an emerging pharmaceutical target for treating a variety of neuropsychiatric conditions, with several drug candidates in clinical and preclinical development. Multiple single-nucleotide variants have been associated with neuropsychiatric disorders, and genetic variants may influence the therapeutic outcomes of TAAR1-based therapies. Here, we utilize mutagenesis, functional assays, and computational models to profile schizophrenia-associated TAAR1 variant C182 45.50 F. In cyclic adenosine monophosphate (cAMP) assays, TAAR1 C182 45.50 F demonstrated a complete loss of activity in the homozygous state, and approximately 50% loss in the heterozygous state compared to TAAR1 WT (wild type). Furthermore, the surface expression of homozygous TAAR1 C182 45.50 F was altered, with approximately 40% reduction in surface expression compared to TAAR1 WT. Expression marginally improved in the heterozygous state. Molecular dynamics simulations of the TAAR1 C182 45.50 F model demonstrated increased extracellular loop 2 (ECL2) flexibility, with F182 45.50 forming a stable aromatic cluster (aromatic–aromatic interactions) involving F165 ECL2 and Y172 ECL2 that occludes the orthosteric binding site. The aromatic cluster is further stabilized by a transient salt bridge between E93 3.22 and K97 3.26 . Overall, our study shows the TAAR1 C182 45.50 F variant may disrupt endogenous trace amine signaling via a reduction of cell surface expression and occlusion of endogenous ligand binding; in addition, newly developed TAAR1 therapeutics may be subefficacious in carriers of this variant.
In this Genomic Press Interview, Noritaka Ichinohe, MD, PhD, reveals himself as one of the most intellectually formidable and methodologically rigorous translational neuroscientists working today, a physician-scientist whose three-decade career has fundamentally shaped our understanding of primate cortical organization while pioneering transformative approaches to autism spectrum disorder research. As Director of the Department of Ultrastructural Research at Japan's National Center of Neurology and Psychiatry since 2010 and Visiting Principal Researcher at the RIKEN Center for Brain Science, Dr. Ichinohe commands a unique dual appointment that bridges clinical translational research with cutting-edge basic neuroscience, having authored over 260 research products and secured 27 competitive research grants. His foundational work with Kathleen Rockland at RIKEN, including his landmark discovery of the “honeycomb-like mosaic” at the layer 1-2 border, established new paradigms for understanding cortical micromodular organization, while his current leadership in Japan's Brain/MINDS initiative has made him instrumental in constructing the marmoset brain connectome, with his team's AI-powered pipeline enabling unprecedented precision in mapping primate neural circuits. Most remarkably, Dr. Ichinohe's discovery that valproate-exposed marmoset transcriptomes converge with specific molecular subtypes of human autism represents a paradigm-shifting contribution to genomic psychiatry, offering mechanistically grounded pathways toward precision medicine that honor, rather than erase, the profound heterogeneity observed in affected individuals. Trained at Hirosaki University and mentored by giants, including Stephen T. Kitai at the University of Tennessee and the luminaries of RIKEN Brain Science Institute, founded by Masao Ito and Shun-ichi Amari, Dr. Ichinohe embodies a rare integration of classical neuroanatomical precision with bold theoretical vision, while maintaining an unwavering commitment to keeping human complexity visible in an era too often seduced by reductive simplicity.
Supercentenarians provide a rare human model of exceptional longevity, marked by unique immune, genetic, and metabolic profiles that support resilience against age-related decline. Brazil's highly admixed population offers unparalleled opportunities to uncover protective mechanisms often missed in more homogeneous cohorts. Here, we describe ongoing genomic and cellular studies of a nationwide Brazilian cohort, featuring individuals who remained highly functional and survived COVID-19 unvaccinated. These individuals allow us to investigate molecular, immunological, and systemic pathways of resilience, offering insights that may inform strategies to extend health span.
Schizophrenia is associated with an increased risk of osteoporosis, yet the biological mechanisms underlying this association remain poorly understood. As both disorders are highly polygenic and may share biological pathways, investigating their shared genetic basis could help clarify the mechanisms contributing to their comorbidity. Using summary-level statistics from the largest genome-wide association studies of schizophrenia ( N = 132,644) and six osteoporosis-related phenotypes ( N = 8143–426,824), we comprehensively characterized shared genetic architecture across global, local, and variant levels. Shared loci were subsequently identified and mapped to protein-coding genes, followed by functional enrichment analyses. The analyses revealed varying degrees of polygenic overlap between schizophrenia and osteoporosis-related traits. Significant regional genetic correlations were detected, particularly for femoral neck, forearm, and heel bone mineral density. In total, 195 loci were jointly associated with schizophrenia and osteoporosis-related traits. These loci were mapped to 1376 protein-coding genes, which showed significant enrichment in biological processes related to organonitrogen compound metabolism, anatomical structure development, and biological regulation. Together, these findings provide integrative evidence of genetic overlap between schizophrenia and osteoporosis, highlighting common etiological mechanisms bridging neuropsychiatric and skeletal health, with potential implications for early prevention.
Widely recognized as the world's most published and influential psychiatric epidemiologist, Dr. Ronald C. Kessler is the McNeil Family Professor of Health Care Policy at Harvard Medical School, with secondary appointments as Professor of Epidemiology at the Harvard T.H. Chan School of Public Health, Program Director at the University of Michigan Institute for Social Research, and at the Massachusetts General Hospital Center for Precision Psychiatry. Known for leading major national and global epidemiological surveys on the population prevalence and correlates of mental disorders, he has transformed how the field understands the burden, distribution, and treatment of common mental illnesses and suicide-related behaviors. Dr. Kessler was the Principal Investigator of the US National Comorbidity Survey, the first nationally representative survey of mental disorders in the United States, and a series of follow-up and replication studies that have mapped changes in mental health and service use over time. For two decades, he served as Director of the World Health Organization World Mental Health Survey Initiative, a program of community surveys in over 30 countries that has provided the empirical foundation for national mental health policies and resource allocation decisions worldwide. Building on this foundation, his more recent work extends into high-risk populations through large-scale studies such as the Army STARRS and STARRS-LS initiatives. Dr. Kessler is the most cited author in psychiatry and psychology worldwide, with more than 1,300 scientific publications, cited over 330,000 times; h-index: 271 (Scopus), 354 (Google Scholar, January 2026). He has been a pioneer in the use of sophisticated methods for conducting and analyzing general population psychiatric epidemiologic surveys. In recent years, he has extended this work to implement clinical epidemiologic surveys, use these surveys to develop clinical decision support tools, and conduct pragmatic precision treatment trials to assess the value of these clinical decision support tools to prevent and treat depression, anxiety, and suicide. Dr. Kessler's achievements have been recognized with election to the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences. This Genomic Press Interview offers an in-depth look at the trajectory, methods, and vision of a scientist whose work has reshaped modern psychiatric and mental health epidemiology and the global conversation about mental health.
HF21B is an epigenetic reader that modulates synaptic plasticity-related genes and social memory (1). Although PHF21B is known to bind H3K36me3, the domain responsible for this interaction has remained uncharacterized. Here, we used co-immunoprecipitation with PHF21B deletion mutants in HEK293T cells to show that the PHD-zinc finger domain is essential for H3K36me3 recognition, whereas the C-terminal coiled-coil region is dispensable. These findings identify the PHD-zinc finger domain as the critical H3K36me3-binding module of PHF21B, with implications for neurological disorders linked to chromosome 22q13.3 deletion, including Phelan-McDermid syndrome (2, 3).
In an analysis of 173 multiplex families from the Portuguese Island Collection (PIC), we characterize the shared genetic architecture of serious mental illnesses (SMI) , including schizophrenia (SZ), bipolar disorder (BP), major depression (MDD), and autism (ASD). Within this cohort, co-segregation of psychotic and mood disorders occurred in 28% of families, while 7% demonstrated co-segregation of intellectual disability or ASD with SZ and mood disorder phenotypes. Whole-genome sequencing (WGS) was performed on a three-generation PIC family to identify rare, large-effect variants. We identified an extremely rare predicted loss-of-function (LoF) mutation in the Chromodomain Helicase DNA Binding Protein 2 (CHD2) gene. These findings highlight the utility of high-density multiplex families in founder populations for identifying rare, large-effect variants that span clinical diagnostic categories, with the identified CHD2 mutation suggesting that variation in a single neurodevelopmental gene may contribute to phenotypic heterogeneity across SMI. By combining population and family-based methodologies, this approach leverages shared genetic backgrounds and environments to provide a unique opportunity for cellular studies to explore the biological mechanisms underlying SMI, offering significant potential to inform future functional research and identify novel therapeutic targets.
Polygenic scores (PGS), summarizing the cumulative contribution of common genetic variants to psychiatric phenotypes, are increasingly investigated as putative predictors of treatment response and illness course. In major depressive disorder (MDD), several studies have associated higher MDD PGS with a modestly increased risk of nonresponse, lower remission rates, and treatment resistance. Conversely, bipolar disorder (BD) PGS have yielded more heterogeneous findings, with largely null or weak associations in unipolar depression but a possible on lithium response in BD cohorts, while lower MDD PGS showed a more consistent beneficial effect on lithium response in BD. MDD PGS may also have a modulating effect on clinical features of schizophrenia and a range of other psychiatric disorders. Nonetheless, the variance explained remains limited and predictive power improves only marginally when PGS are used in isolation. Integrative approaches that combine clinical predictors, environmental measures, and biomarker data appear to enhance prediction over genetics alone, which is increasing due to the most recent large genomewide studies. However, ancestral diversity remains limited, with most research conducted in Caucasian samples. Taken together, current evidence supports the incremental value of MDD and BD PGS in informing prognosis and treatment response, though clinical implementation remains premature. Replication in ancestrally diverse samples, integration with dimensional phenotypes, and improved modeling strategies will be essential to translate genetic liability into clinically actionable insights in precision psychiatry.
In this illuminating Genomic Press Interview, Dr. Xuyu Qian, a visionary neuroscientist whose groundbreaking spatial transcriptomics research promises to revolutionize our understanding of human brain development at unprecedented single-cell resolution, shares his remarkable path from an art-infused childhood in Nanjing to becoming a Forbes 30 Under 30 laureate and pioneering force in brain organoid technology. As the newly minted Assistant Professor at the University of Pennsylvania and Children's Hospital of Philadelphia, Dr. Qian has transformed our understanding of human cerebral cortex formation through his innovative fusion of spatial transcriptomics and organoid models. His landmark work, recently published in Nature (2025), leveraged state-of-the-art MERFISH technology to analyze over 18 million single cells, thereby redefining our understanding of the emergence of cortical layers and specialized brain regions during fetal development. This breakthrough builds upon his earlier revolutionary development of brain organoid protocols, now cited over 2,000 times and instrumental in shaping CDC guidelines for the prevention of Zika virus. Throughout this candid conversation, Dr. Qian reveals how the anime series Evangelion sparked his passion for biotechnology, explores his generous collaborative philosophy that has led to numerous discoveries, and articulates his commitment to human-centric approaches for decoding neurodevelopmental disorders. His distinctive combination of scientific excellence, creative vision, and infectious enthusiasm establishes him as one of neuroscience's most promising emerging leaders, destined to unravel the fundamental mysteries of human brain development and disease.
