Cathy Barr completed her Ph.D. in molecular biology at the University of Texas, Graduate School of Biomedical Sciences (M.D. Anderson Cancer Center) in Houston, Texas, followed by postdoctoral training in the genetics of complex behaviors at Yale University and the Hospital for Sick Children in Toronto. Currently serving as a Senior Scientist at both the Hospital for Sick Children and the Krembil Research Institute (University Health Network) and as a Professor in the Departments of Psychiatry and Physiology at The University of Toronto, Dr. Barr investigates the genetic foundations of behavior, cognition, and psychiatric disorders with established genetic predispositions. Her research mainly focuses on childhood-onset conditions, including depression, attention-deficit/hyperactivity disorder, reading disabilities, and Tourette syndrome, with special emphasis on understanding shared risk factors across disorders – a critical area given that children with neurodevelopmental disorders face a fivefold increased risk of depression. Through innovative approaches, Dr. Barr and her research team have successfully identified risk-contributing genes. They are investigating how DNA variations in these genes influence gene function and neural cell behavior. In this Genomic Press Interview, she generously shares insights from her groundbreaking research into the genetic underpinnings of childhood psychiatric and neurodevelopmental disorders.
As a distinguished James McGill Professor and now Professor Emeritus at McGill University, Michael Meaney's scientific journey is a testament to the power of curiosity in science. His fascination with how our environment shapes our genes, brain function, and mental health has led to discoveries that have changed how we think about human development. After leading groundbreaking research at McGill, he took his expertise to Singapore, where, as Director of the Translational Neuroscience program at ASTAR, he helped shape the innovative GUSTO birth cohort study. His profound impact on neuroscience is reflected not just in his impressive collection of honors – from the Order of Canada to his recent election to the American Academy of Arts and Sciences – but in how his work has touched lives. With over 650 publications to his name, Meaney has helped bridge the gap between molecular biology and public health. We are fortunate to have him share his insights with our readers in this Genomic Press Interview.
Fragile X syndrome is caused by monogenic silencing of the FMR1 gene and is characterized by high rates of autism spectrum disorder. A previous study demonstrated that prepartum administration of bumetanide, a chloride transporter blocker, normalized neonatal vocalization in non-congenic Fmr1 knockout (KO) pups. However, the genuine contribution of Fmr1 deletion to this phenotype in a congenic Fmr1 KO mouse model and the long-lasting effect of prepartum bumetanide administration on postpubertal social interaction remains unclear. The current study aimed to determine the impact of prepartum bumetanide administration on vocalization at postnatal day 7 and social interaction at 6 and 8 weeks of age in a congenic Fmr1 KO mouse model in which the genetic backgrounds were homogeneous between KO and wild-type (WT) littermates. Moreover, we applied a computational analytical algorithm and determined predictive variables of neonatal vocalization for postpubertal social interaction. Our data showed that (1) KO mice exhibited altered numbers and sequences of distinct call types during neonatal vocalization and reduced social interaction at 6 weeks, (2) select sets of neonatal vocalization variables predicted postpubertal social interaction levels, and (3) bumetanide restored neonatal vocalization in KO pups but nonspecifically reduced social interaction in WT and KO mice at 6 weeks. These data indicate that Fmr1 deletion selectively impacts distinct elements of neonatal vocalization and postpubertal social interaction. Additionally, bumetanide selectively restores neonatal vocalization but has a transient nonspecific negative impact on subsequent postpubertal social interaction.
When Genomic Press started, I never imagined our defining moment would come from a children's book. Yet here we are, finding our soul in the story of a lonely color that could not fit in. I remember the first time I encountered Flicts. I was an adult and a good friend gave me the book with a knowing smile. “Trust me,” she said, “this will make sense.” She was right, though not in any way I could have anticipated.Finding Our Place: The Flicts Story and the Heart of Genomic Press
Ziraldo: The Godfather of
For half a century, Edo Ronald (Ron) de Kloet has pursued a fundamental question in neuroscience: how do stress hormones switch from protecting our brain to potentially harming it? After receiving his PhD in 1972 at the University of Utrecht under David de Wied's mentorship, he spent two formative years with Bruce McEwen at Rockefeller University before returning to the Rudolf Magnus Institute. In 1990, he was appointed Professor of Medical Pharmacology at Leiden University, where he discovered how a single hormone – cortisol – could protect and damage the brain through two distinct receptor systems (MR and GR). This finding opened new paths for understanding and treating stress-related mental disorders. His research, spanning over 600 publications, has transformed our grasp of how the brain copes with stress and earned him numerous honours, including the Geoffrey Harris Award (2005), the ECNP Award (2007), and the Golden Emil Kraepelin Medal (2014) for advancing our understanding of depression. Though officially “retired” since 2009, he remains active as an emeritus professor at Leiden University Medical Centre and academy professor at the Royal Netherlands Academy of Arts and Sciences. Recognizing his contributions to science and society, he was knighted in the Order of the Dutch Lion in 2010. Recently, alongside his long-time collaborator Professor Marian Joëls, he received the 2024 Global Stress & Resilience Network Pioneer Award. In this Genomic Press Interview, Dr. de Kloet reflects on his remarkable journey and shares fresh insights into the fascinating world of stress neuroscience.
Peter Falkai stands as one of the world's leading authorities in psychiatric research, particularly in understanding the neurobiology of schizophrenia. As a Scientific Member of the Max Planck Society and Director and Head of the Hospital at the Max Planck Institute of Psychiatry since October 2024, he continues to advance our understanding of mental health disorders. His distinguished career spans over three decades, during which he has held multiple prestigious leadership positions, including President of the European Psychiatric Association (2021–2023) and current President of the World Federation of Societies of Biological Psychiatry. A member of the German Academy of Sciences Leopoldina, where he served as Senator of the Neurosciences Section, Prof. Falkai has been instrumental in shaping modern psychiatric research and treatment approaches. His groundbreaking work on brain plasticity and innovative treatment combinations has opened new pathways for understanding and treating psychotic disorders. As site spokesperson for the German Centre for Mental Health and former President of the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology, he continues to bridge the gap between basic research and clinical application. In this Genomic Press Interview, Prof. Falkai graciously shares insights into his remarkable professional journey and personal life, offering readers a glimpse into the mind of one of psychiatry's most influential figures.
Dr. Natalia Acosta-Baena embodies the rare confluence of clinical and basic science expertise that modern neuroscience demands. As a physician-scientist at the University of Antioquia's Neurosciences Group, she combines her medical training with a master's in clinical epidemiology and doctoral studies in basic biomedical sciences, specializing in Genetics. Her groundbreaking work began with contributing to characterize the world's largest population affected by autosomal dominant genetic Alzheimer's disease (mutation E280A in PSEN1), establishing a foundation for numerous studies on biomarkers, clinical trial design, and genetic modifiers in this pivotal cohort. In a landmark discovery, Dr. Acosta-Baena's research revealed a novel syndrome linked to a SPAG9 variant, demonstrating how a single gene involved in neuronal retrograde transport can drive neurodevelopmental problems and neurodegeneration in affected patients. This finding challenges the traditional separation between these processes and suggests shared biological pathways. Through her continued work with families affected by neurodevelopmental disorders, she has uncovered genetic networks that reshape our understanding of rare brain diseases. Her current translational medicine and genetic epidemiology research focuses on further exploring these unexpected connections between neurodevelopment and neurodegeneration. In a Genomic Press Interview, Dr. Acosta-Baena shared her life beyond the laboratory – from her early fascination with the human brain to finding joy in Colombia's mountain sunsets with her husband and son and drawing inspiration from Latin American writers like Cortázar and García Márquez. Her dedication to scientific rigor and human connection is reflected in her philosophy that each failure teaches something essential as she works toward translating genetic discoveries into meaningful healthcare policies and personalized medicine approaches.
Activity-dependent neuroprotective protein (ADNP), essential for brain formation/function, reveals multiple cytoplasmic and chromatin interacting sites. Computational modeling, alongside the Vineland Adaptive Behavior Scales, a leading instrument supporting the diagnosis of intellectual/developmental disabilities, now revealed a protective frame shift/stop mutation in ADNP. Thus, a woman with inherited mutation, ADNP_Glu931Glyfs*12 (VB), showed above average Vineland performance. Bioinformatics/in silico protein modeling indicated that while ADNP contains four 14-3-3 protein interaction sites (instrumental for ADNP nuclear/cytoplasmic shuttling), ADNP_Glu931Glyfs*12 contains an additional fifth 14-3-3 interaction site, implicating stronger associations. Furthermore, the endogenous neuroprotective (investigational drug, davunetide) NAPVSIPQ (NAP) site was involved in the ADNP and ADNP_Glu931Glyfs*12-14-3-3 interactions. In this respect, the mutation also enhanced ADNP-SH3 associations (another NAPVISP interaction site 354-361 aa on ADNP, critical for cytoskeletal/cellular signaling). HB, the 8-year-old VB's son, while inheriting the mother's ADNP mutation, further presented a heterozygous pathogenic de novo mutation ADNP, p.Arg730Thrfs*5. However, in comparison to carriers of a similar p.Arg730* mutation (part of the autistic/intellectual disability ADNP syndrome), HB exhibited overall better Vineland 3 standard score of 70–80 for all measures, compared to the nominal score of 20 in a 27-year-old ADNP, p.Arg730* subject and the 100 ± 15 norm, corroborating ADNP_Glu931Glyfs*12 protection.
The authors are, respectively, the founding and current Directors of the Lothian Birth Cohorts of 1921 and 1936. In this invited and, admittedly, self-regarding and necessarily self-citing piece, we enumerate and explicate some things we learned from working with the cohorts and their data. Some of the lessons are scientific results, some are to do with scientific practice, and some are more general reflections. We hope the paper provides a useful summary of some of the main findings from these too-many-papers-to-read cohorts and an enjoyable account of our building a research team and a network of collaborators. The original aim of assembling the cohorts was to fashion a tool to discover why some people's thinking skills aged better than others’. That tool, we discovered, had many additional uses.
The role of thyroid hormone (TH) in the development and function of the central nervous system (CNS) has been known for many years. However, the role of liver X receptors (LXRs) in TH function and protection against neuronal degeneration was not recognized until recently. The relationship between thyroid hormone receptors (TRs) and LXRs became apparent with the cloning of steroid hormone receptors, leading to the discovery of the nuclear receptor superfamily. This family includes not only receptors for classical steroid hormones but also many newly discovered ligand-activated nuclear receptors. LXRs and TRs regulate overlapping pathways in lipid and carbohydrate metabolism, as well as in overall CNS development and function. These CNS pathways include neuronal migration during cortical and cerebellar layering, myelination, oligodendrocyte maturation, microglial activation, and astrocyte functions. Furthermore, LXRs likely have unique functions, as evidenced by the inability of TH to compensate for microglial activation, oligodendrocyte maturation, spinal motor neuron death, and degeneration of retinal and cochlear neurons in LXRβ knockout mice. The common and unique functions of these two receptors are the subject of this review. We analyzed some of the most relevant literature on the regulation and function of LXRs and TRs and investigated why both receptors are required in the human body. We conclude that LXRs and TRs do not represent parallel pathways but rather constitute a single pathway through which the TH endocrine system regulates cholesterol homeostasis. Subsequently, LXRs, activated by cholesterol metabolites, function as a paracrine/autocrine system that modulates the target cell response to TH.
Our modern syndrome of major depression developed over the 19th century and assumed its largely current form in Europe during the last decades of that century. A defining monograph in that historical development in German-speaking Europe was published by Krafft-Ebing in 1874. In this article, we provide a detailed commentary (and an English translation) of key sections of a monograph—“La Mélancolie” (The Melancholy) published by Roubinovitch and Toulouse in 1897—that plays a parallel role in the Francophone world. We emphasize six features of this important document. First, is it thoroughness, covering, with often vivid descriptions, the symptoms, signs, subtypes, course of illness, and outcome of melancholia. Second, this work describes the key features of the evolution of the concept of melancholia over the prior century. Third, we also see in this monograph important references to the leading explanatory psychophysiological model for melancholia developed in the middle third of the 19th century—melancholia as psychalgia or “mental pain.” Fourth, the authors are committed to attempting to understand, in psychological terms, key features of the melancholic syndrome and in particular the development of delusions. Fifth, they give great emphasis to a symptom/sign pair in their diagnosis and description of melancholia: psychological suffering accompanied with resignation and “psychophysical decrease.” Sixth, these authors attend to the lived experienced of their melancholic patients, considering some key themes, such as derealization, now emphasized in phenomenological studies of depression. Seventh, they have an insightful view of the evolution of psychiatric diagnoses that applies to the modern day—that disease identification in psychiatry lags behind that most parts of medicine as our diagnostic categories are still “only provisional symptomatic groupings which will one day be replaced by more exact conceptions of the nature of the relationships which unite the facts.”
Philippe Courtet is a distinguished figure in psychiatry and suicidology who has significantly contributed to the field. As an influential PU-PH (Professeur des Universités-Praticien Hospitalier), he is a Professor of Psychiatry at the University of Montpellier, France, and head of Emergency Psychiatry at the University Hospital of Montpellier. Leading the Chair of Excellence in suicide prevention at the Fundamental Foundation and the ‘biomarkers, environment and neuropsychiatry’ research group at the National Institute of Health and Medical Research (Institut National de la Santé et de la Recherche Médicale, INSERM), Professor Courtet has focused on understanding the vulnerability to suicidal behaviour in mood disorders. His innovative work combines genomics, brain imaging, and social research. With over 500 peer-reviewed articles, an H-index of 82, and 27,000 citations, he stands as one of France's most productive psychiatrists and an international leader in suicidology. His role as Chair of the Suicidology and Suicide Prevention Section of the European Psychiatric Association further cements his influence in the field. Professor Courtet's groundbreaking research and dedication to improving care through the development of connected health tools for suicide risk assessment underscore his commitment to advancing treatment. We are pleased that Professor Courtet has participated in an exclusive Genomic Press Interview, which he entitled “Hell is other people.1” How social pressure shapes suicidal thoughts, offering our readers unique insights into his life and vision for the future of psychiatry and suicide prevention.
Robin Dunbar is an eminent evolutionary psychologist and anthropologist whose pioneering work has permanently redefined how we think about human social relationships. Dunbar, who is an emeritus Professor of Evolutionary Psychology at the University of Oxford, became world-renowned for, among other contributions, his formulation of “Dunbar's number,” a theoretical limit to the number of stable social relationships an individual can maintain, typically cited as about 150. That idea, which he developed as he studied the relationship between brain size and social group size in various primate species, has since had broad influences across areas from social media design to organizational management. Over time, Dunbar's number has become more widely known and discussed, particularly with the advent of social media and online social networks. This has led to renewed interest in its implications for digital social interactions. Dunbar's illustrious career spans multiple prestigious institutions, including, prior to joining Oxford in 2007, the University of Cambridge, the University of Stockholm (Sweden), University College London and the University of Liverpool. He is a fellow of the British Academy and the Royal Anthropological Institute, a Foreign Member of the Finnish Academy of Science and Letters, and an elected Honorary Member of the Hungarian Academy of Sciences. His interdisciplinary expertise is reflected in his professorships in psychology, evolutionary biology, and anthropology at institutions such as Liverpool and Oxford Universities. He has held a visiting chair in statistical physics and computer science at Aalto University, Finland, which has also awarded him an honorary doctorate. Dunbar studies the evolution of social processes in primates and humans, with work that blends neurobiology, cognitive science, and the social dynamics of how we communicate via friendship networks. His insights into friendships and community cohesion continue to shape our understanding of human social behaviour in the digital age. It is an absolute pleasure that Professor Dunbar answered the Genomic Press Interview as we celebrate the extraordinary story of his scientific odyssey with our readers.
Epilepsy and bipolar disorder (BD) exhibit considerable biochemical and genetic overlap. Our study unveiled a significant genetic correlation (rg = 0.154, P = 9.24 × 10–6) between BD-I and epilepsy, indicating a meaningful causal effect of epilepsy on BD-I (P = 0.0079, bxy = 0.1721, SE = 0.0648). Additionally, we identified 1.3k shared genetic variants and 6 significant loci, demonstrating substantial polygenic overlap. Notably, the rs9639379 variant within the SP4 gene exhibited strong associations with both BD-I and epilepsy, implicating SP4 in the etiology of both disorders.
Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for the treatment of neuropsychiatric conditions. Several TAAR1-targeted therapeutics are currently in clinical and preclinical development. Emerging studies highlight links between TAAR1 single-nucleotide variants/polymorphisms and neuropsychiatric disorders. An improved understanding of TAAR1 genetic variants and their functional impact will inform the potential role of the TAAR1 system in the pathophysiology of neuropsychiatric conditions and for better therapeutic dosing. This viewpoint examines clinical and molecular studies involving TAAR1 genetic variants and their association with neuropsychiatric disorders.
It is well established that both genetic and environmental factors contribute to risk for schizophrenia (SCZ), and much progress has been made in identifying the specific factors conferring risk. However, the nature and extent of interactions between them has long been a topic of debate. Both the data and methods available to address this have evolved rapidly, enabling new prospects for identifying gene–environment interactions in SCZ. To date, there is limited evidence of strong gene–environment interactions, with environmental factors, molecular genetic risk, and family history simultaneously contributing to risk of SCZ. Still, there are several enduring challenges, some of which can likely be addressed with new tools, methods, and approaches for investigating gene–environment interplay. Consequently, advancements in this field will enhance our capacity to identify individuals most vulnerable to specific environmental exposures, which is pivotal for targeted prevention and intervention.
This report outlines the clinical features of a complex neurological phenotype shared by three siblings from a consanguineous family, characterized by intellectual disabilities, speech developmental delay, gait disturbance, cerebellar syndrome signs, cataracts, and dysmorphic features (square and coarse facial features, thick lips, deep palate, small and spaced teeth, low-set ears, strabismus, eyelid ptosis, and blond hair). Seizures and brain atrophy were later evident. In the cosegregation analysis, five family members and 12 family controls were studied by whole-exome and Sanger sequencing. The structural and functional effects of the protein were explored to define the mutated variant's potential deleterious impairment. Neurological and neuropsychological follow-ups and brain magnetic resonance imaging (MRI) were performed. We identified a single frameshift homozygous nucleotide deletion in the SPAG9/JIP4 gene (NM_001130528.3): c.2742del (p. Tyr914Ter), causing a premature stop codon and truncating the protein and originating a possible loss of function. The variant cosegregated in affected individuals as an autosomal recessive trait. The in silico protein functional analyses indicate a potential loss of 66 phosphorylation and 29 posttranslational modification sites. Additionally, a mutated protein structure model shows a significant modification of the folding that very likely will compromise functional interactions. SPAG9/JIP4 is a dynein-dynactin motor adapter for retrograde axonal transport, regulating the constitutive movement of neurotrophic factor signaling and autophagy-lysosomal products. Under stress conditions, it can potentiate this transport by the p38 mitogen-activated protein kinases (p38MAPK) signaling cascade. Both functions could be associated with the disease mechanism, altering the axon's development and growth, neuronal specification, dendrite formation, synaptogenesis, neuronal pruning, recycling neurotransmitters and finally, neuronal homeostasis—promising common mechanisms to be used with investigational molecules for neurodevelopmental diseases and neurodegeneration.
Short hairpin RNAs (shRNA), targeting knockdown of specific genes, hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. We designed an AAV9-shRNA targeting the downregulation of the 5-HT2A receptor, and recently demonstrated that intranasal delivery of this shRNA (referred to as COG-201), decreased anxiety and enhanced memory in mice and rats. In the current study, we provide additional in vivo data supporting a role of COG-201 in enhancing memory and functional in vitro data, whereby knockdown of the 5-HT2A receptor in primary mouse cortical neurons led to a significant decrease in mRNA expression (p = 0.0007), protein expression p-value = 0.0002, and in spontaneous electrical activity as measured by multielectrode array. In this regard, we observed a significant decrease in the number of spikes (p-value = 0.002), the mean firing rate (p-value = 0.002), the number of bursts (p-value = 0.015), and a decrease in the synchrony index (p-value = 0.005). The decrease in mRNA and protein expression, along with reduced spontaneous electrical activity in primary mouse cortical neurons, corroborate our in vivo findings and underscore the efficacy of COG-201 in decreasing HTR2A gene expression. This convergence of in vitro and in vivo evidence solidifies the potential of COG-201 as a targeted therapeutic strategy. The ability of COG-201 to decrease anxiety and enhance memory in animal models suggests that similar benefits might be achievable in humans. This could lead to the development of new treatments for conditions like generalized anxiety disorder, post-traumatic stress disorder (PTSD), and cognitive impairments associated with aging or neurodegenerative diseases.
Unipolar and bipolar depression [major depressive disorder (MDD) and bipolar disorder (BD)] are complex psychiatric disorders characterized by disturbances in mood, affect, and cognition. Increasing evidence has confirmed epigenetic malfunctioning at the core of these two mental conditions; however, the exact molecular nature of that epigenetic maladaptivity is less known. Lately, long noncoding RNAs (lncRNAs) have emerged as essential epigenetic regulators of gene expression and cellular processes, offering new avenues for exploring the pathophysiology of mood disorders. In this report, we present a comprehensive review of recent clinical studies investigating the involvement of lncRNA in MDD and BD, and emphasizing their disease-specific contribution as potential biomarkers. We explore the dysregulation of specific lncRNAs detected in peripheral blood samples of individuals with mood disorders, while underscoring their significance for clinical diagnosis, prognosis, and predicting treatment response. Additionally, we provide future directions for lncRNA research in the context of mood disorders.
Alternative polyadenylation (APA) is a pervasive regulatory mechanism in the human brain that controls the stability and cellular localization of mRNA transcripts. Single-nucleotide polymorphisms associated with psychiatric disorders may exert their deleterious effects by altering 3’ untranslated site usage, which may change the stability and processing of mRNA transcripts. The authors previously performed a 3’APA transcriptomic-wide association study using the DePars2 framework and the GTEx v8, PsychENCODE, and ROS/MAP datasets to identify APA-linked genes associated with eleven brain disorders. Here we focus on 3’APA-linked genes associated with the major psychiatric conditions: schizophrenia, bipolar disorder, and depression. There are 286 APA-linked genes associated with these psychiatric disorders, and 60%–65% of these genes have not been associated with the major psychiatric disorders through their expression and/or splicing. Protein–protein interaction networks indicate that APA-linked genes associated with schizophrenia are involved in intracellular transport and cellular localization pathways. Future research is needed to elucidate the role of alternative 3’ untranslated region usage of APA-linked genes on neuronal function and phenotypic expression in psychiatric disorders.
This conceptual review focuses on recent insights into the nature of the relationship between genetic predisposition and cognitive impairment as risk factors for schizophrenia, and the factors that influence the degree of cognitive impairment in those with the disorder. There is clear evidence that premorbid cognitive impairment is frequently present in those who develop schizophrenia, and, across the range of abilities, poorer premorbid cognition is associated with higher liability to the disorder. Evidence from genetic and population studies strongly supports the hypothesis that premorbid cognitive impairment is a marker for underlying neurodevelopmental risk factors for the disorder, rather than a prodromal manifestation. The premorbid cognitive deficit seems to be largely explained by non-familial factors rather than by familial factors that jointly influence liability to schizophrenia and cognitive ability, and these non-familial risk factors appear act to sensitize individuals to familial risk. There is also evidence that neurodevelopmental risk may be better indexed by the degree to which premorbid cognitive ability deviates from familial expectations than by cognitive ability per se. Premorbid cognitive impairment thus does not itself lie on the causal pathway to schizophrenia, rather it is a marker of a neurodevelopmental abnormality that is substantially non-familial, and which increases risk for schizophrenia. Genetic risk factors, including both common and rare alleles, that influence IQ in the general population also contribute both to liability for schizophrenia and to the degree of cognitive impairment in those with the disorder. There is also evidence for further decline in cognitive function after diagnosis in some individuals as well as an increased risk of dementia. This does not appear to reflect substantial shared heritability with neurodegenerative disorders, but the causes of postonset cognitive decline and its relationship to schizophrenia pathophysiology remain uncertain.
Pierre-Éric Lutz, a permanent researcher at France's CNRS (Centre National de la Recherche Scientifique) and Strasbourg's Institute of Cellular and Integrative Neuroscience, investigates epigenetic mechanisms underlying brain disorders such as addiction and depression. His lab employs genetic engineering in mice, high-throughput multiomics in mouse models and human cohorts, and bioinformatics. We are thrilled that in this Genomic Press Interview Dr Lutz shares insights into his life and career with our readers.
In this viewpoint, we explore the provocative argument by Hernán and Greenland, presented in JAMA, regarding the traditional necessity of stating hypotheses in grant applications. They propose that this convention may hinder the explorative nature of research, calling for a reevaluation that could impact global research practices and methodologies. Hypotheses provide a structured framework crucial for clarifying research questions and facilitating successful funding. However, Hernán and Greenland merge grant writing with research execution, potentially undervaluing the strategic role of hypotheses. We discuss the perspectives of philosophers Karl Popper and Thomas Kuhn, emphasizing the essential role of hypotheses in fostering scientific progress through critical scrutiny and paradigm shifts. While acknowledging the value in Hernán and Greenland's flexibility for data-driven research, we assert that hypotheses remain fundamental in guiding scientific inquiry, balancing innovation with traditional rigor. Our discussion aims to contribute to the evolution of research methodologies, ensuring they are both innovative and grounded in systematic, hypothesis-driven approaches.
On Valentine's Day 2024, The Los Angeles Times published a story entitled, “Inside the plan to diagnose Alzheimer's in people with no memory problems—and who stands to benefit” (1). The story focuses on the financial implications for drug companies and patient advocates. The National Institute on Aging's AHEAD3451 study (2) is a legitimate, federally funded, randomized clinical trial that is designed to the highest clinical research standards. This is a proven method for new drugs to be put to the most rigorous test using a placebo-controlled, double-blind, state-of-the-art design. The AHEAD345Introduction
Dr. C. Robert Cloninger's contributions have been foundational in understanding temperament, personality, and their biological and genetic underpinnings. Cloninger explored how temperament, character, and personality traits are influenced by genetic factors and how they predict various psychological disorders, such as alcoholism and personality disorders. His prospective studies involving adoptees reared apart from their biological parents provided crucial insights into the heritability and development of personality traits independent of environmental influences. Moreover, Cloninger's pioneering work in conducting the first genome-wide association and linkage studies of normal personality traits laid the groundwork for subsequent research in psychiatry and behavioral genetics, linking specific genetic profiles to patterns of temperament and personality. He is also the creator of two extensively employed personality assessment instruments: the Tridimensional Personality Questionnaire (TPQ) and the Temperament and Character Inventory (TCI). Dr. Cloninger serves as Director of the Anthropedia Institute and Professor Emeritus at Washington University in St. Louis, where he studies the biopsychosocial foundations of personality that influence health and illness. The Anthropedia Institute is the research branch of the Anthropedia Foundation, a non-profit organization dedicated to the promotion of human well-being through initiatives in health care and education. He served as Wallace Renard Professor of Psychiatry & Genetics, Professor of Psychological and Brain Sciences, and founding Director of the Sansone Center for Well-being at Washington University until July 2019. Dr. Cloninger is a member of the National Academy of Medicine USA, Fellow of the American Academy for Advancement of Science, and an editor of various journals in psychiatry, psychology, and genetics. We are pleased to share Dr. Cloninger's answers to the Genomic Press Interview.
Dr. Yogesh Dwivedi is the Elesabeth Ridgely Shook Endowed Chair and Professor in the Department of Psychiatry and Behavioral Neurobiology at the University of Alabama at Birmingham (UAB). He joined UAB in 2013 after working at the University of Illinois at Chicago for about 20 years, where he rose to tenured Professor. He is the Vice Chair for Faculty Affairs and Faculty Development, Co-Director of the UAB Depression and Suicide Center, Director of Translational Research of the UAB Mood Disorder Program, and the Director of the Alabama Brain Bank. He has published over 160 papers in peer-reviewed journals and serves on the editorial board of several scientific journals. He leads multiple National Institute of Mental Health-funded studies and has also edited a book entitled The Neurobiological Basis of Suicide. The recipient of several national and international awards, Dr. Dwivedi is a member of the Scientific Council of the American Foundation for Suicide Prevention and a Fellow of the American College of Neuropsychopharmacology (ACNP), International College of Neuropsychopharmacology (CINP), and International Neuropsychiatric Association. His research broadly elucidates the molecular and cellular mechanisms associated with early-life stress, mood disorders, and suicidal behavior by integrating basic and clinical neuroscience. More specifically, his studies focus on gene regulation through epigenetic, epitranscriptomic, and non-coding RNAs and whether these mechanisms play a role in mood regulation and suicidal behavior. He is also working on translating these findings into biomarkers for depression, suicidality, and treatment response. Dr. Yogesh Dwivedi kindly agreed to engage in the Genomic Press Interview, sharing his distinctive blend of personal and professional narratives.
Dr. Yoshikawa currently serves as the Administrative Director of the RIKEN Center for Brain Science in Japan. His journey with the institution began in 1999 when he assumed the Principal Investigator (Team Leader) role and established the Laboratory of Molecular Psychiatry. Before this, he gained experience at various esteemed institutes, including the Department of Psychiatry at Tokyo Medical and Dental University, the National Institute of Physiology in Japan, and the National Institute of Mental Health (NIMH) in the USA. For 22 years, Dr Yoshikawa dedicated himself to unraveling the molecular intricacies of psychiatric diseases within his laboratory. Transitioning to his current position, he now lends his expertise to the operational endeavors of the Center. Beyond his administrative responsibilities, Dr. Yoshikawa actively engages with the academic communities, serving as a grant reviewer, scientific advisor, and editorial board member for scientific journals. Remarkably, he maintains his clinical practice, caring for patients as a psychiatrist. Dr Yoshikawa graciously participated in the Genomic Press interview, sharing insights into his life and career and providing valuable reflections for our readers.
The difficulty in classifying a rare genetic variant as “likely pathogenic,” “likely benign,” or VUS (variant of unknown significance) represents a significant challenge in genetic counseling (GC) when trying to establish a diagnosis or as a result of incidental findings. This classification may impact the communication of prognosis in late-onset conditions, such as neuromuscular disorders, and the consultants’ reproductive decisions regarding future offspring. Here, we report two unrelated families, one Brazilian and one of East Asian ancestry, where a rare and previously unreported deletion in the dystrophin gene was identified. In these two families, the analysis of older male relatives (from 56 to 89 years old) who were fully asymptomatic provided relevant information to their families about the potential pathogenicity of this dystrophin variant. These cases support our previous suggestion highlighting the relevance of genome sequencing of older healthy individuals or family members, above the age of 50 and going into the 80's ad 90's, and the importance of sharing new relevant information for decision-making with families who previously underwent genetic counseling. In addition, these case reports contribute to the classification of VUS, enhancing our knowledge of the impact of specific mutations in functional studies.
Mayana Zatz has been a Professor of Genetics at the Institute of Biosciences, University of São Paulo (USP), Brazil, since 1982. She became an assistant professor after a postdoc at the University of São Paulo and a second postdoc at the University of California, Los Angeles. Her current research is focused on neuromuscular disorders, aging, genomics, and, more recently, xenotransplantation and the use of the Zika virus as an oncolytic therapy against brain tumors. Functional studies are done in genetically engineered mouse and cell models. She is particularly interested in investigating protective mechanisms in rare patients with Duchenne dystrophy and a milder clinical course, as well as in centenarians' health determinants. Mayana Zatz is also involved in ethical aspects of genomic studies and government political decisions related to science. Professor Zatz is pleased to offer our readers insights into her personal and professional experiences.
Professor Noboru Hiroi is a faculty member in the Departments of Pharmacology, Cellular and Integrative Physiology, and Cell Systems & Anatomy at the University of Texas Health Science Center at San Antonio (UT Health San Antonio), USA. He joined his current institution in 2019 after working at Albert Einstein College of Medicine in New York for 21 years. His current work is focused on the cellular and developmental origins of the dimensions of neuropsychiatric disorders in genetically engineered mouse and cell models. Professor Hiroi is happy to provide our readers with reflections on his life and career.
After finishing his postdoc at NYU in the Physiology Department under the direction of Rodolfo Llinas, Dr. Grace started as an Assistant Professor of Psychology and Psychiatry at the University of Pittsburgh in the fall of 1985. He was promoted early in the fall of 1991 to Associate Professor of Behavioral Neuroscience and Psychiatry and to Professor of Neuroscience and Psychiatry in July 2003. In September 2010, he was again promoted to Distinguished Professor of Neuroscience and Professor of Psychiatry and Psychology, his current position. He is the Editor-in-Chief of the International Journal of Neuropsychopharmacology, the journal of the Collegium Internationale Neuropsychopharmacologicum (CINP, International College of Neuropsychopharmacology). Dr. Grace has offered insights into his personal and professional journey.
Gustavo Turecki MD PhD FRSC is a clinician scientist whose work focuses on understanding brain molecular changes that occur in major depressive disorder and suicide, as well as molecular processes that explain antidepressant treatment response. Dr. Turecki is Full Professor and Chair of the Department of Psychiatry at McGill University, the Scientific Director and Psychiatrist-in-Chief of the Douglas Institute in Montreal, Canada, where he also heads the Depressive Disorders Program. He has authored over 600 publications, including research articles in leading peer-reviewed journals such as Nature Neuroscience, Nature Medicine, and The Lancet and is among the world's most highly cited scientists according to Clarivate, Web of Science. He has received several national and international awards and sits on several advisory boards. Dr. Turecki graciously offers our audience a glimpse into his personal and professional journey.
We are delighted to introduce Genomic Psychiatry, a new and groundbreaking medical research journal that aims to revolutionize the field of mental health. Unlike traditional genetics journals, Genomic Psychiatry will bridge the gap between genes and the vast array of interconnected disciplines that contribute to our understanding of mental health, advancing science from genes to society. In recent years, the field of genomics has made significant strides in unraveling the genetic basis of psychiatric disorders. Yet, our editorial conviction is that far more monumental advances will emerge from a nuanced examination of the unbroken spectrumIntroduction
Dr. Maria Oquendo is Ruth Meltzer Professor and Chairman of Psychiatry at University of Pennsylvania and Psychiatrist-in-Chief at the Hospital of the University of Pennsylvania. A summa cum laude graduate of Tufts University, she attended College of Physicians and Surgeons, Columbia University and completed residency at Payne Whitney Clinic, New York Hospital, Cornell. She is a member of the National Academy of Medicine, one of the highest honors in medicine. Dr. Oquendo has used Positron Emission Tomography and Magnetic Resonance Imaging to map brain abnormalities in mood disorders and suicidal behavior. Her expertise ranges from psychopharmacology to Global Mental Health. She has over 500 peer-reviewed publications, an H-index 116 and 49,472 citations (Google Scholar). In terms of organizational leadership positions, Dr. Oquendo is Past President of the American Psychiatric Association (APA), the International Academy of Suicide Research, the American College of Neuropsychopharmacology (ACNP), and the American Foundation for Suicide Prevention's Board of Directors. She is Vice President of the College of International Neuropsychopharmacology and has served on the National Institute of Mental Health's Advisory Council. Dr. Oquendo serves on Tufts University's Board of Trustees, serves on its Executive Committee and chairs Tufts’ Academic Affairs Committee. A recipient of multiple awards in the United States, Europe, and South America, most recently, she was honored with the Symonds Award (APA 2017), the APA's Research Award (2018), the Shockley Award (ACNP 2018), and the Glassman Award (Columbia University 2021). Dr. Oquendo has shared some of her thoughts and perspectives on her life and career.
