David C Glahn

David C Glahn
Yale University | YU · Department of Psychiatry

PhD

About

538
Publications
92,762
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35,113
Citations
Additional affiliations
July 2008 - present
Yale University
Position
  • Professor

Publications

Publications (538)
Article
Full-text available
Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,7...
Article
Application of machine learning (ML) algorithms to structural magnetic resonance imaging (sMRI) data has yielded behaviorally meaningful estimates of the biological age of the brain (brain‐age). The choice of the ML approach in estimating brain‐age in youth is important because age‐related brain changes in this age‐group are dynamic. However, the c...
Article
Importance: Rare genetic disorders modulating gene expression-as exemplified by gene dosage disorders (GDDs)-represent a collectively common set of high-risk factors for neuropsychiatric illness. Research on GDDs is rapidly expanding because these variants have high effect sizes and a known genetic basis. Moreover, the prevalence of recurrent GDDs...
Article
Full-text available
Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761...
Article
Background Polygenic risk scores (PRSs) are indices of genetic liability for illness, but their clinical utility for predicting risk for a specific psychiatric disorder is limited. Genetic overlap among disorders and their effects on allied phenotypes may be a possible explanation, but this has been difficult to quantify given focus on singular dis...
Preprint
Mechanisms underpinning neurotypical age-related variations in cortical thickness in the human brain remain insufficiently specified. Here we used cell-specific marker genes, followed by gene ontology and enrichment analyses, to quantify the association between gene-expression levels and inter-regional age-related variations in neurotypical cortica...
Article
Full-text available
Bipolar disorder is an often-severe mental health condition characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 common variant risk loci of small effect, pathophysiological mechanisms remain unknown. Here, we analyzed genome sequences from 41 multiply-affe...
Article
Importance: Psychiatric and cognitive phenotypes have been associated with a range of specific, rare copy number variants (CNVs). Moreover, IQ is strongly associated with CNV risk scores that model the predicted risk of CNVs across the genome. But the utility of CNV risk scores for psychiatric phenotypes has been sparsely examined. Objective: To d...
Article
Full-text available
Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight ¹ . Here we assemble an...
Article
Full-text available
Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 ×...
Preprint
Mechanisms underpinning age-related variations in cortical thickness in the human brain remain poorly understood. We investigated whether inter-regional age-related variations in cortical thinning (in a multicohort neuroimaging dataset from the ENIGMA Lifespan Working Group totalling 14,248 individuals, aged 4-89 years) depended on cell-specific ma...
Article
Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the...
Preprint
Background Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. Methods We sought to discover risk variants with larger effects by conducting a genome-wide association s...
Article
Full-text available
Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual level when phenotypes are not necessarily already known. We investigated the stability o...
Article
Full-text available
The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has...
Article
The direct effect of genetic variations on clinical phenotypes within schizophrenia (SZ) remains elusive. We examined the previously identified association of reduced gray matter concentration in the insula - medial prefrontal cortex and a quantitative trait locus located in 12q24 in a SZ dataset. The main analysis was performed on 1461 SNPs and 83...
Article
Mitochondria are the main energy source for normal neuronal functions. Mitochondrial DNA (mtDNA) copy number (CN), a measure of mtDNA levels in the cell, correlates with cellular energy generating capacity and metabolic status. Previous studies have observed a significant decrease of circulating cell‐free mtDNA content in the cerebrospinal fluid of...
Conference Paper
Neuropsychiatric disorders involve complex polygenic determinants as well as brain alterations. The combination of genetic inheritance and neuroimaging approaches could advance our understanding of psychiatric disorders. However, cross-disorder overlap is a current issue since psychiatric conditions share some neurogenetic correlates, symptoms, and...
Article
Full-text available
Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape diff...
Article
Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOP...
Article
Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymph...
Article
Full-text available
Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, compr...
Article
An opportunity has opened for research into primary prevention of psychotic disorders, based on progress in endophenotypes, genetics, and genomics. Primary prevention requires reliable prediction of susceptibility before any symptoms are present. We studied a battery of measures where published data supports abnormalities of these measurements prio...
Preprint
Full-text available
Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual patient level when phenotypes are not necessarily already known. Hence, we investigated...
Preprint
Full-text available
Over the past 25 years, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, there are no reference standards against which to anchor measures of individual differences in brain morphology, in contrast to growth charts for traits such as height and weight. Here, we built an interactive online...
Preprint
Full-text available
Bipolar disorder is an often-severe mental health disorder characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 loci of small effect, pathophysiological mechanisms and much of the genetic risk remain unknown. Here, through genome sequencing and linkage and...
Preprint
Full-text available
Polygenicity and pleiotropy are key properties of the genomic architecture of psychiatric disorders. An optimistic interpretation of polygenicity is that genomic variants converge on a limited set of mechanisms at some level from genes to behavior. Alternatively, convergence may be minimal or absent. We took advantage of brain connectivity, measure...
Preprint
Full-text available
Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls. Although these alterations affect multiple and widespread cortical regional asymmetries, the extent to which specific structural networks might be affec...
Article
Full-text available
Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently present...
Article
Full-text available
Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorde...
Article
Background The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease is of fundamental importance given its global health and economic burden. Inhibition of ANGPTL3 (angiopoietin-like 3) has demonstrated a cardioprotective effect, showing promise for atherosclerotic cardiovascular disease treatment, and...
Article
Full-text available
The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Hum Brain Mapp 40(12):3575-3588, 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post hoc analys...
Article
Full-text available
Background Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation. Methods Using data from 9,421 individuals aged 8–21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psych...
Article
Full-text available
We present an exploratory cross-sectional analysis of the effect of season and weather on Freesurfer-derived brain volumes from a sample of 3,279 healthy individuals collected on two MRI scanners in Hartford, CT, USA over a 15 year period. Weather and seasonal effects were analyzed using a single linear regression model with age, sex, motion, scan...
Article
Full-text available
Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods: We analyzed...
Article
Full-text available
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain st...
Article
Background Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measur...
Article
Full-text available
The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has...
Article
Full-text available
Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,07...
Article
Full-text available
Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,07...
Article
Full-text available
Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resource...
Article
Full-text available
Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resource...
Article
Full-text available
Successful cognitive development between childhood and adulthood has important consequences for future mental and physical wellbeing, as well as occupational and financial success. Therefore, delineating the genetic influences underlying changes in cognitive abilities during this developmental period will provide important insights into the biologi...
Preprint
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain str...
Preprint
The Enhancing Neuroimaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has...
Article
Full-text available
Although previous studies have highlighted associations of cannabis use with cognition and brain morphometry, critical questions remain with regard to the association between cannabis use and brain structural and functional connectivity. In a cross‐sectional community sample of 205 African Americans (age 18–70) we tested for associations of cannabi...
Article
Full-text available
Bipolar disorder and schizophrenia are associated with brain morphometry alterations. This study investigates inter-individual variability in brain structural profiles, both within diagnostic groups and between patients and healthy individuals. Brain morphometric measures from three independent samples of patients with schizophrenia ( n = 168), bip...
Article
Background Progress in precision psychiatry is predicated on identifying reliable individual-level diagnostic biomarkers. For psychosis, measures of structural and functional connectivity could be promising biomarkers given consistent reports of dysconnectivity across psychotic disorders using magnetic resonance imaging. Methods We leverage data f...
Article
Full-text available
Visual processing abnormalities in schizophrenia (SZ) are poorly understood, yet predict functional outcomes in the disorder. Bipolar disorder (BD) may involve similar visual processing deficits. Converging evidence suggests that visual processing may be relatively normal at early stages of visual processing such as early visual cortex (EVC) but th...
Article
Full-text available
For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international da...
Article
Full-text available
First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to co...
Article
Full-text available
First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to co...
Article
Full-text available
miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA-mRNA regulatory interactions in human nervous system development, well characte...
Preprint
Full-text available
By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P < 2.14 x 10^-6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular...
Article
Full-text available
Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be rel...
Article
Objective: Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, levels of autism risk conferred by most rare CNVs remain unknown. The authors recently developed statistical models to estimate the effect size on IQ of all CNVs, including undocumented ones. In this study, the authors extended this...
Article
Full-text available
Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal app...
Article
Importance Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. Objective To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: atten...
Article
Full-text available
MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder...
Article
Full-text available
Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns simila...
Article
Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto-cerebellar and meso-cortico-limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions , and until recently there has been few large-scale investigations to compare such fi...