Roel A. Ophoff

Genome-wide association studies (GWASs) have uncovered susceptibility loci associated with psychiatric disorders such as bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome, and the causal mechanisms of the link between genetic variation and disease risk is unknown. Expression quantitative trait locus (eQTL) analysis of bulk tissue is a common approach used for deciphering underlying mechanisms, although this can obscure cell-type-specific signals and thus mask trait-relevant mechanisms. Although single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell-type proportions and cell-type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-seq from 1,730 samples derived from whole blood in a cohort ascertained from individuals …

Conclusions: These findings advance our understanding of the acute effects of ketamine administration on neural activation, which may inform future investigations of its cognitive effects and development of clinical applications. Future research should continue to explore the complex neural effects and mechanisms of action of ketamine at multiple levels and time scales and in diverse samples of healthy and clinical groups.

BackgroundCarriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.MethodsMagnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference.ResultsFor the 1q21.1 distal deletion carriers, cortical …

BackgroundThe study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex.ResultsWe found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific …

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

BackgroundTwo established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging.MethodsIn total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of …

Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD, supporting the hypothesis that Controls — MDD — BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD …

Background: Although hand surgery is generally safe and effective, some patients experience complications or poor outcomes prompting them to seek compensation. This study reviews malpractice claims in hand surgery using a national data set to assess reasons for litigation and identify predictors of outcome.Methods: The Westlaw database was queried for cases related to hand surgery and medical malpractice between 1989 and 2018. Jury verdicts and settlements were reviewed for relevance, and variables including plaintiff and defendant demographics, diagnosis, alleged reason for malpractice, verdicts, and payouts were recorded.Results: Four hundred thirty relevant claims were identified. Distal radius fractures (21 percent), carpal tunnel syndrome (14 percent), and tendon lacerations (6 percent) were the most common diagnoses. Alleged reasons for malpractice included failure to diagnose/treat (34 percent), surgical negligence (29 percent), and improper procedure/treatment (19 percent). Thirtysix cases (8 percent) resolved in settlement for a mean payout of $551,957. A plaintiff verdict was reached in 98 cases (25 percent of trials), with a mean payout of $832,258. The remaining 296 cases (75 percent of trials) resulted in defendant verdicts (no payout). Plaintiff age, plaintiff sex, defendant sex, and defendant degree had no impact on trial outcome. Cases involving surgeons without subspecialty certification in hand surgery were significantly more likely to result in plaintiff verdicts (27 percent versus 7 percent with hand subspecialization; p= 0.003).Conclusions: This study reviews malpractice claims in hand surgery over the past 30 …

Background:Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin.Methods:The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds …

Bipolar disorder (BD) is a heritable disorder characterized by shifts in mood that manifest in manic or depressive episodes. Clinical studies have identified abnormalities of the circadian system in BD patients as a hallmark of underlying pathophysiology. Fibroblast cells collected from BD patients show temporal differences in the expression of core circadian genes. We set out to examine the underlying genetic architecture of circadian rhythm in an in vitro fibroblast model, in order to disentangle the polygenic nature of BD disease risk. We collected, from primary cell lines of 6 healthy individuals, temporal genomic features over a 48 hour period from transcriptomic data (RNA-seq) and open chromatin data (ATAC-seq). The RNA-seq data showed that only a limited number of genes, such as ARNTL, CRY1, PER3, NR1D2 and TEF display circadian patterns of expression consistently across cell cultures. The ATAC-seq data identified that distinct transcription factor families, like those with the basic helix-loop-helix motif, were associated with regions that were increasing in accessibility over time. Further evaluation of these regions using stratified linkage disequilibrium score regression (sLDSC) analysis failed to identify a significant presence of them in the known genetic architecture of BD, and other psychiatric disorders or neurobehavioral traits in which the circadian rhythm is affected. This study characterizes the biological pathways that are activated in this in vitro circadian model, evaluating the relevance of these processes in the context of the genetic architecture of BD and other disorders, highlighting its limitations and future applications for …

Expansion of a CGG repeat in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome is the cause of Fragile X Syndrome (FXS). The repeat length of unaffected individuals varies between 5–40 repeats, whereas >200 repeats are observed in cases of FXS. The intermediate range between 55–200 repeats is considered the premutation range and is observed in roughly 1:300 females and 1:900 males in the general population. With the availability of large-scale whole genome sequence (WGS) data and the development of computational tools to detect repeat expansions, we systematically examined the role of FMR1 premutation alleles in autism spectrum disorder (ASD) susceptibility, assess the prevalence, and consider the allelic stability between parents and offspring. We analyzed the WGS data of 22,053 subjects, including 32 FXS positive controls, 1359 population controls, and 5467 ASD families. We observed no FMR1 full mutation range repeats among the ASD parent-offspring families but identified 180 family members with premutation range alleles, which represents a higher prevalence compared to the independent WGS control sample and previous reports in the literature. A sex-specific analysis between probands and unaffected siblings did not reveal a significant increase in the burden of premutation alleles in either males or females with ASD. PCR validation, however, suggests an overestimation of the frequency of FMR1 premutation range alleles through computational analysis of WGS data. Overall, we show the utility of large-scale repeat expansion screening in WGS data and conclude that there is no …

BackgroundTourette syndrome (TS) is an early-onset neurodevelopmental disorder (NDD) characterized by vocal and motor tics. TS is highly heritable (60-80%) and has a complex genetic architecture with both rare and common variants contributing to the genetic etiology. However, the contribution of de novo variants has not been widely studied due to the lack of large-scale high-quality family-structured sequencing datasets and insufficient statistical power.MethodsIn this study, we generated whole-exome sequencing (WES) data for over 1,300 TS trio families and jointly called the data with a selected subset of over 6,600 families from SSC and SPARK datasets containing at least one Autism Spectrum Disorder (ASD) proband. This produced a high-quality unified dataset with 30,803 individuals and 4,425,974 variants.ResultsOur principal component analysis showed a diverse ancestry background with all major …

AlzheimerLs disease (AD) is a complex genetic neurodegenerative disorder and the most common cause of dementia worldwide. AD is biologically defined by the presence of extracellular amyloid-b (Ab) plaques and intracellular neurofibrillary tau tangles in the brain (1), which can be detected even in early clinical stages of the disease. AD starts in the asymptomatic stage, where pathophysiological changes are present but individuals are cognitively unimpaired (preclinical), followed by mild cognitive impairment (prodromal) and AD-type dementia as pathophysiological processes in the brain progress. Around 50% of patients in the prodromal stage of AD develop dementia within 4 years, but studies have observed large differences in disease course among patients (2, 3). Heterogeneity in the course of disease and uncertainty in prognosis pose great challenges to clinicians, patients, caregivers, and trialists …

BackgroundSub-anesthetic ketamine prompts rapid and robust antidepressant response in 60-70% of patients with treatment resistant depression (TRD), however the underlying mechanism driving this response remains unclear. Studying changes in whole blood gene expression related to antidepressant response has the potential to provide new mechanistic insight into the therapeutic effects of ketamine. Only one prior study has investigated peripheral gene expression in ketamine treatment and found genes involved in glutamate signaling were enriched in treatment responders when compared to non-responders prior to one single ketamine infusion (Cathomas et al. 2022). In the current study, we perform an exploratory investigation of changes in transcriptional profiles pre and post serial ketamine treatment.MethodsPatients with TRD (N=54, 27M/27W, age=39.7土10.8) received four intravenous infusions of …

Bipolar disorder (BD) is a heritable disorder characterized by shifts in mood that manifest in manic or depressive episodes. Clinical studies have identified abnormalities of the circadian system in BD patients as a hallmark of underlying pathophysiology. Fibroblast cells collected from BD patients show temporal differences in the expression of core circadian genes. We set out to examine the underlying genetic architecture of circadian rhythm in an in vitro fibroblast model, in order to disentangle the polygenic nature of BD disease risk. We collected, from primary cell lines of 6 healthy individuals, temporal genomic features over a 48 hour period from transcriptomic data (RNA-seq) and open chromatin data (ATAC-seq). The RNA-seq data showed that only a limited number of genes, such as ARNTL, CRY1, PER3, NR1D2 and TEF display circadian patterns of expression consistently across cell cultures. The ATAC-seq data identified that distinct transcription factor families, like those with the basic helix-loop-helix motif, were associated with regions that were increasing in accessibility over time. Further evaluation of these regions using stratified linkage disequilibrium score regression (sLDSC) analysis failed to identify a significant presence of them in the known genetic architecture of BD, and other psychiatric disorders or neurobehavioral traits in which the circadian rhythm is affected. This study characterizes the biological pathways that are activated in this in vitro circadian model, evaluating the relevance of these processes in the context of the genetic architecture of BD and other disorders, highlighting its limitations and future applications for …

BackgroundThe use of functional phenotypes within genome-wide association contexts has provided mechanistic insights into complex disease architectures, though these insights lag behind particularly for neuropsychiatric diseases. In this study, we use metabolomics to measure the levels of 5,543 CSF metabolite levels, both targeted and untargeted, in 977 Dutch individuals with cerebrospinal fluid (CSF) and genetic data. Individuals originated from two separate cohorts including the Utrecht cohort (n=490 cognitively healthy subjects) and the Amsterdam Dementia Cohort (n=487 subjects from a well-characterized memory clinic cohort).MethodsWe performed genome-wide metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics. We also imputed the CSF levels of the significant metabolites into the GWAS of various brain-related diseases, including bipolar disorder and Alzheimer's disease …

ObjectiveSuicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.MethodsThis study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression …

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar …

BackgroundCopy-number variants (CNVs) are structural mutations in the genome resulting from deletions or duplications of large segments of DNA and can affect a wide range of functional units, from parts of a gene to numerous genes in their entirety. Like SNPs, CNVs certain CNVs have been associated with susceptibility to neuropsychiatric diseases, including schizophrenia, autism, and Tourette syndrome (TS). There are several means of detecting CNVs. However, the most common high-throughput genome-wide approach is the utilization of Hidden Markov Models (HMM) to analyze intensity measurements from genotyping arrays to identify clusters of relatively stronger or weaker signals corresponding to duplications or deletions, respectively. Like with GWASes, the power of CNV analyses (CNVAs) is dependent on the sample sizes, given the small effect sizes of individual CNVs. Unlike GWASes, CNVAs …

BackgroundObesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.MethodsWe obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.ResultsBMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric …