Biology subjects

Ripke, S.

Publications and source records attributed to Ripke, S..

16 recordsLinked to original sources

bioRxiv2026

Estrogen receptor alpha regulates alcohol craving in females: convergent evidence from mouse models and human genetics

Alcohol craving and consumption fluctuate across the reproductive cycle in females with alcohol use disorder (AUD), suggesting that estrogen signaling contributes to disease vulnerability. Here, we investigated the role of estrogen receptor alpha (ER; Esr1; ESR1) in alcohol seeking using complementary mouse and human approaches, as this receptor was previously identified as a risk factor for AUD. Female mice were characterized in an IntelliCage-based multidimensional AUD paradigm that stratifies individuals into AUD-prone and AUD-resistant phenotypes. Transcriptomic profiling of the amygdala revealed that Esr1 is a top transcription factor for differentially expressed genes in mice drinking alcohol, and the estrogen signaling pathway was deregulated specifically in AUD-prone mice. Although alcohol exposure did not alter overall Esr1/ER mRNA or protein abundance, both transcript and protein levels positively correlated with cue-induced alcohol seeking, indicating that inter-individual variation in ER signaling predicts relapse-like behavior. Causal manipulations confirmed a functional role of ER. Local knockdown of Esr1 in the basolateral amygdala reduced excitatory synaptic transmission, attenuated alcohol motivation, cue-induced seeking, and relapse drinking, and impaired cue-associated memory recall without affecting anxiety-like behavior. Similarly, ovariectomy decreased amygdala ER expression, altered synaptic protein markers, and reduced alcohol-seeking behaviors, supporting regulation by endogenous ovarian hormones. Extending these findings to humans, ESR1 gene polymorphisms (rs6902771, rs11155819 and rs6557171) were associated with the probability of alcohol binge drinking and alcohol consumption days as well as craving and loss of control in real world in a longitudinal clinical cohort, while ESR1 mRNA blood levels were increased in women with AUD diagnosis. Together, these convergent molecular, circuit, behavioral, and genetic data identify ER signaling in the amygdala as an important modulator of alcohol-seeking behavior induced by alcohol cue and relapse vulnerability, highlighting estrogen pathways as potential therapeutic targets and markers for AUD.

neuroscience↗

bioRxiv2023

Gene Set-Based Analysis of the Endosomal Sorting Processes Cargo Selection and Membrane Tubulation with Human Reward System Reactivity

Dysfunction of the dopaminergic reward system has been implicated in the pathophysiology of several neuropsychiatric disorders. The endosomal network encompasses important processes related to neurotransmission in dopamine neurons, e.g, endocytosis, sorting, recycling and degradation of receptors. In the present study, we investigated whether genetic variation influencing the endosomal sorting machinery, in particular cargo selection and membrane tubulation, may impact on the activation strength in key regions of the mesolimbic reward system, i.e. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). To test our hypothesis, the VTA and NAc responses to conditioned reward stimuli were investigated using the desire-reason dilemma (DRD) paradigm during functional magnetic resonance imaging (fMRI). Association of these neural responses with a set of genetic variants related to endosomal sorting processes were tested in two independent samples (N = 182; N = 214). In the first sample, the gene set was associated with both VTA and NAc responses to conditioned reward stimuli [empirical P -values: R-VTA 0.0036; R-NAc 0.0016; L-NAc 0.0094], while the effect in the R-VTA could be replicated in the second sample [empirical P -value: R-VTA 0.0443] at the level of the gene set. For the NAc, an additional exploratory analysis of a patient-only subsample of the first sample (N = 64) suggested that the gene set may express its effect in this brain region predominantly in patients. These findings provide first evidence that the endosomal sorting processes cargo selection and membrane tubulation influence neural responses of the reward system to conditioned stimuli. Further studies are required to clarify the role of endosomal sorting processes in the pathophysiology of neuropsychiatric disorders.

genetics↗

bioRxiv2022

DNAJC13 influences responses of the extended reward system to conditioned stimuli: a genome-wide association study

Reward system dysfunction is implicated in the pathogenesis of major psychiatric disorders. We conducted a genome-wide association study (GWAS) to identify genes that influence activation strength of brain regions within the extended reward system in humans. A large homogeneous sample of 214 participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All subjects performed the desire-reason dilemma (DRD) paradigm allowing systematic investigation of systems-level mechanisms of reward processing in humans. As a main finding, we identified the single nucleotide variant rs113408797 in the DnaJ Heat Shock Protein Family Member C13 gene (DNAJC13, alias RME-8), that strongly influenced the activation of the ventral tegmental area (VTA; p = 2.50E-07) and the nucleus accumbens (NAcc; p = 5.31E-05) in response to conditioned reward stimuli. Moreover, haplotype analysis assessing the information across the entire DNAJC13 locus demonstrated an impact of a five-marker haplotype on VTA activation (p = 3.21E-07), which further corroborates a link between this gene and reward processing. The present findings provide first direct empirical evidence that genetic variation of DNAJC13 influences neural responses within the extended reward system to conditioned stimuli. Further studies are required to investigate the role of this gene in the pathogenesis and pathophysiology of neuropsychiatric disorders.

genomics↗

bioRxiv2019

Shared Genetic Risk between Eating Disorder- and Substance-Use-Related Phenotypes: Evidence from Genome-Wide Association Studies

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; q<0.0001), and cannabis initiation and AN with binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to -0.23; qs<0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for MDD loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors.

genetics↗

bioRxiv2019

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression.

IntroductionIts imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression.\n\nMethodsPolygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank.\n\nResultsAll cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression.\n\nConclusionsThe phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.

genetics↗

bioRxiv2019

RICOPILI: Rapid Imputation for COnsortias PIpeLIne

MotivationGenome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open sourced Perl-based pipeline was developed to address the challenges of rapidly processing large scale multi-cohort GWAS studies including quality control, imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing (HPC) environments.\n\nSummaryRICOPILI was created as the Psychiatric Genomics Consortium (PGC) pipeline for GWAS and has been adopted by other users. The pipeline features i) technical and genomic quality control in case-control and trio cohorts ii) genome-wide phasing and imputation iv) association analysis v) meta-analysis vi) polygenic risk scoring and vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all of the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work.\n\nAvailability and ImplementationRICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home\n\nContactsripke@broadinstitute.org\n\nSupplementary informationSupplementary data are available.

genetics↗

bioRxiv2019

Genomewide Analyses of Psychological Resilience in US Army Soldiers

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genomewide association studies (GWAS) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from pre- to post-deployment) resilience among European (EUR) ancestry soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). Self-assessed resilience (N=11,492) was found to have significant common-variant heritability (h2=0.162, se=0.050, p=5.37e-4), and to be significantly negatively genetically correlated with neuroticism (rg= -0.388, p=0.0092). GWAS results from the EUR soldiers revealed a genomewide significant locus (4 SNPs in LD; top SNP: rs4260523, p=5.654e-09) on an intergenic region on Chr 4 upstream from DCLK2 (Doublecortin-Like Kinase 2), a member of the doublecortin (DCX) family of kinases that promote survival and regeneration of injured neurons. A second gene, KLHL36 (Kelch Like Family Member 36) was detected at gene-wise genomewide significance (p=1.89e-06). A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genomewide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015) on Chr 12 downstream from SLC15A5 (solute carrier family 15 member 5) in the small group (N=581) of subjects exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and potentially point to new avenues for therapeutic intervention.

genetics↗

bioRxiv2018

Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals

Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

genetics↗

bioRxiv2018

Genome-wide association study of suicide attempt in psychiatric disorders identifies association with major depression polygenic risk scores

ObjectiveOver 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium.\n\nMethodSamples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders.\n\nResultsThree genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006).\n\nConclusionsThis study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.

genetics↗

bioRxiv2017

Common risk variants identified in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.

genetics↗

bioRxiv2017

Genomewide association study identifies 30 loci associated with bipolar disorder

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P<1x10-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

genetics↗

bioRxiv2017

Genome-wide Association Study of Clinical Features in the Schizophrenia Psychiatric Genomics Consortium: Confirmation of Polygenic Effect on Negative Symptoms

Schizophrenia is a clinically heterogeneous disorder. Proposed revisions in DSM - 5 included dimensional measurement of different symptom domains. We sought to identify common genetic variants influencing these dimensions, and confirm a previous association between polygenic risk of schizophrenia and the severity of negative symptoms. The Psychiatric Genomics Consortium study of schizophrenia comprised 8,432 cases of European ancestry with available clinical phenotype data. Symptoms averaged over the course of illness were assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID, and CASH. Factor analyses of each constituent PGC study identified positive, negative, manic, and depressive symptom dimensions. We examined the relationship between the resultant symptom dimensions and aggregate polygenic risk scores indexing risk of schizophrenia. We performed genome - wide association study (GWAS) of each quantitative traits using linear regression and adjusting for significant effects of sex and ancestry. The negative symptom factor was significantly associated with polygene risk scores for schizophrenia, confirming a previous, suggestive finding by our group in a smaller sample, though explaining only a small fraction of the variance. In subsequent GWAS, we observed the strongest evidence of association for the positive and negative symptom factors, with SNPs in RFX8 on 2q11.2 (P = 6.27x10-8) and upstream of WDR72 / UNC13C on 15q21.3 (P = 7.59x10-8), respectively. We report evidence of association of novel modifier loci for schizophrenia, though no single locus attained established genome - wide significance criteria. As this may have been due to insufficient statistical power, follow - up in additional samples is warranted. Importantly, we replicated our previous finding that polygenic risk explains at least some of the variance in negative symptoms, a core illness dimension.

genetics↗

bioRxiv2017

Discovery Of The First Genome-Wide Significant Risk Loci For ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of school-age children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no individual variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes, as well as around brain-expressed regulatory marks. These findings, based on clinical interviews and/or medical records are supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population. Meta-analyzing these data with our primary scan yielded a total of 16 genome-wide significant loci. The results support the hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits.

genetics↗

bioRxiv2017

Genetics of educational attainment aid in identifying biological subcategories of schizophrenia

Higher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigated possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1,169 controls; 1,067 cases) with deeply phenotyped SZ patients. We found strong genetic dependence between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, several genes seem to have pleiotropic effects on EA and SZ, but without a clear pattern of sign concordance. Genetic heterogeneity of SZ contributes to this finding. We demonstrate this by showing that the polygenic prediction of clinical SZ symptoms can be improved by taking the sign concordance of loci for EA and SZ into account. Furthermore, using EA as a proxy phenotype, we isolate FOXO6 and SLITRK1 as novel candidate genes for SZ.

genetics↗

bioRxiv2016

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability [Formula] of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

genomics↗

bioRxiv2016

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by both common polygenic and de novo variation. The purpose of this analysis was to clarify the influence of common polygenic risk for ASDs and to identify subgroups of cases, including those with strong acting de novo variants, in which different types of polygenic risk are relevant. To do so, we extend the transmission disequilibrium approach to encompass polygenic risk scores, and introduce the polygenic transmission disequilibrium test. Using data from more than 6,400 children with ASDs and 15,000 of their family members, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs in two independent samples, but not to their unaffected siblings. These findings hold independent of proband IQ. We find that common polygenic variation contributes additively to risk in ASD cases that carry a very strong acting de novo variant. Lastly, we find evide ...

genetics↗