Translating genome-wide association findings into new therapeutics for psychiatry.
paper
Cited
Public
- Authors
- Breen, Gerome; Li, Qingqin; Roth, Bryan L; O'Donnell, Patricio; Didriksen, Michael; Dolmetsch, Ricardo; O'Reilly, Paul F; Gaspar, HΓ©lΓ©na A; Manji, Husseini; Huebel, Christopher; Kelsoe, John R; Malhotra, Dheeraj; Bertolino, Alessandro; Posthuma, Danielle; Sklar, Pamela; Kapur, Shitij; Sullivan, Patrick F; Collier, David A; Edenberg, Howard J
- Year
- 2016
- Journal
- Nature neuroscience
- PMID
- 27786187
- DOI
- 10.1038/nn.4411
- PMCID
- PMC5676453
Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. These approaches complement the other main aim of GWAS studies, risk prediction approaches for improving detection, differential diagnosis, and clinical trial design. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC phase 3 findings into new therapeutics.
PGC GWAS Drug Target Analysis Strategy: utilising diverse information sources for drug target discovery.
| # | Section | Preview |
|---|---|---|
| 20 | PGC phase 3: Target identification in Psychiatric GWAS data | drug mechanisms of action and rational drug repurposing39. Rare variants, discovered by large scale⦠|
| 21 | PGC phase 3: Target identification in Psychiatric GWAS data | Using these data sources, three broad strategies are possible (see Figure 1). First, pathway⦠|
| 22 | Conclusions | These approaches require substantial and integrated efforts, involving consortia such as the PGC,β¦ |
β Prev
21β23 of 23
| Name | Type |
|---|---|
| ADHD | phenotype |
| Alzheimer's disease | phenotype |
| anorexia nervosa | phenotype |
| anti-diabetes drugs local | drug |
| Aripiprazole lauroxil local | drug |
| autism | phenotype |
| bipolar disorder | phenotype |
| brain circuits | anatomy |
| Brainseq25 local | cohort |
| BrainSeq25 local | cohort |
| Brexpiprazole local | drug |
| C4 local | gene |
| cardiovascular disease risk local | phenotype |
| Cariprazine local | drug |
| clinical trials | cohort |
| CommonMind Consortium | cohort |
| common variants | cohort |
| complex disorders | phenotype |
| compounds | drug |
| copy number variation | variant |
| de-novo damaging mutations local | variant |
| disorder | phenotype |
| dopamine receptors | drug |
| eQTLGen Consortium | cohort |
| First episode psychosis local | phenotype |
| genes | gene |
| genetic risk | cohort |
| genetic variants | cohort |
| GWAS | cohort |
| HMGCR | gene |
| humans | cohort |
| hypercholesterolemia local | phenotype |
| intellectual disability | phenotype |
| intermediate phenotypes | phenotype |
| Large, deeply phenotyped longitudinal samples local | cohort |
| LDL cholesterol | phenotype |
| LDL cholesterol metabolism local | phenotype |
| lipid levels | phenotype |
| LPA local | gene |
| major depressive disorder | phenotype |
| mQTL | variant |
| mutations | variant |
| neuronal networks local | anatomy |
| novel therapeutics local | drug |
| PCSK9 | gene |
| pervasive developmental delay local | phenotype |
| PGC | cohort |
| PGC3 disorders local | phenotype |
| plasma lipoprotein(a) levels local | phenotype |
| polygenic risk score | cohort |
| postmortem brain | anatomy |
| pQTL | variant |
| PsychENCODE | cohort |
| psychiatric disorders | phenotype |
| Psychiatric Genomics Consortium | cohort |
| rare variant | cohort |
| risk allele | cohort |
| rodents | cohort |
| schizophrenia | phenotype |
| Serotonin receptors local | drug |
| SLC30A8 | gene |
| SNP | cohort |
| type 2 diabetes | phenotype |
No uploaded files.
Not in any collection.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Functional Annotation of Bipolar Disorder 2 Risk Location Implicates Novel Susceptibility Genes. | Can GΕ et al. | β | 2025 | β |
| Validated metabolomic biomarkers in psychiatric disorders: a narrative review. | Konjevod M et al. | β | 2025 | β |
| Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. | Nievergelt CM et al. | β | 2024 | β |
| Genomic strategies for drug repurposing. | Dave K et al. | β | 2024 | β |
| How Real-World Data Can Facilitate the Development of Precision Medicine Treatment in Psychiatry. | Koch E et al. | β | 2024 | β |
| Progress and Implications from Genetic Studies of Bipolar Disorder. | Kong L et al. | β | 2024 | β |
| The effects of methylphenidate and atomoxetine on Drosophila brain at single-cell resolution and potential drug repurposing for ADHD treatment. | Qu S et al. | β | 2024 | β |
| Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders | Nievergelt CM et al. | β | 2023 | β |
| Ethnic, gender and other sociodemographic biases in genome-wide association studies for the most burdensome non-communicable diseases: 2005-2022. | Fitipaldi H et al. | β | 2023 | β |
| Examining the shared etiology of psychopathology with genome-wide association studies. | Mallard TT et al. | β | 2023 | β |
| Exploring Genetic and Neural Risk of Specific Reading Disability within a Nuclear Twin Family Case Study: A Translational Clinical Application. | Thomas T et al. | β | 2023 | β |
| multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results. | Khatiwada A et al. | β | 2023 | β |
| Multi-omics cannot replace sample size in genome-wide association studies. | Baranger DAA et al. | β | 2023 | β |
| New "drugs and targets" in the GWAS era of bipolar disorder. | Qi HX et al. | β | 2023 | β |
| Regulation of Human Endogenous Metabolites by Drug Transporters and Drug Metabolizing Enzymes: An Analysis of Targeted SNP-Metabolite Associations. | Granados JC et al. | β | 2023 | β |
| CACNA1C (Ca<sub>V</sub>1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology. | Harrison PJ et al. | β | 2022 | β |
| Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation. | Hindley G et al. | β | 2022 | β |
| Detecting associated genes for complex traits shared across East Asian and European populations under the framework of composite null hypothesis testing. | Qiao J et al. | β | 2022 | β |
| Genetics and neurobiology of eating disorders. | Bulik CM et al. | β | 2022 | β |
| Mapping the genetic architecture of cortical morphology through neuroimaging: progress and perspectives. | van der Meer D et al. | β | 2022 | β |
| Overview of CAPICE-Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe-an EU Marie SkΕodowska-Curie International Training Network. | Rajula HSR et al. | β | 2022 | β |
| Genetic contributions to anxiety disorders: where we are and where we are heading. | Ask H et al. | β | 2021 | β |
| Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. | Lam M et al. | β | 2021 | β |
| Insights into attention-deficit/hyperactivity disorder from recent genetic studies. | Brikell I et al. | β | 2021 | β |
| Pathway analysis for genome-wide genetic variation data: Analytic principles, latest developments, and new opportunities. | Silberstein M et al. | β | 2021 | β |
| Perspective on Beyond Statistical Significance: Finding Meaningful Effects. | Edenberg HJ | β | 2021 | β |
| Signature-based approaches for informed drug repurposing: targeting CNS disorders. | Shukla R et al. | β | 2021 | β |
| Translational genomics and beyond in bipolar disorder. | Zhang C et al. | β | 2021 | β |
| Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. | Glanville KP et al. | β | 2020 | β |
| Genetic liability in individuals at ultra-high risk of psychosis: A comparison study of 9 psychiatric traits. | Lim K et al. | β | 2020 | β |
| Genetics and major depressive disorder: clinical implications for disease risk, prognosis and treatment. | Fabbri C et al. | β | 2020 | β |
| Integrative analyses prioritize GNL3 as a risk gene for bipolar disorder. | Meng Q et al. | β | 2020 | β |
| Molecular genetics in psychology and personality neuroscience: On candidate genes, genome wide scans, and new research strategies. | Montag C et al. | β | 2020 | β |
| Multiparametric Assays for Accelerating Early Drug Discovery. | Herholt A et al. | β | 2020 | β |
| RICOPILI: Rapid Imputation for COnsortias PIpeLIne. | Lam M et al. | β | 2020 | β |
| Synaptic and brain-expressed gene sets relate to the shared genetic risk across five psychiatric disorders. | Hammerschlag AR et al. | β | 2020 | β |
| The genetics of bipolar disorder. | Gordovez FJA et al. | β | 2020 | β |
| The Heterogeneity of Mental Health Assessment. | Newson JJ et al. | β | 2020 | β |
| Turning genome-wide association study findings into opportunities for drug repositioning. | Lau A et al. | β | 2020 | β |
| Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal. | Harrison PJ et al. | β | 2020 | β |
| Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. | Werling DM et al. | β | 2020 | β |
| A Bayesian framework that integrates multi-omics data and gene networks predicts risk genes from schizophrenia GWAS data. | Wang Q et al. | β | 2019 | β |
| Bioinformatic and biological avenues for understanding alcohol use disorder. | Grantham EK et al. | β | 2019 | β |
| Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals. | Coleman JRI et al. | β | 2019 | β |
| [Breakthrough in understanding the molecular causes of psychiatric disorders]. | NΓΆthen MM et al. | β | 2019 | β |
| Cognitive functions associated with developing prefrontal cortex during adolescence and developmental neuropsychiatric disorders. | Sakurai T et al. | β | 2019 | β |
| Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent. | HΓΌbel C et al. | β | 2019 | β |
| Genetics of Anxiety Disorders. | Meier SM et al. | β | 2019 | β |
| Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of complex traits and disease. | Hatcher C et al. | β | 2019 | β |
| Mapping causal pathways from genetics to neuropsychiatric disorders using genome-wide imaging genetics: Current status and future directions. | Le BD et al. | β | 2019 | β |
| National Institute on Drug Abuse genomics consortium white paper: Coordinating efforts between human and animal addiction studies. | Cates HM et al. | β | 2019 | β |
| Psychiatric genetics and the structure of psychopathology. | Smoller JW et al. | β | 2019 | β |
| Recent advances in understanding of attention deficit hyperactivity disorder (ADHD): how genetics are shaping our conceptualization of this disorder. | Zayats T et al. | β | 2019 | β |
| Rediscovering the value of families for psychiatric genetics research. | Glahn DC et al. | β | 2019 | β |
| Scalable Measurements of Intrinsic Excitability in Human iPS Cell-Derived Excitatory Neurons Using All-Optical Electrophysiology. | Williams LA et al. | β | 2019 | β |
| Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. | Vadodaria KC et al. | β | 2019 | β |
| The Emerging Neurobiology of Bipolar Disorder. | Harrison PJ et al. | β | 2019 | β |
| The Genetic Links to Anxiety and Depression (GLAD) Study: Online recruitment into the largest recontactable study of depression and anxiety. | Davies MR et al. | β | 2019 | β |
| The genomics of major psychiatric disorders in a large pedigree from Northern Sweden. | Szatkiewicz J et al. | β | 2019 | β |
| The international postpartum depression: action towards causes and treatment (PACT) consortium. | Guintivano J et al. | β | 2019 | β |
| Tobacco Genomics: Complexity and Translational Challenges. | Bergen AW et al. | β | 2019 | β |
| Chromosomal Conformations and Epigenomic Regulation in Schizophrenia. | Rajarajan P et al. | β | 2018 | β |
| Conference Report: Psychiatric Genomics Consortium Meeting: Pathways to Drugs, London, March 2017. | Gaspar HA et al. | β | 2018 | β |
| Cross-species molecular dissection across alcohol behavioral domains. | Farris SP et al. | β | 2018 | β |
| Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. | Wray NR et al. | β | 2018 | β |
| Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice. | Ferguson LB et al. | β | 2018 | β |
| Modeling psychiatric disorders using patient stem cell-derived neurons: a way forward. | Vadodaria KC et al. | β | 2018 | β |
| Polygenic Risk Scores in Clinical Psychology: Bridging Genomic Risk to Individual Differences. | Bogdan R et al. | β | 2018 | β |
| Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps. | Dick DM et al. | β | 2018 | β |
| Precision pharmacotherapy: psychiatry's future direction in preventing, diagnosing, and treating mental disorders. | Menke A | β | 2018 | β |
| Psychiatric Genomics: An Update and an Agenda. | Sullivan PF et al. | β | 2018 | β |
| Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia. | Kauppi K et al. | β | 2018 | β |
| Rigor and reproducibility in genetic research on eating disorders. | HΓΌbel C et al. | β | 2018 | β |
| The Emerging Neurobiology of Bipolar Disorder. | Harrison PJ et al. | β | 2018 | β |
| The Lancet Commission on global mental health and sustainable development. | Patel V et al. | β | 2018 | β |
| The value of polygenic analyses in psychiatry. | Middeldorp CM et al. | β | 2018 | β |
| Translating GWAS Findings to Novel Therapeutic Targets for Coronary Artery Disease. | Shu L et al. | β | 2018 | β |
| Analysis of genome-wide association data highlights candidates for drug repositioning in psychiatry. | So HC et al. | β | 2017 | β |
| Challenges and opportunities for the development of new antipsychotic drugs. | Forray C et al. | β | 2017 | β |
| Drug enrichment and discovery from schizophrenia genome-wide association results: an analysis and visualisation approach. | Gaspar HA et al. | β | 2017 | β |
| Functional mapping and annotation of genetic associations with FUMA. | Watanabe K et al. | β | 2017 | β |
| Precision medicine and pharmacogenetics: what does oncology have that addiction medicine does not? | Kranzler HR et al. | β | 2017 | β |
| The epigenomics of schizophrenia, in the mouse. | Javidfar B et al. | β | 2017 | β |
| Focus on psychiatric disorders. | β | β | 2016 | β |