Search

Your search keyword '"Richard M. Myers"' showing total 276 results
Start Over Author "Richard M. Myers" Topic humans
276 results on '"Richard M. Myers"'

1. Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia

Author

Adriana M. Medina, Megan Hastings Hagenauer, David M. Krolewski, Evan Hughes, Liam Cannon Thew Forrester, David M. Walsh, Maria Waselus, Evelyn Richardson, Cortney A. Turner, P. Adolfo Sequeira, Preston M. Cartagena, Robert C. Thompson, Marquis P. Vawter, Blynn G. Bunney, Richard M. Myers, Jack D. Barchas, Francis S. Lee, Alan F. Schatzberg, William E. Bunney, Huda Akil, and Stanley J. Watson

Subjects
Bipolar Disorder, Adolescent, Clinical Sciences, Neurosciences, Gene Expression, Serious Mental Illness, Synaptic Transmission, Frontal Lobe, Brain Disorders, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Mental Health, Good Health and Well Being, Schizophrenia, Genetics, Public Health and Health Services, Humans, 2.1 Biological and endogenous factors, Psychology, Aetiology, Biological Psychiatry
Abstract

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Published
2023

2. Three dimensional modeling of biologically relevant fluid shear stress in human renal tubule cells mimics in vivo transcriptional profiles

Author

Nancy J. Cox, Roshan Darji, Emily J. Ross, Hanna Sothers, Emily R Gordon, Balabhaskar Prabhakarpandian, Oakley Baron, Sara J. Cooper, Dustin Haithcock, Richard M. Myers, and Kapil Pant

Subjects
0301 basic medicine, Science, Kidney, Endocytosis, Cell morphology, Models, Biological, Article, Kidney Tubules, Proximal, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Genetics, medicine, Humans, Biological models, Genome, Multidisciplinary, Lab-on-a-chip, Reabsorption, Chemistry, Gene Expression Profiling, Cilium, Computational Biology, Biological Transport, Epithelial Cells, Cell biology, Kidney Tubules, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Cell culture, 030220 oncology & carcinogenesis, Medicine, Stress, Mechanical, Shear Strength, Biomarkers, Signal Transduction
Abstract

The kidney proximal tubule is the primary site for solute reabsorption, secretion and where kidney diseases can originate, including drug-induced toxicity. Two-dimensional cell culture systems of the human proximal tubule cells (hPTCs) are often used to study these processes. However, these systems fail to model the interplay between filtrate flow, fluid shear stress (FSS), and functionality essential for understanding renal diseases and drug toxicity. The impact of FSS exposure on gene expression and effects of FSS at differing rates on gene expression in hPTCs has not been thoroughly investigated. Here, we performed RNA-sequencing of human RPTEC/TERT1 cells in a microfluidic chip-based 3D model to determine transcriptomic changes. We measured transcriptional changes following treatment of cells in this device at three different fluidic shear stress. We observed that FSS changes the expression of PTC-specific genes and impacted genes previously associated with renal diseases in genome-wide association studies (GWAS). At a physiological FSS level, we observed cell morphology, enhanced polarization, presence of cilia, and transport functions using albumin reabsorption via endocytosis and efflux transport. Here, we present a dynamic view of hPTCs response to FSS with increasing fluidic shear stress conditions and provide insight into hPTCs cellular function under biologically relevant conditions.

Published
2021

3. Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition

Author

Ryne C. Ramaker, Richard M. Myers, Emily R Gordon, Andrew A. Hardigan, Sara J. Cooper, and Carter A. Wright

Subjects
0301 basic medicine, Cancer Research, Abcg2, Histone Deacetylase 1, Drug resistance, 0302 clinical medicine, Cell Movement, Gene expression, CRISPR, RNA-Seq, RC254-282, 0303 health sciences, biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Precision oncology, Phenotype, Drug Resistance, Multiple, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Chromatin Immunoprecipitation Sequencing, Efflux, Co-Repressor Proteins, Carcinoma, Pancreatic Ductal, Epithelial-Mesenchymal Transition, ABCG2, Antineoplastic Agents, 03 medical and health sciences, Pancreatic cancer, Cell Line, Tumor, Genetics, medicine, Humans, Epithelial–mesenchymal transition, Gene, 030304 developmental biology, Genome-wide screen, Research, medicine.disease, digestive system diseases, HDAC1, Multiple drug resistance, Pancreatic Neoplasms, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, biology.protein, CRISPR-Cas Systems
Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) patients suffer poor outcomes, including a five-year survival of below 10%. Poor outcomes result in part from therapeutic resistance that limits the impact of cytotoxic first-line therapy. Novel therapeutic approaches are needed, but currently no targeted therapies exist to treat PDAC. Methods To assess cellular resistance mechanisms common to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin) used to treat PDAC patients, we performed four genome-wide CRISPR activation (CRISPRact) and CRISPR knock-out (CRISPRko) screens in two common PDAC cell lines (Panc-1 and BxPC3). We used pathway analysis to identify gene sets enriched among our hits and conducted RNA-sequencing and chromatin immunoprecipitation-sequencing (ChIP-seq) to characterize top hits from our screen. We used scratch assays to assess changes in cellular migration with HDAC1 overexpression. Results Our data revealed activation of ABCG2, a well-described efflux pump, as the most consistent mediator of resistance in each of our screens. CRISPR-mediated activation of genes involved in transcriptional co-repressor complexes also conferred resistance to multiple drugs. Expression of many of these genes, including HDAC1, is associated with reduced survival in PDAC patients. Up-regulation of HDAC1 in vitro increased promoter occupancy and expression of several genes involved in the epithelial-to-mesenchymal transition (EMT). These cells also displayed phenotypic changes in cellular migration consistent with activation of the EMT pathway. The expression changes resulting from HDAC1 activation were also observed with activation of several other co-repressor complex members. Finally, we developed a publicly available analysis tool, PancDS, which integrates gene expression profiles with our screen results to predict drug sensitivity in resected PDAC tumors and cell lines. Conclusion Our results provide a comprehensive resource for identifying cellular mechanisms of drug resistance in PDAC, mechanistically implicate HDAC1, and co-repressor complex members broadly, in multi-drug resistance, and provide an analytical tool for predicting treatment response in PDAC tumors and cell lines.

Published
2021

4. The Therapeutic Odyssey: Positioning Genomic Sequencing in the Search for a Child’s Best Possible Life

Author

Janet Elizabeth Childerhose, Carla Rich, Kelly M. East, Whitley V. Kelley, Shirley Simmons, Candice R. Finnila, Kevin Bowling, Michelle Amaral, Susan M. Hiatt, Michelle Thompson, David E. Gray, James M. J. Lawlor, Richard M. Myers, Gregory S. Barsh, Edward J. Lose, Martina E. Bebin, Greg M. Cooper, and Kyle Bertram Brothers

Subjects
Parents, Motivation, Health (social science), Base Sequence, Health Policy, Genomic sequencing, Genomics, Computational biology, medicine.disease, Article, DNA sequencing, Philosophy, Intellectual disability, medicine, Humans, Family, Child, Genetic diagnosis, Psychology, human activities
Abstract

BACKGROUND: The desire of parents to obtain a genetic diagnosis for their child with intellectual disability and associated symptoms has long been framed as a diagnostic odyssey, an arduous and sometimes perilous journey focused on the goal of identifying a cause for the child’s condition. METHODS: Semi-structured interviews (N=60) were conducted with parents of children (N=59, aged 2–24 years) with intellectual disability and/or developmental delay (IDD) who underwent genome sequencing at a single pediatric multispecialty clinic. Interviews were conducted after parents received their child’s sequencing result (positive findings, negative findings, or variants of unknown significance). Thematic analysis was performed on all interviews. RESULTS: Parents reported that obtaining a genetic diagnosis was one important step in their overall goal of helping their child live their best life possible life. They intended to use the result as a tool to help their child by seeking the correct school placement and obtaining benefits and therapeutic services. CONCLUSIONS: For the parents of children with IDD, the search for a genetic diagnosis is best conceptualized as a part of parents’ ongoing efforts to leverage various diagnoses to obtain educational and therapeutic services for their children. Cleaving parents’ search for a genetic diagnosis from these broader efforts obscures the value that some parents place on a sequencing result in finding and tailoring therapies and services beyond the clinic. Interviews with parents reveal, therefore, that genomic sequencing is best understood as one important stage of an ongoing therapeutic odyssey that largely takes place outside the clinic. Findings suggest the need to expand translational research efforts to contextualize a genetic diagnosis within parents’ broader efforts to obtain educational and therapeutic services outside clinical contexts.

Published
2021

5. Identification of potential blood biomarkers associated with suicide in major depressive disorder

Author

Firoza Mamdani, Matthieu D. Weber, Blynn Bunney, Kathleen Burke, Preston Cartagena, David Walsh, Francis S. Lee, Jack Barchas, Alan F. Schatzberg, Richard M. Myers, Stanley J. Watson, Huda Akil, Marquis P. Vawter, William E. Bunney, and Adolfo Sequeira

Subjects
Depressive Disorder, Major, Suicide, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Amino Acid Transport Systems, Calcium-Binding Proteins, mental disorders, Brain, Humans, Prefrontal Cortex, behavioral disciplines and activities, Biomarkers, Biological Psychiatry
Abstract

Suicides have increased to over 48,000 deaths yearly in the United States. Major depressive disorder (MDD) is the most common diagnosis among suicides, and identifying those at the highest risk for suicide is a pressing challenge. The objective of this study is to identify changes in gene expression associated with suicide in brain and blood for the development of biomarkers for suicide. Blood and brain were available for 45 subjects (53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) samples in total). Samples were collected from MDD patients who died by suicide (MDD-S), MDDs who died by other means (MDD-NS) and non-psychiatric controls. We analyzed gene expression using RNA and the NanoString platform. In blood, we identified 14 genes which significantly differentiated MDD-S versus MDD-NS. The top six genes differentially expressed in blood were: PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1. Additionally, four genes showed significant changes in brain and blood between MDD-S and MDD-NS; SOX9 was decreased and PER3 was increased in MDD-S in both tissues, while CD19 and TERF1 were increased in blood but decreased in DLPFC. To our knowledge, this is the first study to analyze matched blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide. Our results strongly suggest that blood gene expression is highly informative to understand molecular changes in suicide. Developing a suicide biomarker signature in blood could help health care professionals to identify subjects at high risk for suicide.

Published
2022

6. Rare coding variants in ten genes confer substantial risk for schizophrenia

Author

Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D. Barchas, Nicholas Bass, Tim B. Bigdeli, Gerome Breen, Evelyn J. Bromet, Peter F. Buckley, William E. Bunney, Jonas Bybjerg-Grauholm, William F. Byerley, Sinéad B. Chapman, Wei J. Chen, Claire Churchhouse, Nicholas Craddock, Caroline M. Cusick, Lynn DeLisi, Sheila Dodge, Michael A. Escamilla, Saana Eskelinen, Ayman H. Fanous, Stephen V. Faraone, Alessia Fiorentino, Laurent Francioli, Stacey B. Gabriel, Diane Gage, Sarah A. Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C. Glahn, Jakob Grove, Mei-Hua Hall, Eija Hämäläinen, Henrike O. Heyne, Matti Holi, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Hai-Gwo Hwu, René S. Kahn, Hyun Min Kang, Konrad J. Karczewski, George Kirov, James A. Knowles, Francis S. Lee, Douglas S. Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R. Marder, Steven A. McCarroll, Andrew M. McIntosh, Helena Medeiros, Lili Milani, Christopher P. Morley, Derek W. Morris, Preben Bo Mortensen, Richard M. Myers, Merete Nordentoft, Niamh L. O’Brien, Ana Maria Olivares, Dost Ongur, Willem H. Ouwehand, Duncan S. Palmer, Tiina Paunio, Digby Quested, Mark H. Rapaport, Elliott Rees, Brandi Rollins, F. Kyle Satterstrom, Alan Schatzberg, Edward Scolnick, Laura J. Scott, Sally I. Sharp, Pamela Sklar, Jordan W. Smoller, Janet L. Sobell, Matthew Solomonson, Eli A. Stahl, Christine R. Stevens, Jaana Suvisaari, Grace Tiao, Stanley J. Watson, Nicholas A. Watts, Douglas H. Blackwood, Anders D. Børglum, Bruce M. Cohen, Aiden P. Corvin, Tõnu Esko, Nelson B. Freimer, Stephen J. Glatt, Christina M. Hultman, Andrew McQuillin, Aarno Palotie, Carlos N. Pato, Michele T. Pato, Ann E. Pulver, David St. Clair, Ming T. Tsuang, Marquis P. Vawter, James T. Walters, Thomas M. Werge, Roel A. Ophoff, Patrick F. Sullivan, Michael J. Owen, Michael Boehnke, Michael C. O’Donovan, Benjamin M. Neale, Mark J. Daly, Psychiatry, HUS Psychiatry, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Department of Psychiatry, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, and Aarno Palotie / Principal Investigator

Subjects
Multidisciplinary, Schizophrenia/genetics, MUTATIONS, Receptors, N-Methyl-D-Aspartate/genetics, Genetic Predisposition to Disease/genetics, 3112 Neurosciences, ASSOCIATION, Neurodevelopmental Disorders/genetics, Receptors, N-Methyl-D-Aspartate, INDIVIDUALS, Neurodevelopmental Disorders, Case-Control Studies, Mutation, Schizophrenia, Humans, Genetic Predisposition to Disease, Exome, 3111 Biomedicine, BURDEN
Abstract

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 × 10−6) and 32 genes at a false discovery rate of 1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Published
2022

7. STAT3 and GR Cooperate to Drive Gene Expression and Growth of Basal-Like Triple-Negative Breast Cancer

Author

James Turkson, Peibin Yue, Katherine E. Varley, Joy M. McDaniel, Stephanie L. Parker, Donald J. Buchsbaum, Bryan E. Welm, Katrin P. Guillen, Richard M. Myers, Patsy G. Oliver, Megan E. Conway, and James M. Graham

Subjects
STAT3 Transcription Factor, 0301 basic medicine, Chromatin Immunoprecipitation, Cancer Research, Triple Negative Breast Neoplasms, Kaplan-Meier Estimate, Regulatory Sequences, Nucleic Acid, Dexamethasone, Disease-Free Survival, Article, 03 medical and health sciences, Receptors, Glucocorticoid, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, Gene expression, medicine, Humans, STAT3, Transcription factor, Triple-negative breast cancer, Regulation of gene expression, Binding Sites, biology, DNA Methylation, Prognosis, medicine.disease, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, biology.protein, Female, Estrogen receptor alpha
Abstract

Breast cancers are divided into subtypes with different prognoses and treatment responses based on global differences in gene expression. Luminal breast cancer gene expression and proliferation are driven by estrogen receptor alpha, and targeting this transcription factor is the most effective therapy for this subtype. By contrast, it remains unclear which transcription factors drive the gene expression signature that defines basal-like triple-negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype. In this study, we utilized integrated genomic analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. Glucocorticoid receptor (GR) and STAT3 bind to the same genomic regulatory regions, which were specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperated to regulate expression of hundreds of genes in the basal-like gene expression signature, which were associated with poor prognosis. Combination treatment with small-molecule inhibitors of both transcription factors resulted in synergistic decreases in cell growth in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triple-negative breast cancer through rational combination of STAT3 and GR inhibitors. Significance: This study demonstrates that GR and STAT3 cooperate to activate the canonical gene expression signature of basal-like triple-negative breast cancer and that combination treatment with STAT3 and GR inhibitors could provide synergistic therapeutic efficacy.

Published
2020

8. Occupancy maps of 208 chromatin-associated proteins in one human cell type

Author

Barbara J. Wold, Laurel A. Brandsmeier, Jeremy W. Prokop, Richard M. Myers, Shan Jiang, Mark Mackiewicz, Sarah Meadows, Ali Mortazavi, Camden Jansen, Eric M. Mendenhall, Daniel Savic, Ryne C. Ramaker, Candice J. Coppola, Andrew A. Hardigan, Surya B. Chhetri, Emma C. Dean, E. Christopher Partridge, Kimberly M. Newberry, C. Luke Messer, and Say-Tar Goh

Subjects
Epigenomics, Gene regulatory network, Datasets as Topic, Computational biology, Regulatory Sequences, Nucleic Acid, Biology, Article, Humans, Nucleotide Motifs, Promoter Regions, Genetic, Transcriptomics, Enhancer, Transcription factor, Gene, Multidisciplinary, Molecular Sequence Annotation, Promoter, Hep G2 Cells, DNA, Chromatin, Gene regulation, DNA-Binding Proteins, Enhancer Elements, Genetic, Chromatin Immunoprecipitation Sequencing, Chromatin immunoprecipitation, Protein Binding, Transcription Factors
Abstract

Transcription factors are DNA-binding proteins that have key roles in gene regulation1,2. Genome-wide occupancy maps of transcriptional regulators are important for understanding gene regulation and its effects on diverse biological processes3–6. However, only a minority of the more than 1,600 transcription factors encoded in the human genome has been assayed. Here we present, as part of the ENCODE (Encyclopedia of DNA Elements) project, data and analyses from chromatin immunoprecipitation followed by high-throughput sequencing (ChIP–seq) experiments using the human HepG2 cell line for 208 chromatin-associated proteins (CAPs). These comprise 171 transcription factors and 37 transcriptional cofactors and chromatin regulator proteins, and represent nearly one-quarter of CAPs expressed in HepG2 cells. The binding profiles of these CAPs form major groups associated predominantly with promoters or enhancers, or with both. We confirm and expand the current catalogue of DNA sequence motifs for transcription factors, and describe motifs that correspond to other transcription factors that are co-enriched with the primary ChIP target. For example, FOX family motifs are enriched in ChIP–seq peaks of 37 other CAPs. We show that motif content and occupancy patterns can distinguish between promoters and enhancers. This catalogue reveals high-occupancy target regions at which many CAPs associate, although each contains motifs for only a minority of the numerous associated transcription factors. These analyses provide a more complete overview of the gene regulatory networks that define this cell type, and demonstrate the usefulness of the large-scale production efforts of the ENCODE Consortium., ChIP–seq and CETCh–seq data are used to analyse binding maps for 208 transcription factors and other chromatin-associated proteins in a single human cell type, providing a comprehensive catalogue of the transcription factor landscape and gene regulatory networks in these cells.

Published
2020

9. Probable Vertical Transmission of SARS-CoV-2 Infection

Author

Rachel Herbert, Richard M. Myers, Deenan Pillay, Shona Perkins, Joanna Ellis, Frances Blackburn, Jennifer Handforth, Peter Hinstridge, Maria Zambon, Sam Douthwaite, Marc Tebruegge, Alejandra Alonso, Shahjahan Miah, Christopher I. S. Meadows, Mariyam Mirfenderesky, Alicia Demirjian, Meera Chand, Cheentan Singh, V Jones, Julia Kenny, Ranjika Seneviratne, Mark Butler, and Nehal Draz

Subjects
Adult, Microbiology (medical), Pediatrics, medicine.medical_specialty, viruses, Pneumonia, Viral, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Meconium, Pregnancy, Nasopharyngeal aspirate, 030225 pediatrics, medicine, Humans, Infection control, Pediatrics, Perinatology, and Child Health, 030212 general & internal medicine, Pregnancy Complications, Infectious, Respiratory system, Pandemics, biology, Cesarean Section, SARS-CoV-2, Transmission (medicine), business.industry, Infant, Newborn, COVID-19, medicine.disease, biology.organism_classification, Infectious Disease Transmission, Vertical, Pneumonia, Infectious Diseases, Pediatrics, Perinatology and Child Health, Female, Coronavirus Infections, business
Abstract

BACKGROUND: To date, although neonatal infections with severe acute respiratory syndrome coronovirus 2 (SARS-CoV-2) have been described, none of these have been proven to be the result of vertical transmission of SARS-CoV-2. METHODS: We describe the probable vertical transmission of SARS-CoV-2 in a neonate born to a mother with coronavirus disease 2019 (COVID-19). RESULTS: Following cesarean section, the neonate was kept in strict isolation. Molecular tests for SARS-CoV-2 on respiratory samples, blood, and meconium were initially negative, but positive on a nasopharyngeal aspirate on the third day of life. On day 5, the neonate developed fever and coryza, which spontaneously resolved. Viral genomic analysis from the mother and neonate showed identical sequences except for 1 nucleotide. CONCLUSION: This report has important implications for infection control and clinical management of pregnant women with COVID-19 and their newborns.

Published
2020

10. Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations

Author

Ryne C. Ramaker, Say-Tar Goh, Andrew A. Hardigan, Barbara J. Wold, Richard M. Myers, Sara J. Cooper, and E. Christopher Partridge

Subjects
Computational biology, Biology, Genome, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Gene expression, Genetics, Transcriptional regulation, Humans, Nucleotide Motifs, Promoter Regions, Genetic, Enhancer, Transcription factor, Genetics (clinical), 030304 developmental biology, Base Composition, 0303 health sciences, Reporter gene, Research, Promoter, DNA, Hep G2 Cells, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, chemistry, Genetic Loci, Mutagenesis, 030220 oncology & carcinogenesis, Mutation, Chromatin Immunoprecipitation Sequencing, Hypersensitive site, 030217 neurology & neurosurgery, Transcription Factors
Abstract

DNA associated proteins (DAPs) classically regulate gene expression by binding to regulatory loci such as enhancers or promoters. As expanding catalogs of genome-wide DAP binding maps reveal thousands of loci that, unlike the majority of conventional enhancers and promoters, associate with dozens of different DAPs with apparently little regard for motif preference, an understanding of DAP association and coordination at such regulatory loci is essential to deciphering how these regions contribute to normal development and disease. In this study, we aggregated publicly available ChIP-seq data from 469 human DAPs assayed in three cell lines and integrated these data with an orthogonal dataset of 352 non-redundant, in vitro-derived motifs mapped to the genome within DNase hypersensitivity footprints in an effort to characterize regions of the genome that have exceptionally high numbers of DAP associations. We subsequently performed a massively parallel mutagenesis assay to search for sequence elements driving transcriptional activity at such loci and explored plausible biological mechanisms underlying their formation. We establish a generalizable definition for High Occupancy Target (HOT) loci and identify putative driver DAP motifs in HEPG2 cells, including HNF4A, SP1, SP5, and ETV4, that are highly prevalent and exhibit sequence conservation at HOT loci. The number of different DAPs associated with an element is positively associated with evidence of regulatory activity and, by systematically mutating 245 HOT loci, we localized regulatory activity to a central core region that depends on the motif sequences of our previously nominated driver DAPs. In sum, this work leverages the increasingly large number of DAP motif and ChIP-seq data publicly available to explore how DAP associations contribute to genome-wide transcriptional regulation.

Published
2020

11. TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer

Author

Brian S. Roberts, Andres Forero-Torres, Lisa A. Carey, Anna Maria Storniolo, Richard M. Myers, Nan Lin, Rita Nanda, Minetta C. Liu, Katherine E. Varley, Yufeng Li, Albert F. LoBuglio, Hope S. Rugo, Christos Vaklavas, Mansoor N. Saleh, William E. Grizzle, Jennifer F. Delossantos, and Shannon Puhalla

Subjects
Receptor, ErbB-2, Preoperative therapy, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, Luminal breast cancer, Antineoplastic Combined Chemotherapy Protocols, Aged, 80 and over, 0303 health sciences, Proteinuria, medicine.diagnostic_test, Hormone receptor-positive breast cancer, Letrozole, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Postmenopause, Vascular endothelial growth factor, Bevacizumab, Receptors, Estrogen, 030220 oncology & carcinogenesis, Postmenopausal, Female, medicine.symptom, Receptors, Progesterone, Research Article, medicine.drug, medicine.medical_specialty, Neoplasms, Hormone-Dependent, Breast Neoplasms, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, Biopsy, Biomarkers, Tumor, medicine, Humans, Adverse effect, Aged, Neoplasm Staging, 030304 developmental biology, business.industry, medicine.disease, Discontinuation, chemistry, Transcriptome, business
Abstract

Background In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. Methods Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. Results Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7–24.1%) achieved pCR and 4 (9%; 95% CI, 2.5–21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0–14.2%). The rates of downstaging were 44.4% (95% CI, 29.6–60.0%) and 37.5% (95% CI, 18.8–59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. Conclusion In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. Trial registration This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.

Published
2020

12. Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis

Author

Antonio Julià, Antonio Gómez, María López-Lasanta, Francisco Blanco, Alba Erra, Antonio Fernández-Nebro, Antonio Juan Mas, Carolina Pérez-García, Ma Luz García Vivar, Simón Sánchez-Fernández, Mercedes Alperi-López, Raimon Sanmartí, Ana María Ortiz, Carlos Marras Fernandez-Cid, César Díaz-Torné, Estefania Moreno, Tianlu Li, Sergio H. Martínez-Mateu, Devin M. Absher, Richard M. Myers, Jesús Tornero Molina, Sara Marsal, Institut Català de la Salut, [Julià A, Gómez A, López-Lasanta M, Li T, Martínez-Mateu SH, Marsal S] Grup de Recerca en Reumatologia, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Blanco F] Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain. [Erra A] Grup de Recerca en Reumatologia, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Rheumatology Department, Hospital de San Rafael, Barcelona, Spain. [Fernández-Nebro A] Rheumatology Department, Hospital Regional Universitario de Málaga, Málaga, Spain. [Moreno E] Grup de Recerca en Reumatologia, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Rheumatology Unit, Consorci Sanitari de l'Alt Penedès, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic Agents [CHEMICALS AND DRUGS], DNA methylation, Tumor Necrosis Factor-alpha, Artritis reumatoide - Tractament, ADN - Metilació, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], General Medicine, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Treatment response, Factor de necrosi tumoral - Inhibidors, Chemical Phenomena::Biochemical Phenomena::Alkylation::Methylation::DNA Methylation [PHENOMENA AND PROCESSES], General Biochemistry, Genetics and Molecular Biology, enfermedades musculoesqueléticas::artropatías::artritis::artritis reumatoide [ENFERMEDADES], fenómenos químicos::fenómenos bioquímicos::alquilación::metilación::metilación del ADN [FENÓMENOS Y PROCESOS], Arthritis, Rheumatoid, Cohort Studies, TNF inhibitors, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antirreumáticos [COMPUESTOS QUÍMICOS Y DROGAS], Antirheumatic Agents, Humans, Tumor Necrosis Factor Inhibitors, Epigenetics, Rheumatoid arthritis, Musculoskeletal Diseases::Joint Diseases::Arthritis::Arthritis, Rheumatoid [DISEASES]
Abstract

Background Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. & nbsp; Methods Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. & nbsp; Findings Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR < 0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4 +T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. & nbsp; Interpretation Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems.& nbsp; & nbsp; Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Superscript/Subscript Available

Published
2022

13. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O'Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C. B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Penninx, Brenda W. J. H., Perlis, Roy H., Porteous, David J., Potash, James B., Preisig, Martin, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., O'Connell, Kevin S., Coombes, Brandon, Qiao, Zhen, Als, Thomas D., Børte, Sigrid, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Gizer, Ian R., Gordon-Smith, Katherine, Greenwood, Tiffany A., Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lundberg, Martin, Magnusson, Sigurdur H., Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, McGregor, Nathaniel W., McKay, James D., Medeiros, Helena, Millischer, Vincent, Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Quested, Digby, Raj, Towfique, Rapaport, Mark H., Regeer, Eline J., Rivas, Fabio, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Xi, Simon, Xu, Wei, Kay Yang, Jessica Mei, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dikeos, Dimitris, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Mitchell, Philip B., Morken, Gunnar, Mowry, Bryan, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Oedegaard, Ketil J., Olsson, Tomas, Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Stordal, Eystein, Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., Andreassen, Ole A., Adan, Roger A. H., Ando, Tetsuya, Aschauer, Harald, Baker, Jessica H., Bencko, Vladimir, Bergen, Andrew W., Birgegård, Andreas, Boden, Joseph M., Boehm, Ilka, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Buehren, Katharina, Bulik, Cynthia M., Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Clementi, Maurizio, Cone, Roger D., Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S. P., de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dina, Christian, Dmitrzak-Weglarz, Monika, Martinez, Elisa Docampo, Duncan, Laramie E., Egberts, Karin, Marshall, Christian R., Mattingsdal, Morten, McDevitt, Sara, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Munn-Chernoff, Melissa A., Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, Olsen, Catherine M., O'Toole, Julie K., Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Parker, Richard, Pearson, John F., Ehrlich, Stefan, Escaramís, Geòrgia, Espeseth, Thomas, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Fischer, Krista, Floyd, James A. B., Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Franklin, Christopher S., Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Giuranna, Johanna, Giusti-Rodríquez, Paola, Gonidakis, Fragiskos, Gordon, Scott, Gorwood, Philip, Mayora, Monica Gratacos, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hanscombe, Ken B., Hatzikotoulas, Konstantinos, Hebebrand, Johannes, Helder, Sietske G., Henders, Anjali K., Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Horwood, L. John, Hübel, Christopher, Petersen, Liselotte V., Pinto, Dalila, Purves, Kirstin L., Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Schork, Nicholas J., Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op 't Landt, Margarita C. T., Slopien, Agnieszka, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar W., Strober, Michael, Huckins, Laura M., Hudson, James I., Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jennifer, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaplan, Allan S., Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J. H., Kaye, Walter H., Kennedy, Martin A., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Kirk, Katherine M., Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., Larsen, Janne T., Le Hellard, Stephanie, Leppä, Virpi M., Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lin, Bochao Danae, Lundervold, Astri, Luykx, Jurjen, Magistretti, Pierre J., Maj, Mario, Mannik, Katrin, Marsal, Sara, Stuber, Garret D., Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Thornton, Laura M., Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Wade, Tracey D., Wagner, Gudrun, Walton, Esther, Watson, Hunna J., Whiteman, David C., Wichmann, H. Erich, Widen, Elisabeth, Woodside, D. Blake, Yao, Shuyang, Yilmaz, Zeynep, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Jungkunz, Martin, Mullins, N., Kang, J., Campos, A. I., Coleman, J. R. I., Edwards, A. C., Galfalvy, H., Levey, D. F., Lori, A., Shabalin, A., Starnawska, A., Su, M. -H., Watson, H. J., Adams, M., Awasthi, S., Gandal, M., Hafferty, J. D., Hishimoto, A., Kim, M., Okazaki, S., Otsuka, I., Ripke, S., Ware, E. B., Bergen, A. W., Berrettini, W. H., Bohus, M., Brandt, H., Chang, X., Chen, W. J., Chen, H. -C., Crawford, S., Crow, S., Diblasi, E., Duriez, P., Fernandez-Aranda, F., Fichter, M. M., Gallinger, S., Glatt, S. J., Gorwood, P., Guo, Y., Hakonarson, H., Halmi, K. A., Hwu, H. -G., Jain, S., Jamain, S., Jimenez-Murcia, S., Johnson, C., Kaplan, A. S., Kaye, W. H., Keel, P. K., Kennedy, J. L., Klump, K. L., Li, D., Liao, S. -C., Lieb, K., Lilenfeld, L., Liu, C. -M., Magistretti, P. J., Marshall, C. R., Mitchell, J. E., Monson, E. T., Myers, R. M., Pinto, D., Powers, A., Ramoz, N., Roepke, S., Rozanov, V., Scherer, S. W., Schmahl, C., Sokolowski, M., Strober, M., Thornton, L. M., Treasure, J., Tsuang, M. T., Witt, S. H., Woodside, D. B., Yilmaz, Z., Zillich, L., Adolfsson, R., Agartz, I., Air, T. M., Alda, M., Alfredsson, L., Andreassen, O. A., Anjorin, A., Appadurai, V., Soler Artigas, M., Van der Auwera, S., Azevedo, M. H., Bass, N., Bau, C. H. D., Baune, B. T., Bellivier, F., Berger, K., Biernacka, J. M., Bigdeli, T. B., Binder, E. B., Boehnke, M., Boks, M. P., Bosch, R., Braff, D. L., Bryant, R., Budde, M., Byrne, E. M., Cahn, W., Casas, M., Castelao, E., Cervilla, J. A., Chaumette, B., Cichon, S., Corvin, A., Craddock, N., Craig, D., Degenhardt, F., Djurovic, S., Edenberg, H. J., Fanous, A. H., Foo, J. C., Forstner, A. J., Frye, M., Fullerton, J. M., Gatt, J. M., Gejman, P. V., Giegling, I., Grabe, H. J., Green, M. J., Grevet, E. H., Grigoroiu-Serbanescu, M., Gutierrez, B., Guzman-Parra, J., Hamilton, S. P., Hamshere, M. L., Hartmann, A., Hauser, J., Heilmann-Heimbach, S., Hoffmann, P., Ising, M., Jones, I., Jones, L. A., Jonsson, L., Kahn, R. S., Kelsoe, J. R., Kendler, K. S., Kloiber, S., Koenen, K. C., Kogevinas, M., Konte, B., Krebs, M. -O., Landen, M., Lawrence, J., Leboyer, M., Lee, P. H., Levinson, D. F., Liao, C., Lissowska, J., Lucae, S., Mayoral, F., Mcelroy, S. L., Mcgrath, P., Mcguffin, P., Mcquillin, A., Medland, S. E., Mehta, D., Melle, I., Milaneschi, Y., Mitchell, P. B., Molina, E., Morken, G., Mortensen, P. B., Muller-Myhsok, B., Nievergelt, C., Nimgaonkar, V., Nothen, M. M., O'Donovan, M. C., Ophoff, R. A., Owen, M. J., Pato, C., Pato, M. T., Penninx, B. W. J. H., Pimm, J., Pistis, G., Potash, J. B., Power, R. A., Preisig, M., Quested, D., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Richarte, V., Rietschel, M., Rivera, M., Roberts, A., Roberts, G., Rouleau, G. A., Rovaris, D. L., Rujescu, D., Sanchez-Mora, C., Sanders, A. R., Schofield, P. R., Schulze, T. G., Scott, L. J., Serretti, A., Shi, J., Shyn, S. I., Sirignano, L., Sklar, P., Smeland, O. B., Smoller, J. W., Sonuga-Barke, E. J. S., Spalletta, G., Strauss, J. S., Swiatkowska, B., Trzaskowski, M., Turecki, G., Vilar-Ribo, L., Vincent, J. B., Volzke, H., Walters, J. T. R., Shannon Weickert, C., Weickert, T. W., Weissman, M. M., Williams, L. M., Wray, N. R., Zai, C. C., Ashley-Koch, A. E., Beckham, J. C., Hauser, E. R., Hauser, M. A., Kimbrel, N. A., Lindquist, J. H., Mcmahon, B., Oslin, D. W., Qin, X., Mattheisen, M., Abdellaoui, A., Adams, M. J., Agerbo, E., Andlauer, T. F. M., Bacanu, S. -A., Baekvad-Hansen, M., Beekman, A. T. F., Bryois, J., Buttenschon, H. N., Bybjerg-Grauholm, J., Cai, N., Christensen, J. H., Clarke, T. -K., Colodro-Conde, L., Couvy-Duchesne, B., Crawford, G. E., Davies, G., Derks, E. M., Direk, N., Dolan, C. V., Dunn, E. C., Eley, T. C., Escott-Price, V., Hassan Kiadeh, F. F., Finucane, H. K., Frank, J., Gaspar, H. A., Gill, M., Goes, F. S., Gordon, S. D., Weinsheimer, S. M., Wellmann, J., Willemsen, G., Wu, Y., Xi, H. S., Yang, J., Zhang, F., Arolt, V., Boomsma, D. I., Dannlowski, U., Depaulo, J. R., Domenici, E., Domschke, K., Esko, T., Grove, J., Hall, L. S., Hansen, C. S., Hansen, T. F., Herms, S., Hickie, I. B., Homuth, G., Horn, C., Hottenga, J. -J., Hougaard, D. M., Howard, D. M., Jansen, R., Jorgenson, E., Knowles, J. A., Kohane, I. S., Kraft, J., Kretzschmar, W. W., Kutalik, Z., Li, Y., Lind, P. A., Macintyre, D. J., Mackinnon, D. F., Maier, R. M., Maier, W., Marchini, J., Mbarek, H., Middeldorp, C. M., Mihailov, E., Milani, L., Mondimore, F. M., Montgomery, G. W., Mostafavi, S., Nauck, M., Ng, B., Nivard, M. G., Nyholt, D. R., O'Reilly, P. F., Oskarsson, H., Hayward, C., Heath, A. C., Lewis, G., Li, Q. S., Madden, P. A. F., Magnusson, P. K., Martin, N. G., Mcintosh, A. M., Metspalu, A., Mors, O., Nordentoft, M., Paciga, S. A., Pedersen, N. L., Painter, J. N., Pedersen, C. B., Pedersen, M. G., Peterson, R. E., Peyrot, W. J., Posthuma, D., Quiroz, J. A., Qvist, P., Rice, J. P., Riley, B. P., Mirza, S. S., Schoevers, R., Schulte, E. C., Shen, L., Sigurdsson, E., Sinnamon, G. C. B., Smit, J. H., Smith, D. J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K. E., Teismann, H., Teumer, A., Thompson, W., Thomson, P. A., Thorgeirsson, T. E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A. G., Umbricht, D., der Auwera, S. V., van Hemert, A. M., Viktorin, A., Visscher, P. M., Wang, Y., Webb, B. T., Perlis, R. H., Porteous, D. J., Schaefer, C., Stefansson, K., Tiemeier, H., Uher, R., Werge, T., Lewis, C. M., Breen, G., Borglum, A. D., Sullivan, P. F., O'Connell, K. S., Coombes, B., Qiao, Z., Als, T. D., Borte, S., Charney, A. W., Drange, O. K., Gandal, M. J., Hagenaars, S. P., Ikeda, M., Kamitaki, N., Krebs, K., Panagiotaropoulou, G., Schilder, B. M., Sloofman, L. G., Winsvold, B. S., Won, H. -H., Abramova, L., Adorjan, K., Al Eissa, M., Albani, D., Alliey-Rodriguez, N., Antilla, V., Antoniou, A., Baek, J. H., Bauer, M., Beins, E. C., Bergen, S. E., Birner, A., Boen, E., Brum, M., Brumpton, B. M., Brunkhorst-Kanaan, N., Byerley, W., Cairns, M., Cervantes, P., Cruceanu, C., Cuellar-Barboza, A., Cunningham, J., Curtis, D., Czerski, P. M., Dale, A. M., Dalkner, N., David, F. S., Dobbyn, A. L., Douzenis, A., Elvsashagen, T., Ferrier, I. N., Fiorentino, A., Foroud, T. M., Forty, L., Frei, O., Freimer, N. B., Frisen, L., Gade, K., Garnham, J., Gelernter, J., Gizer, I. R., Gordon-Smith, K., Greenwood, T. A., Ha, K., Haraldsson, M., Hautzinger, M., Heilbronner, U., Hellgren, D., Holmans, P. A., Huckins, L., Johnson, J. S., Kalman, J. L., Kamatani, Y., Kittel-Schneider, S., Koromina, M., Kranz, T. M., Kranzler, H. R., Kubo, M., Kupka, R., Kushner, S. A., Lavebratt, C., Leber, M., Lee, H. -J., Levy, S. E., Lewis, C., Lundberg, M., Magnusson, S. H., Maihofer, A., Malaspina, D., Maratou, E., Martinsson, L., Mcgregor, N. W., Mckay, J. D., Medeiros, H., Millischer, V., Moran, J. L., Morris, D. W., Muhleisen, T. W., O'Brien, N., O'Donovan, C., Olde Loohuis, L. M., Oruc, L., Papiol, S., Pardinas, A. F., Perry, A., Pfennig, A., Porichi, E., Raj, T., Rapaport, M. H., Regeer, E. J., Rivas, F., Roth, J., Roussos, P., Ruderfer, D. M., Senner, F., Sharp, S., Shilling, P. D., Slaney, C., Sobell, J. L., Artigas, M. S., Spijker, A. T., Stein, D. J., Terao, C., Toma, C., Tooney, P., Tsermpini, E. -E., Vawter, M. P., Vedder, H., Xi, S., Xu, W., Kay Yang, J. M., Young, A. H., Young, H., Zandi, P. P., Zhou, H., HUNT All-In, Psychiatry, Babadjanova, G., Backlund, L., Bengesser, S., Blackwood, D. H. R., Carr, V. J., Catts, S., Dikeos, D., Etain, B., Ferentinos, P., Gawlik, M., Gershon, E. S., Henskens, F., Hillert, J., Hong, K. S., Hultman, C. M., Hveem, K., Iwata, N., Jablensky, A. V., Kirov, G., Lochner, C., Loughland, C., Mathews, C. A., Mcmahon, F. J., Michie, P., Mowry, B., Neale, B. M., Nievergelt, C. M., Oedegaard, K. J., Olsson, T., Pantelis, C., Patrinos, G. P., Reininghaus, E. Z., Saito, T., Schall, U., Schalling, M., Scott, R. J., Weickert, C. S., Stordal, E., Vaaler, A. E., Vieta, E., Waldman, I. D., Zwart, J. -A., Nurnberger, J. I., Stahl, E. A., Di Florio, A., Adan, R. A. H., Ando, T., Aschauer, H., Baker, J. H., Bencko, V., Birgegard, A., Boden, J. M., Boehm, I., Boni, C., Perica, V. B., Buehren, K., Bulik, C. M., Burghardt, R., Carlberg, L., Cassina, M., Clementi, M., Cone, R. D., Courtet, P., Crowley, J. J., Danner, U. N., Davis, O. S. P., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J. E., Dick, D. M., Dina, C., Dmitrzak-Weglarz, M., Martinez, E. D., Duncan, L. E., Egberts, K., Mattingsdal, M., Mcdevitt, S., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., Ntalla, I., Olsen, C. M., O'Toole, J. K., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Parker, R., Pearson, J. F., Ehrlich, S., Escaramis, G., Espeseth, T., Estivill, X., Farmer, A., Favaro, A., Fischer, K., Floyd, J. A. B., Focker, M., Foretova, L., Forzan, M., Franklin, C. S., Gambaro, G., Giuranna, J., Giusti-Rodriquez, P., Gonidakis, F., Gordon, S., Mayora, M. G., Guillaume, S., Hanscombe, K. B., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Henders, A. K., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Horwood, L. J., Hubel, C., Petersen, L. V., Purves, K. L., Raevuori, A., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op 't Landt, M. C. T., Slopien, A., Soranzo, N., Sorbi, S., Southam, L., Steen, V. W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jordan, J., Julia, A., Kalsi, G., Kaminska, D., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, M. A., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Kirk, K. M., Klareskog, L., Knudsen, G. P. S., Larsen, J. T., Le Hellard, S., Leppa, V. M., Lichtenstein, P., Lin, B. D., Lundervold, A., Luykx, J., Maj, M., Mannik, K., Marsal, S., Stuber, G. D., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wade, T. D., Wagner, G., Walton, E., Whiteman, D. C., Wichmann, H. E., Widen, E., Yao, S., Zeggini, E., Zerwas, S., Zipfel, S., Jungkunz, M., Dietl, L., Schwarze, C. E., Dahmen, N., Schott, B. H., Mobascher, A., Crivelli, S., Dennis, M. F., Harvey, P. D., Carter, B. W., Huffman, J. E., Jacobson, D., Madduri, R., Olsen, M. K., Pestian, J., Gaziano, J. M., Muralidhar, S., Ramoni, R., Beckham, J., Chang, K. -M., O'Donnell, C. J., Tsao, P. S., Breeling, J., Huang, G., Romero, J. P. C., Moser, J., Whitbourne, S. B., Brewer, J. V., Aslan, M., Connor, T., Argyres, D. P., Stephens, B., Brophy, M. T., Humphries, D. E., Selva, L. E., Do, N., Shayan, S., Cho, K., Pyarajan, S., Hauser, E., Sun, Y., Zhao, H., Wilson, P., Mcardle, R., Dellitalia, L., Mattocks, K., Harley, J., Zablocki, C. J., Whittle, J., Jacono, F., Gutierrez, S., Gibson, G., Hammer, K., Kaminsky, L., Villareal, G., Kinlay, S., Xu, J., Hamner, M., Mathew, R., Bhushan, S., Iruvanti, P., Godschalk, M., Ballas, Z., Ivins, D., Mastorides, S., Moorman, J., Gappy, S., Klein, J., Ratcliffe, N., Florez, H., Okusaga, O., Murdoch, M., Sriram, P., Yeh, S. S., Tandon, N., Jhala, D., Aguayo, S., Cohen, D., Sharma, S., Liangpunsakul, S., Oursler, K. A., Whooley, M., Ahuja, S., Constans, J., Meyer, P., Greco, J., Rauchman, M., Servatius, R., Gaddy, M., Wallbom, A., Morgan, T., Stapley, T., Sherman, S., Ross, G., Tsao, P., Strollo, P., Boyko, E., Meyer, L., Gupta, S., Huq, M., Fayad, J., Hung, A., Lichy, J., Hurley, R., Robey, B., Striker, R., Erlangsen, A., Kessler, R. C., Porteous, D., Ursano, R. J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards A.C., Galfalvy H., Levey D.F., Lori A., Shabalin A., Starnawska A., Su M.-H., Watson H.J., Adams M., Awasthi S., Gandal M., Hafferty J.D., Hishimoto A., Kim M., Okazaki S., Otsuka I., Ripke S., Ware E.B., Bergen A.W., Berrettini W.H., Bohus M., Brandt H., Chang X., Chen W.J., Chen H.-C., Crawford S., Crow S., DiBlasi E., Duriez P., Fernandez-Aranda F., Fichter M.M., Gallinger S., Glatt S.J., Gorwood P., Guo Y., Hakonarson H., Halmi K.A., Hwu H.-G., Jain S., Jamain S., Jimenez-Murcia S., Johnson C., Kaplan A.S., Kaye W.H., Keel P.K., Kennedy J.L., Klump K.L., Li D., Liao S.-C., Lieb K., Lilenfeld L., Liu C.-M., Magistretti P.J., Marshall C.R., Mitchell J.E., Monson E.T., Myers R.M., Pinto D., Powers A., Ramoz N., Roepke S., Rozanov V., Scherer S.W., Schmahl C., Sokolowski M., Strober M., Thornton L.M., Treasure J., Tsuang M.T., Witt S.H., Woodside D.B., Yilmaz Z., Zillich L., Adolfsson R., Agartz I., Air T.M., Alda M., Alfredsson L., Andreassen O.A., Anjorin A., Appadurai V., Soler Artigas M., Van der Auwera S., Azevedo M.H., Bass N., Bau C.H.D., Baune B.T., Bellivier F., Berger K., Biernacka J.M., Bigdeli T.B., Binder E.B., Boehnke M., Boks M.P., Bosch R., Braff D.L., Bryant R., Budde M., Byrne E.M., Cahn W., Casas M., Castelao E., Cervilla J.A., Chaumette B., Cichon S., Corvin A., Craddock N., Craig D., Degenhardt F., Djurovic S., Edenberg H.J., Fanous A.H., Foo J.C., Forstner A.J., Frye M., Fullerton J.M., Gatt J.M., Gejman P.V., Giegling I., Grabe H.J., Green M.J., Grevet E.H., Grigoroiu-Serbanescu M., Gutierrez B., Guzman-Parra J., Hamilton S.P., Hamshere M.L., Hartmann A., Hauser J., Heilmann-Heimbach S., Hoffmann P., Ising M., Jones I., Jones L.A., Jonsson L., Kahn R.S., Kelsoe J.R., Kendler K.S., Kloiber S., Koenen K.C., Kogevinas M., Konte B., Krebs M.-O., Landen M., Lawrence J., Leboyer M., Lee P.H., Levinson D.F., Liao C., Lissowska J., Lucae S., Mayoral F., McElroy S.L., McGrath P., McGuffin P., McQuillin A., Medland S.E., Mehta D., Melle I., Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

14. The role of viral genomics in understanding COVID-19 outbreaks in long-term care facilities

Author

Thomas R. Connor, Ian Goodfellow, Meera Chand, Maria Zambon, M. Estée Török, Niamh Tumelty, Emma Meader, Andrew J. Page, Samuel Robson, Darren Smith, Declan Bradley, Laura Shallcross, Sharon J. Peacock, William L Hamilton, Tehmina Bharucha, Justin O'Grady, Richard M. Myers, Matthew Bashton, Colin S Brown, Dinesh Aggarwal, Aggarwal, Dinesh [0000-0002-5938-8172], Tumelty, Niamh [0000-0002-9894-6034], Goodfellow, Ian [0000-0002-9483-510X], Peacock, Sharon [0000-0002-1718-2782], and Apollo - University of Cambridge Repository

Subjects
Microbiology (medical), Medicine (General), medicine.medical_specialty, Genomics, Review, Biology, Disease cluster, Microbiology, Disease Outbreaks, R5-920, Virology, Environmental health, Epidemiology, medicine, Infection control, Humans, Whole genome sequencing, Transmission (medicine), SARS-CoV-2, Outbreak, COVID-19, C500, Long-Term Care, QR1-502, B900, Long-term care, Infectious Diseases
Abstract

We reviewed all genomic epidemiology studies on COVID-19 in long term care facilities (LTCF) that had been published to date. We found that staff and residents were usually infected with identical, or near identical, SARS-CoV-2 genomes. Outbreaks usually involved one predominant cluster, and the same lineages persisted in LTCFs despite infection control measures. Outbreaks were most commonly due to single or few introductions followed by spread rather than a series of seeding events from the community into LTCFs. Sequencing of samples taken consecutively from the same cases showed persistence of the same genome sequence indicating that the sequencing technique was robust over time. When combined with local epidemiology, genomics facilitated likely transmission sources to be better characterised. Transmission between LTCFs was detected in multiple studies. The mortality rate amongst residents was high in all cases, regardless of the lineage. Bioinformatics methods were inadequate in one third of the studies reviewed, and reproducing the analyses was difficult as sequencing data were not available in many cases., BBSRC, Research England E3 Fund, Wellcome Trust, Academy of Medical Sciences and the Health Foundation, MRC, NIHR

Published
2021

15. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author

Arianna DiFlorio, Patrick F. Sullivan, Sebastian Zöllner, Margarita Rivera, Richard M. Myers, Stanley J. Watson, Jun Li, Anders Juréus, Sarah E. Bergen, Gonçalo R. Abecasis, Jordan W. Smoller, Michael Conlon O'Donovan, Neil Risch, Hoang T. Nguyen, Chen Jiang, Xiaoming Jia, Mehdi Pirooznia, Danielle Posthuma, Adam E. Locke, Peter P. Zandi, John B. Vincent, Niamh Mullins, Duncan Palmer, Shaun Purcell, Gerome Breen, Christina M. Hultman, Andreas Reif, Khanh K. Thai, Virginia L. Willour, Pui-Yan Kwok, Laura J. Scott, Anne U. Jackson, Michael John Owen, Fernando S. Goes, Steven A. McCarroll, James B. Potash, Mikael Landén, Jennifer L. Moran, Michele T. Pato, Hyun Min Kang, Marco P. Boks, Sinéad B. Chapman, W. Richard McCombie, Janet L. Sobell, Matthew Zawistowski, Rolf Adolfsson, Yongwen Zhuang, Michael Boehnke, René S. Kahn, Huda Akil, James T.R. Walters, Margit Burmeister, Douglas Blackwood, Cathryn M. Lewis, Eli A. Stahl, Mark N. Kvale, Melissa DelaBastide, Catherine Schaefer, Benjamin M. Neale, Giulio Genovese, Carlos N. Pato, Nicholas John Craddock, Andrew McQuillin, Shawn Levy, Aiden Corvin, Pamela Sklar, Weiqing Wang, Andrew M. McIntosh, Ling Shen, Eric T. Monson, Derek W. Morris, Douglas M. Ruderfer, Roel A. Ophoff, Peter McGuffin, Sarah Cohen-Woods, Willem H. Ouwehand, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Goes, Fernando S [0000-0001-6262-8264], Locke, Adam E [0000-0001-6227-198X], Palmer, Duncan [0000-0002-0824-0047], Wang, Weiqing [0000-0003-1565-0148], Genovese, Giulio [0000-0003-3066-5575], Jackson, Anne U [0000-0002-9672-2547], Nguyen, Hoang [0000-0001-6910-7269], Pirooznia, Mehdi [0000-0002-4210-6458], Zawistowski, Matthew [0000-0002-3005-083X], Abecasis, Gonçalo [0000-0003-1509-1825], Bergen, Sarah [0000-0002-5888-0034], Burmeister, Margit [0000-0002-1914-2434], Kwok, Pui-Yan [0000-0002-5087-3059], Li, Jun Z [0000-0001-6727-0812], Levy, Shawn E [0000-0002-1369-5740], Watson, Stanley [0000-0003-4980-5523], Blackwood, Douglas [0000-0002-4076-9346], Boehnke, Michael [0000-0002-6442-7754], Breen, Gerome [0000-0003-2053-1792], Landen, Mikael [0000-0002-4496-6451], Lewis, Cathryn [0000-0002-8249-8476], McCarroll, Steven A [0000-0002-6954-8184], McIntosh, Andrew [0000-0002-0198-4588], McQuillin, Andrew [0000-0003-1567-2240], Morris, Derek [0000-0002-3413-570X], O'Donovan, Michael [0000-0001-7073-2379], Boks, Marco [0000-0001-6163-7484], Kahn, Rene [0000-0001-5909-8004], Ouwehand, Willem [0000-0002-7744-1790], Owen, Michael [0000-0003-4798-0862], Potash, James B [0000-0002-5802-8079], Reif, Andreas [0000-0002-0992-634X], Vincent, John [0000-0003-0692-2519], Neale, Benjamin [0000-0003-1513-6077], Purcell, Shaun [0000-0002-7402-5812], Schaefer, Catherine [0000-0003-2644-055X], Stahl, Eli A [0000-0002-1192-0561], Zandi, Peter P [0000-0001-8423-2623], Scott, Laura J [0000-0002-4886-5084], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health

Subjects
Bipolar Disorder, Genome-wide association study, Biology, Medical and Health Sciences, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Clinical Research, Genetic variation, medicine, Genetics, 2.1 Biological and endogenous factors, Humans, Exome, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Molecular Biology, Gene, 030304 developmental biology, Medicinsk genetik, Psychiatry, 0303 health sciences, Prevention, Human Genome, Psychology and Cognitive Sciences, Genetic Variation, Single Nucleotide, Heritability, Biological Sciences, medicine.disease, Serious Mental Illness, Phenotype, 3. Good health, Brain Disorders, Psychiatry and Mental health, Mental Health, Schizophrenia, Medical Genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., International Bipolar Sequencing Consortium (NIMH) R01 MH 110437, Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) UO1 MH105653, Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) R01 MH 094145, Multi-ethnic GWAS of Bipolar I Disorder (NIH) R01 MH 085543, Genetic Epidemiology Research in Adult Health and Aging (GERA) RC2 AG036607, Kaiser Permanente Research Program on Genes, Environment, and Health, Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) R01 MH 087979 MH 087992, 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH095034, 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106531, 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH077139, 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106527, Dalio Foundation

Published
2021

16. A study of elective genome sequencing and pharmacogenetic testing in an unselected population

Author

Molly C Schroeder, Troy Moore, Richard M. Myers, Katherine Odom, Kelly M. East, Whitley V. Kelley, Melissa Kelly, Meagan Cochran, David Bick, and Veronica Greve

Subjects
Adult, Male, medicine.medical_specialty, Pharmacogenomic Variants, elective genome, Population, clonal hematopoiesis of indeterminate potential, Genomics, Disease, QH426-470, DNA sequencing, Gene Frequency, carrier, Internal medicine, Genetics, Medicine, Humans, Medical history, Genetic Testing, Molecular Biology, Genetics (clinical), Likely pathogenic, pharmacogenetics, Whole Genome Sequencing, business.industry, Original Articles, Middle Aged, Healthy Volunteers, Phenotype, Unselected population, Original Article, Female, Personalized medicine, business, Pharmacogenetics
Abstract

Background Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. Methods Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. Results Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty‐four participants (85%) were carriers of a recessive or X‐linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. Conclusion Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS., Genome sequencing (GS) of individuals without a medical indication is referred to as elective GS. Among 52 individuals undergoing elective GS, 11.5% (6/52) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history, 19% (10/52) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential, 85% (44/52) were carriers of a recessive or X‐linked disorder, and 100% of individuals with pharmacogenetic testing had variants that affected current and/or future medications.

Published
2021

17. A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Author

Juliana Acosta-Uribe, David Aguillón, J. Nicholas Cochran, Margarita Giraldo, Lucía Madrigal, Bradley W. Killingsworth, Rijul Singhal, Sarah Labib, Diana Alzate, Lina Velilla, Sonia Moreno, Gloria P. García, Amanda Saldarriaga, Francisco Piedrahita, Liliana Hincapié, Hugo E. López, Nithesh Perumal, Leonilde Morelo, Dionis Vallejo, Juan Marcos Solano, Eric M. Reiman, Ezequiel I. Surace, Tatiana Itzcovich, Ricardo Allegri, Raquel Sánchez-Valle, Andrés Villegas-Lanau, Charles L. White, Diana Matallana, Richard M. Myers, Sharon R. Browning, Francisco Lopera, and Kenneth S. Kosik

Subjects
Flujo Genético, Efecto Fundador, Genetic Drift, Neurodegenerative Diseases, Enfermedades Neurodegenerativas, Colombia, Founder Effect, Alzheimer Disease, Enfermedad de Alzheimer, Frontotemporal Dementia, Mutation, Genetics, Demografía, Molecular Medicine, Humans, Enfermedad de la Neurona Motora, Motor Neuron Disease, Frontotemporal Lobar Degeneration, Molecular Biology, Genetics (clinical), Demography, Demencia Frontotemporal
Abstract

Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Published
2021

18. Targeting of the CD80/86 proinflammatory axis as a therapeutic strategy to prevent severe COVID-19

Author

Mireia López-Corbeto, Antonio Gomez, Richard M. Myers, Iván Rodríguez-Núñez, Irene Bonafonte-Pardàs, Sergio H Martínez-Mateu, Antonio Julià, María López-Lasanta, Jordi Lladós, S. Marsal, Institut Català de la Salut, [Julià A, Bonafonte-Pardàs I, Gómez A, López-Lasanta M, López-Corbeto M, Martínez-Mateu SH, Lladós J, Marsal S] Grup de Recerca en Reumatologia, Servei de Reumatologia, Vall d’Hebron Hospital Institut de Recerca (VHIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, medicine.medical_treatment, Inflammatory diseases, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Severity of Illness Index, Arthritis, Rheumatoid, 0302 clinical medicine, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Medicine, RNA-Seq, 0303 health sciences, Multidisciplinary, medicine.diagnostic_test, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Middle Aged, Up-Regulation, enfermedades musculoesqueléticas::artropatías::artritis::artritis reumatoide [ENFERMEDADES], 3. Good health, Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Immunologic Factors::Immunosuppressive Agents [CHEMICALS AND DRUGS], Observational Studies as Topic, Cytokine release syndrome, Cytokine, 030220 oncology & carcinogenesis, Cohort, B7-1 Antigen, Female, Single-Cell Analysis, Cytokine Release Syndrome, Bronchoalveolar Lavage Fluid, Musculoskeletal Diseases::Joint Diseases::Arthritis::Arthritis, Rheumatoid [DISEASES], Immunosuppressive Agents, Signal Transduction, medicine.drug, China, Science, Artritis reumatoide - Tractament, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Article, Proinflammatory cytokine, Abatacept, 03 medical and health sciences, Therapeutic approach, COVID-19 (Malaltia) - Tractament, Target identification, Humans, Aged, 030304 developmental biology, SARS-CoV-2, business.industry, COVID-19, Medicaments immunosupressors - Ús terapèutic, medicine.disease, United States, COVID-19 Drug Treatment, Bronchoalveolar lavage, Viral infection, Spain, Immunology, B7-2 Antigen, business, Cytokine storm, acciones y usos químicos::acciones farmacológicas::efectos fisiológicos de los fármacos::factores inmunitarios::inmunosupresores [COMPUESTOS QUÍMICOS Y DROGAS]
Abstract

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Malalties inflamatòries; Identificació de l'objectiu; Infecció viral Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Enfermedades inflamatorias; Identificación del objetivo; Infección viral Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflammatory diseases; Target identification; Viral infection An excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19. The PACTABA project was funded Bristol-Myers Squibb. We thank all participants from the PACTABA study for their collaboration. AJ and SM are supported by the DoCTIS project funded by the European Union’s H2020 programme (Grant #848028). This work was supported by funds from the Vall d’Hebron Hospital Research Institute and from IMIDomics S.L. We thank Dr Ariel Jaitovich (Albany Medical Centre, USA) for providing additional clinical data on the late COVID-19 cohort.

Published
2021

19. A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS

Author

Hemali Phatnani, Sarah A. Dugger, Timothy F. Harris, Cristiane de Araújo Martins Moreno, Zhong Ren, Brittany N. Lasseigne, Neil A. Shneider, Slavé Petrovski, Elizabeth T. Cirulli, Andrew S. Allen, Sahar Gelfman, Charles J. Wolock, Tom Maniatis, Matthew B. Harms, Guy A. Rouleau, David Goldstein, Richard M. Myers, Aaron D. Gitler, and Robert H. Brown

Subjects
Male, Candidate gene, DNA Mutational Analysis, Protein domain, Method, Genome-wide association study, Computational biology, Biology, Genome, TARDBP, White People, 03 medical and health sciences, Superoxide Dismutase-1, 0302 clinical medicine, Protein Domains, Risk Factors, Exome Sequencing, Genetic variation, Genetics, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, Amyotrophic Lateral Sclerosis, Genetic Variation, NIMA-Related Kinase 1, Mutation, RNA-Binding Protein FUS, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes, including SOD1, NEK1, TARDBP, and FUS. While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

Published
2019

20. Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr)

Author

Lucia Madrigal, Margarita Giraldo, Ana Baena, Kenneth S. Kosik, J. Nicholas Cochran, Yakeel T. Quiroz, G. Garcia, Amanda Saldarriaga, Richard M. Myers, Daniel Camilo Aguirre-Acevedo, Ethan G. Geier, David Aguillon, Juliana Acosta-Uribe, Laura Ramirez Aguilar, Francisco Lopera, Jennifer S. Yokoyama, Rosario Cuastumal, Alexander Navarro, Sonia Moreno, and Diana Alzate

Subjects
Male, 0301 basic medicine, Aging, Epidemiology, Neurodegenerative, Alzheimer's Disease, Genetic analysis, Admixture in Latin America, 0302 clinical medicine, PSEN1, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Age of Onset, Autosomal dominant Alzheimer's disease, Genetics, education.field_of_study, Presenilin 1, Health Policy, Founder effect, Genetic Bottleneck, Middle Aged, Psychiatry and Mental health, Phenotype, Neurological, Mutation (genetic algorithm), Female, Adult, Clinical Sciences, Population, Mutation, Missense, Colombia, Biology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Genetic drift, Alzheimer Disease, Acquired Cognitive Impairment, Presenilin-1, Humans, education, Whole Genome Sequencing, Human Genome, Haplotype, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, 030104 developmental biology, Phenotype genotype correlation, Geriatrics, Mutation, Dementia, Neurology (clinical), Missense, Geriatrics and Gerontology, 030217 neurology & neurosurgery
Abstract

Introduction A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. Methods We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. Results Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). Discussion Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Published
2019

21. Genome-wide strand asymmetry in massively parallel reporter activity favors genic strands

Author

Jay Shendure, Gregory M. Cooper, Bryan A. Moyers, Vikram Agarwal, E. Christopher Partridge, Brian S. Roberts, Richard M. Myers, Kimberly M. Newberry, and Beth Martin

Subjects
0303 health sciences, Genome evolution, Genome, Human, Research, Alu element, Retrotransposon, Computational biology, Biology, Regulatory Sequences, Nucleic Acid, Genome, 03 medical and health sciences, 0302 clinical medicine, Sense strand, Gene Expression Regulation, Transcription (biology), Genes, Reporter, Genetics, Humans, Human genome, Enhancer, Gene, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Abstract

Massively parallel reporter assays (MPRAs) are useful tools to characterize regulatory elements in human genomes. An aspect of MPRAs that is not typically the focus of analysis is their intrinsic ability to differentiate activity levels for a given sequence element when placed in both of its possible orientations relative to the reporter construct. Here, we describe pervasive strand asymmetry of MPRA signals in data sets from multiple reporter configurations in both published and newly reported data. These effects are reproducible across different cell types and in different treatments within a cell type and are observed both within and outside of annotated regulatory elements. From elements in gene bodies, MPRA strand asymmetry favors the sense strand, suggesting that function related to endogenous transcription is driving the phenomenon. Similarly, we find that within Alu mobile element insertions, strand asymmetry favors the transcribed strand of the ancestral retrotransposon. The effect is consistent across the multiplicity of Alu elements in human genomes and is more pronounced in less diverged Alu elements. We find sequence features driving MPRA strand asymmetry and show its prediction from sequence alone. We see some evidence for RNA stabilization and transcriptional activation mechanisms and hypothesize that the effect is driven by natural selection favoring efficient transcription. Our results indicate that strand asymmetry is a pervasive and reproducible feature in MPRA data. More importantly, the fact that MPRA asymmetry favors naturally transcribed strands suggests that it stems from preserved biological functions that have a substantial, global impact on gene and genome evolution.

Published
2021

22. Mass testing after a single suspected or confirmed case of COVID-19 in London care homes, April–May 2020: implications for policy and practice

Author

Anita Bell, Shamez N Ladhani, Richard M. Myers, Maria Saavedra-Campos, Nandini Shetty, Edward Wynne-Evans, Thomas Ma, B. Patel, Jonathan Fok, Suzanne Tang, Marina Sanchez Perez, Emma Crawley-Boevey, Kate Dun-Campbell, Elena Fernandez, Yimmy Chow, Zahin Amin-Chowdhury, Amoolya Vusirikala, Karthikeyan Paranthaman, Roshni Janarthanan, and Maria Zambon

Subjects
Aging, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Care homes, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 030204 cardiovascular system & hematology, Disease Outbreaks, older people, 03 medical and health sciences, AcademicSubjects/MED00280, 0302 clinical medicine, COVID-19 Testing, Pandemic, medicine, Humans, 030212 general & internal medicine, mass testing, Transmission (medicine), business.industry, SARS-CoV-2, Public health, Outbreak, COVID-19, General Medicine, Long-Term Care, long-term care facility, Family medicine, care home, Geriatrics and Gerontology, Outbreak control, business, Research Paper
Abstract

Introduction Previous investigations have identified high rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among residents and staff in care homes reporting an outbreak of coronavirus disease 2019 (COVID-19). We investigated care homes reporting a single suspected or confirmed case to assess whether early mass testing might reduce risk of transmission during the peak of the pandemic in London. Methods Between 18 and 27 April 2020, residents and staff in care homes reporting a single case of COVID-19 to Public Health England had a nasal swab to test for SARS-CoV-2 infection by reverse transcription polymerase chain reaction and subsequent whole-genome sequencing. Residents and staff in two care homes were re-tested 8 days later. Results Four care homes were investigated. SARS-CoV-2 positivity was 20% (65/333) overall, ranging between 3 and 59%. Among residents, positivity ranged between 3 and 76% compared with 3 and 40% in staff. Half of the SARS-CoV-2-positive residents (23/46, 50%) and 63% of staff (12/19) reported symptoms within 14 days before or after testing. Repeat testing 8 days later in two care homes with the highest infection rates identified only two new cases. Genomic analysis demonstrated a small number of introduction of the virus into care homes, and distinct clusters within three of the care homes. Conclusions We found extensive but variable rates of SARS-CoV-2 infection among residents and staff in care homes reporting a single case of COVID-19. Although routine whole-home testing has now been adopted into practice, care homes must remain vigilant and should be encouraged to report a single suspected case, which should trigger appropriate outbreak control measures.

Published
2021

23. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno

Subjects
Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

24. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Niamh, Mullins, Andreas J, Forstner, Kevin S, O'Connell, Brandon, Coombes, Jonathan R I, Coleman, Zhen, Qiao, Thomas D, Als, Tim B, Bigdeli, Sigrid, Børte, Julien, Bryois, Alexander W, Charney, Ole Kristian, Drange, Michael J, Gandal, Saskia P, Hagenaars, Masashi, Ikeda, Nolan, Kamitaki, Minsoo, Kim, Kristi, Krebs, Georgia, Panagiotaropoulou, Brian M, Schilder, Laura G, Sloofman, Stacy, Steinberg, Vassily, Trubetskoy, Bendik S, Winsvold, Hong-Hee, Won, Liliya, Abramova, Kristina, Adorjan, Esben, Agerbo, Mariam, Al Eissa, Diego, Albani, Ney, Alliey-Rodriguez, Adebayo, Anjorin, Verneri, Antilla, Anastasia, Antoniou, Swapnil, Awasthi, Ji Hyun, Baek, Marie, Bækvad-Hansen, Nicholas, Bass, Michael, Bauer, Eva C, Beins, Sarah E, Bergen, Armin, Birner, Carsten, Bøcker Pedersen, Erlend, Bøen, Marco P, Boks, Rosa, Bosch, Murielle, Brum, Ben M, Brumpton, Nathalie, Brunkhorst-Kanaan, Monika, Budde, Jonas, Bybjerg-Grauholm, William, Byerley, Murray, Cairns, Miquel, Casas, Pablo, Cervantes, Toni-Kim, Clarke, Cristiana, Cruceanu, Alfredo, Cuellar-Barboza, Julie, Cunningham, David, Curtis, Piotr M, Czerski, Anders M, Dale, Nina, Dalkner, Friederike S, David, Franziska, Degenhardt, Srdjan, Djurovic, Amanda L, Dobbyn, Athanassios, Douzenis, Torbjørn, Elvsåshagen, Valentina, Escott-Price, I Nicol, Ferrier, Alessia, Fiorentino, Tatiana M, Foroud, Liz, Forty, Josef, Frank, Oleksandr, Frei, Nelson B, Freimer, Louise, Frisén, Katrin, Gade, Julie, Garnham, Joel, Gelernter, Marianne, Giørtz Pedersen, Ian R, Gizer, Scott D, Gordon, Katherine, Gordon-Smith, Tiffany A, Greenwood, Jakob, Grove, José, Guzman-Parra, Kyooseob, Ha, Magnus, Haraldsson, Martin, Hautzinger, Urs, Heilbronner, Dennis, Hellgren, Stefan, Herms, Per, Hoffmann, Peter A, Holmans, Laura, Huckins, Stéphane, Jamain, Jessica S, Johnson, Janos L, Kalman, Yoichiro, Kamatani, James L, Kennedy, Sarah, Kittel-Schneider, James A, Knowles, Manolis, Kogevinas, Maria, Koromina, Thorsten M, Kranz, Henry R, Kranzler, Michiaki, Kubo, Ralph, Kupka, Steven A, Kushner, Catharina, Lavebratt, Jacob, Lawrence, Markus, Leber, Heon-Jeong, Lee, Phil H, Lee, Shawn E, Levy, Catrin, Lewis, Calwing, Liao, Susanne, Lucae, Martin, Lundberg, Donald J, MacIntyre, Sigurdur H, Magnusson, Wolfgang, Maier, Adam, Maihofer, Dolores, Malaspina, Eirini, Maratou, Lina, Martinsson, Manuel, Mattheisen, Steven A, McCarroll, Nathaniel W, McGregor, Peter, McGuffin, James D, McKay, Helena, Medeiros, Sarah E, Medland, Vincent, Millischer, Grant W, Montgomery, Jennifer L, Moran, Derek W, Morris, Thomas W, Mühleisen, Niamh, O'Brien, Claire, O'Donovan, Loes M, Olde Loohuis, Lilijana, Oruc, Sergi, Papiol, Antonio F, Pardiñas, Amy, Perry, Andrea, Pfennig, Evgenia, Porichi, James B, Potash, Digby, Quested, Towfique, Raj, Mark H, Rapaport, J Raymond, DePaulo, Eline J, Regeer, John P, Rice, Fabio, Rivas, Margarita, Rivera, Julian, Roth, Panos, Roussos, Douglas M, Ruderfer, Cristina, Sánchez-Mora, Eva C, Schulte, Fanny, Senner, Sally, Sharp, Paul D, Shilling, Engilbert, Sigurdsson, Lea, Sirignano, Claire, Slaney, Olav B, Smeland, Daniel J, Smith, Janet L, Sobell, Christine, Søholm Hansen, Maria, Soler Artigas, Anne T, Spijker, Dan J, Stein, John S, Strauss, Beata, Świątkowska, Chikashi, Terao, Thorgeir E, Thorgeirsson, Claudio, Toma, Paul, Tooney, Evangelia-Eirini, Tsermpini, Marquis P, Vawter, Helmut, Vedder, James T R, Walters, Stephanie H, Witt, Simon, Xi, Wei, Xu, Jessica Mei Kay, Yang, Allan H, Young, Hannah, Young, Peter P, Zandi, Hang, Zhou, Lea, Zillich, Rolf, Adolfsson, Ingrid, Agartz, Martin, Alda, Lars, Alfredsson, Gulja, Babadjanova, Lena, Backlund, Bernhard T, Baune, Frank, Bellivier, Susanne, Bengesser, Wade H, Berrettini, Douglas H R, Blackwood, Michael, Boehnke, Anders D, Børglum, Gerome, Breen, Vaughan J, Carr, Stanley, Catts, Aiden, Corvin, Nicholas, Craddock, Udo, Dannlowski, Dimitris, Dikeos, Tõnu, Esko, Bruno, Etain, Panagiotis, Ferentinos, Mark, Frye, Janice M, Fullerton, Micha, Gawlik, Elliot S, Gershon, Fernando S, Goes, Melissa J, Green, Maria, Grigoroiu-Serbanescu, Joanna, Hauser, Frans, Henskens, Jan, Hillert, Kyung Sue, Hong, David M, Hougaard, Christina M, Hultman, Kristian, Hveem, Nakao, Iwata, Assen V, Jablensky, Ian, Jones, Lisa A, Jones, René S, Kahn, John R, Kelsoe, George, Kirov, Mikael, Landén, Marion, Leboyer, Cathryn M, Lewis, Qingqin S, Li, Jolanta, Lissowska, Christine, Lochner, Carmel, Loughland, Nicholas G, Martin, Carol A, Mathews, Fermin, Mayoral, Susan L, McElroy, Andrew M, McIntosh, Francis J, McMahon, Ingrid, Melle, Patricia, Michie, Lili, Milani, Philip B, Mitchell, Gunnar, Morken, Ole, Mors, Preben Bo, Mortensen, Bryan, Mowry, Bertram, Müller-Myhsok, Richard M, Myers, Benjamin M, Neale, Caroline M, Nievergelt, Merete, Nordentoft, Markus M, Nöthen, Michael C, O'Donovan, Ketil J, Oedegaard, Tomas, Olsson, Michael J, Owen, Sara A, Paciga, Chris, Pantelis, Carlos, Pato, Michele T, Pato, George P, Patrinos, Roy H, Perlis, Danielle, Posthuma, Josep Antoni, Ramos-Quiroga, Andreas, Reif, Eva Z, Reininghaus, Marta, Ribasés, Marcella, Rietschel, Stephan, Ripke, Guy A, Rouleau, Takeo, Saito, Ulrich, Schall, Martin, Schalling, Peter R, Schofield, Thomas G, Schulze, Laura J, Scott, Rodney J, Scott, Alessandro, Serretti, Cynthia, Shannon Weickert, Jordan W, Smoller, Hreinn, Stefansson, Kari, Stefansson, Eystein, Stordal, Fabian, Streit, Patrick F, Sullivan, Gustavo, Turecki, Arne E, Vaaler, Eduard, Vieta, John B, Vincent, Irwin D, Waldman, Thomas W, Weickert, Thomas, Werge, Naomi R, Wray, John-Anker, Zwart, Joanna M, Biernacka, John I, Nurnberger, Sven, Cichon, Howard J, Edenberg, Eli A, Stahl, Andrew, McQuillin, Arianna, Di Florio, Roel A, Ophoff, and Ole A, Andreassen

Subjects
Major Histocompatibility Complex, Multifactorial Inheritance, Bipolar Disorder, Phenotype, Genome, Human, Risk Factors, Case-Control Studies, Quantitative Trait Loci, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2020

25. Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients

Author

Xuefeng Niu, Song Li, Pingchao Li, Wenjing Pan, Qian Wang, Ying Feng, Xiaoneng Mo, Qihong Yan, Xianmiao Ye, Jia Luo, Linbing Qu, Daniel Weber, Miranda L. Byrne-Steele, Zhe Wang, Fengjia Yu, Fang Li, Richard M. Myers, Michael T. Lotze, Nanshan Zhong, Jian Han, and Ling Chen

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Adult, Male, T-Lymphocytes, B-cell receptor, Pneumonia, Viral, Immunology, Receptors, Antigen, T-Cell, Receptors, Antigen, B-Cell, Biology, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Immune system, Lymphopenia, medicine, Immunology and Allergy, Humans, Pandemics, B cell, Aged, Original Research, Aged, 80 and over, B-Lymphocytes, B cell receptor, SARS-CoV-2, T-cell receptor, breakpoint cluster region, High-Throughput Nucleotide Sequencing, Correction, COVID-19, Middle Aged, immune repertoire, CD4 Lymphocyte Count, Vaccination, 030104 developmental biology, medicine.anatomical_structure, Immunoglobulin class switching, 030220 oncology & carcinogenesis, Biomarker (medicine), biomarker, Female, T cell receptor, lcsh:RC581-607, Coronavirus Infections
Abstract

Severe COVID-19 is associated with profound lymphopenia and an elevated neutrophil to lymphocyte ratio. We applied a novel dimer avoidance multiplexed polymerase chain reaction next-generation sequencing assay to analyze T (TCR) and B cell receptor (BCR) repertoires. Surprisingly, TCR repertoires were markedly diminished during the early onset of severe disease but recovered during the convalescent stage. Monitoring TCR repertoires could serve as an indicative biomarker to predict disease progression and recovery. Panoramic concurrent assessment of BCR repertoires demonstrated isotype switching and a transient but dramatic early IgA expansion. Dominant B cell clonal expansion with decreased diversity occurred following recovery from infection. Profound changes in T cell homeostasis raise critical questions about the early events in COVID-19 infection and demonstrate that immune repertoire analysis is a promising method for evaluating emergent host immunity to SARS-CoV-2 viral infection, with great implications for assessing vaccination and other immunological therapies.

Published
2020

26. Expanded encyclopaedias of DNA elements in the human and mouse genomes

Author

Carrie A. Davis, Charles B. Epstein, Eric L. Van Nostrand, Valentina Snetkova, Michael J. Purcaro, Manolis Kellis, Yupeng He, Henry Pratt, John A. Stamatoyannopoulos, Ali Mortazavi, Xintao Wei, Michael Snyder, Jialing Zhang, Job Dekker, Anshul Kundaje, Shaimae I. Elhajjajy, Gene W. Yeo, Jessica Halow, Peggy J. Farnham, Kevin P. White, Xiaofeng Wang, Eric M. Mendenhall, Diane E. Dickel, John L. Rinn, Thomas R. Gingeras, Yin Shen, Juan Carlos Rivera-Mulia, David U. Gorkin, William Stafford Noble, Rajinder Kaul, David M. Gilbert, Jill Moore, Xiao-Ou Zhang, Peter Freese, Bing Ren, Joseph R. Ecker, Eric Lécuyer, Christopher B. Burge, Ross C. Hardison, Jing Zhang, Zhiping Weng, Richard M. Myers, Robert J. Klein, Brian A. Williams, Alexander Dobin, Alec Victorsen, Noam Shoresh, Joel Rozowsky, Jack Huey, Bradley E. Bernstein, Mark Mackiewicz, Roderic Guigó, Axel Visel, Brenton R. Graveley, J. Michael Cherry, Trupti Kawli, Mark Gerstein, Cheryl A. Keller, Barbara J. Wold, Jessika Adrian, Len A. Pennacchio, Florencia Pauli-Behn, and Surya B. Chhetri

Subjects
Epigenomics, Transcription, Genetic, DNA Replication Timing, General Science & Technology, DNA Footprinting, Transposases, Mice, Transgenic, Genomics, Context (language use), 610 Medicine & health, Computational biology, Regulatory Sequences, Nucleic Acid, Biology, ENCODE, Genome, Article, Histones, Mice, Databases, Genetic, Animals, Deoxyribonuclease I, Humans, Registries, data integration, Multidisciplinary, Genome, Human, RNA-Binding Proteins, Molecular Sequence Annotation, Functional genomics, DNA, DNA Methylation, Chromatin, epigenomics, DNA methylation, Data integration, functional genomics
Abstract

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes., The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Published
2020

27. Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy

Author

Gregory S. Barsh, Yuliya Voskobiynyk, Megan P. Newton, Erik D. Roberson, Gregory M. Cooper, J. Nicholas Cochran, Stephanie A. Felker, Gopal Battu, Robert A. Kesterson, Laura J. Lambert, and Richard M. Myers

Subjects
Cancer Research, Physiology, Social Sciences, Gene Expression, Epilepsies, Myoclonic, QH426-470, medicine.disease_cause, Toxicology, Pathology and Laboratory Medicine, Biochemistry, Ion Channels, Sodium Channels, Poisons, Exon, Mice, 0302 clinical medicine, Medicine and Health Sciences, Morphogenesis, Coding region, Psychology, Toxins, Gene Knock-In Techniques, RNA-Seq, Pattern Formation, Genetics (clinical), Genetics, Mammals, 0303 health sciences, Mutation, Mammalian Genomics, Animal Behavior, Physics, Eukaryota, Brain, Genomics, Exons, Animal Models, Electrophysiology, Neurology, Experimental Organism Systems, Organ Specificity, RNA splicing, Vertebrates, Physical Sciences, Perspective, Research Article, Toxic Agents, Biophysics, Neurophysiology, Context (language use), Mouse Models, Biology, Genome Complexity, Research and Analysis Methods, Rodents, 03 medical and health sciences, Model Organisms, medicine, Animals, Humans, Gene Regulation, Animal Models of Disease, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Behavior, Epilepsy, Sodium channel, Intron, Organisms, Proteins, Computational Biology, Biology and Life Sciences, Introns, NAV1.1 Voltage-Gated Sodium Channel, Disease Models, Animal, Gene Expression Regulation, Animal Genomics, NAV1.6 Voltage-Gated Sodium Channel, Amniotes, Animal Studies, Zoology, Epileptic Syndromes, 030217 neurology & neurosurgery, Embryonic Pattern Formation, Neuroscience, Developmental Biology
Abstract

Dravet syndrome (DS) is a developmental and epileptic encephalopathy that results from mutations in the Nav1.1 sodium channel encoded by SCN1A. Most known DS-causing mutations are in coding regions of SCN1A, but we recently identified several disease-associated SCN1A mutations in intron 20 that are within or near to a cryptic and evolutionarily conserved “poison” exon, 20N, whose inclusion is predicted to lead to transcript degradation. However, it is not clear how these intron 20 variants alter SCN1A expression or DS pathophysiology in an organismal context, nor is it clear how exon 20N is regulated in a tissue-specific and developmental context. We address those questions here by generating an animal model of our index case, NM_006920.4(SCN1A):c.3969+2451G>C, using gene editing to create the orthologous mutation in laboratory mice. Scn1a heterozygous knock-in (+/KI) mice exhibited an ~50% reduction in brain Scn1a mRNA and Nav1.1 protein levels, together with characteristics observed in other DS mouse models, including premature mortality, seizures, and hyperactivity. In brain tissue from adult Scn1a +/+ animals, quantitative RT-PCR assays indicated that ~1% of Scn1a mRNA included exon 20N, while brain tissue from Scn1a +/KI mice exhibited an ~5-fold increase in the extent of exon 20N inclusion. We investigated the extent of exon 20N inclusion in brain during normal fetal development in RNA-seq data and discovered that levels of inclusion were ~70% at E14.5, declining progressively to ~10% postnatally. A similar pattern exists for the homologous sodium channel Nav1.6, encoded by Scn8a. For both genes, there is an inverse relationship between the level of functional transcript and the extent of poison exon inclusion. Taken together, our findings suggest that poison exon usage by Scn1a and Scn8a is a strategy to regulate channel expression during normal brain development, and that mutations recapitulating a fetal-like pattern of splicing cause reduced channel expression and epileptic encephalopathy., Author summary Dravet syndrome (DS) is a neurological disorder affecting approximately 1:15,700 Americans that causes generalized epilepsy and associated complications. While most patients have a mutation in the SCN1A gene that encodes the Nav1.1 voltage-gated sodium channel, about 20% do not have a mutation identified by exome or targeted sequencing. Recently, we identified variants in intron 20, a noncoding region of SCN1A, in some DS patients. We hypothesized that these variants alter SCN1A transcript processing, decrease Nav1.1 function, and lead to DS pathophysiology via inclusion of exon 20N, a “poison” exon that leads to a premature stop codon. In this study, we generated a knock-in mouse model, Scn1a+/KI, of one of these variants, which resides in a genomic region that is extremely conserved across vertebrate species. We found that Scn1a+/KI mice have reduced levels of Scn1a transcript and Nav1.1 protein and develop DS-related phenotypes. We find that transcripts from brains of Scn1a+/KI mice show elevated rates of Scn1a exon 20N inclusion. We also explored the relationship between exon 20N inclusion and Scn1a expression during development, and found that, during brain development when Scn1a expression is low, exon 20N inclusion is high; postnatally, as Scn1a expression increases, there is a corresponding decrease in exon 20N usage. Expression of another voltage-gated sodium channel transcript, Scn8a (Nav1.6), was similarly regulated. Together, these data demonstrate that poison exon inclusion is a conserved mechanism to control sodium channel expression in the brain, and that an intronic mutation that disrupts the normal developmental regulation of poison exon inclusion leads to reduced Nav1.1 and generalized epilepsy.

Published
2020

28. Epitope Tagging ChIP-Seq of DNA Binding Proteins Using CETCh-Seq

Author

Sarah K, Meadows, Laurel A, Brandsmeier, Kimberly M, Newberry, Michael J, Betti, Amy S, Nesmith, Mark, Mackiewicz, E Christopher, Partridge, Eric M, Mendenhall, and Richard M, Myers

Subjects
Gene Editing, Epitopes, Binding Sites, Cell Adhesion, Chromatin Immunoprecipitation Sequencing, Humans, Hep G2 Cells, CRISPR-Cas Systems, Protein Binding, Transcription Factors
Abstract

Chromatin immunoprecipitation followed by next-generation DNA sequencing (ChIP-seq) has been used to identify transcription factor (TF) binding proteins throughout the genome. Unfortunately, this approach traditionally requires commercially available, ChIP-seq grade antibodies that frequently fail to generate acceptable datasets. To obtain data for the many TFs for which there is no appropriate antibody, we recently developed a new method for performing ChIP-seq by epitope tagging endogenous TFs using CRISPR/Cas9 genome editing technology (CETCh-seq). Here, we describe our general protocol of CETCh-seq for both adherent and nonadherent cell lines using a commercially available FLAG antibody.

Published
2020

29. Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition

Author

Zheng Ruan, Emery Haley, Juan Du, Wei Lü, Richard M. Myers, Rebecca Roth, Mark Sabat, and Ian J. Orozco

Subjects
Intracellular domain, Patch-Clamp Techniques, Protein Conformation, Biophysics, TRPM Cation Channels, Article, 03 medical and health sciences, Closed state, 0302 clinical medicine, Structural Biology, TRPM, Animals, Humans, TRPM5, Molecular Biology, Zebrafish, 030304 developmental biology, 0303 health sciences, Binding Sites, biology, Chemistry, Cell Membrane, Cryoelectron Microscopy, Antagonist, biology.organism_classification, Enzyme Activation, Transmembrane domain, Domain (ring theory), Calcium, 030217 neurology & neurosurgery
Abstract

The Ca(2+)-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca(2+) regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca(2+)-bound open state, and an antagonist-bound inhibited state. We defined two novel ligand binding sites: a Ca(2+) site (Ca(ICD)) in the intracellular domain (ICD), and an antagonist site in the transmembrane domain (TMD). The Ca(ICD) site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca(2+) binding to the Ca(TMD) site that is conserved throughout TRPM channels. Conformational changes initialized from both Ca(2+) sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and pore domain, stabilizing the TMD in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents.

Published
2022

30. Molecular surveillance of measles and rubella in the WHO European Region: new challenges in the elimination phase

Author

Mick N. Mulders, Sabine Santibanez, Richard M. Myers, O. Donoso Mantke, Annette Mankertz, Kevin E. Brown, M Muscat, Judith M. Hübschen, Claude P. Muller, M. Ben Mamou, Sergey V. Shulga, Dirk Brockmann, Patrick O'Connor, and Heinz Zeichhardt

Subjects
0301 basic medicine, Microbiology (medical), Laboratory Proficiency Testing, Genotyping Techniques, 030106 microbiology, Population, World Health Organization, medicine.disease_cause, Rubella, Measles, Phase (combat), Disease Outbreaks, Measles virus, 03 medical and health sciences, 0302 clinical medicine, Environmental health, External quality assessment, Disease Transmission, Infectious, Humans, Medicine, 030212 general & internal medicine, education, Molecular Epidemiology, education.field_of_study, biology, business.industry, Transmission (medicine), Rubella virus, General Medicine, biology.organism_classification, medicine.disease, Virology, Europe, Infectious Diseases, Epidemiological Monitoring, business
Abstract

Background The WHO European Region (EUR) has adopted the goal of eliminating measles and rubella but individual countries perform differently in achieving this goal. Measles virus spread across the EUR by mobile groups has recently led to large outbreaks in the insufficiently vaccinated resident population. As an instrument for monitoring the elimination process and verifying the interruption of endemic virus transmission, molecular surveillance has to provide valid and representative data. Irrespective of the country's specific situation, it is required to ensure the functionality of the laboratory surveillance that is supported by the WHO Global Measles and Rubella Laboratory Network. Aims To investigate whether the molecular surveillance in the EUR is adequate for the challenges in the elimination phase, we addressed the quality assurance of molecular data, the continuity and intensity of molecular monitoring, and the analysis of transmission chains. Sources Published articles, the molecular External Quality Assessment Programme of the WHO, the Centralized Information System for Infectious Diseases of the WHO EUR and the WHO Measles and Rubella Nucleotide Surveillance databases served as information sources. Content Molecular proficiency testing conducted by the WHO in 2016 has shown that the expertise for measles and rubella virus genotyping exists in all parts of the EUR. The analysis of surveillance data reported nationally to the WHO in 2013–2016 has revealed some countries with outbreaks but not sufficiently representative molecular data. Long-lasting supranational MV transmission chains were identified. Implications A more systematic molecular monitoring and recording of the transmission pattern for the whole EUR could help to create a meaningful picture of the elimination process.

Published
2017

31. Eliciting preferences on secondary findings: the Preferences Instrument for Genomic Secondary Results

Author

Kyle B. Brothers, Kelly M. East, Whitley V. Kelley, M. Frances Wright, Matthew J. Westbrook, Carla A. Rich, Kevin M. Bowling, Edward J. Lose, E. Martina Bebin, Shirley Simmons, John A. Myers, Greg Barsh, Richard M. Myers, Greg M. Cooper, Jill M. Pulley, Mark A. Rothstein, and Ellen Wright Clayton

Subjects
Adult, Male, Parents, 0301 basic medicine, Health Knowledge, Attitudes, Practice, Applied psychology, 030105 genetics & heredity, Choice Behavior, Article, 03 medical and health sciences, Intellectual Disability, Surveys and Questionnaires, Research participant, Intellectual disability, Humans, Medicine, Genetic Testing, Genetics (clinical), Aged, Genetic testing, Incidental Findings, Genome, medicine.diagnostic_test, business.industry, Patient Preference, Genomics, Sequence Analysis, DNA, Focus Groups, Middle Aged, 16. Peace & justice, medicine.disease, Focus group, Information overload, 3. Good health, Test (assessment), Comprehension, Female, business, Raw data
Abstract

Purpose Eliciting and understanding patient and research participant preferences regarding return of secondary test results is a key aspect of genomic medicine. A valid instrument should be easily understood without extensive pre-test counseling, while still faithfully eliciting patients’ preferences. Methods We conducted focus groups with 110 adults to understand patient perspectives on secondary genomic findings and the role preferences should play. We then developed and refined a draft instrument, and used it to elicit preferences from parents participating in a genomic sequencing study in children with intellectual disabilities. Results Patients preferred filtering of secondary genomic results to avoid information overload and to avoid learning what the future holds, among other reasons. Patients preferred to make autonomous choices about which categories of results to receive and to have their choices applied automatically before results are returned to them and their clinicians. The Preferences Instrument for Genomic Secondary Results (PIGSR) is designed to be completed by patients or research participants without assistance and to guide bioinformatic analysis of genomic raw data. Most participants wanted to receive all secondary results, but a significant minority indicated other preferences. Conclusions Our novel instrument – PIGSR – should be useful in a wide range of clinical and research settings.

Published
2017

32. Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases

Author

Erik D. Roberson, Michelle L. Thompson, Ethan G. Geier, Bruce L. Miller, Brittany N. Lasseigne, Michelle D. Amaral, Anna Karydas, Richard M. Myers, Gil D. Rabinovici, Luke W. Bonham, J Scott Newberry, Alzheimer’s Disease Neuroimaging Initiative, Jennifer S. Yokoyama, Gregory M. Cooper, and J. Nicholas Cochran

Subjects
0301 basic medicine, Male, amyotrophic lateral sclerosis, Aging, Disease, Neurodegenerative, Alzheimer's Disease, frontotemporal dementia, Medical and Health Sciences, Mice, 0302 clinical medicine, Cognition, Loss of Function Mutation, 80 and over, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, Genetics (clinical), Genetics, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Neurodegeneration, FTD, Neurodegenerative Diseases, Biological Sciences, 3. Good health, genome sequencing, DNA-Binding Proteins, Frontotemporal Dementia, DNA methylation, Neurological, Female, Frontotemporal dementia, Biology, DNA sequencing, Article, Dioxygenases, 03 medical and health sciences, Alzheimer Disease, Proto-Oncogene Proteins, medicine, Acquired Cognitive Impairment, non-coding, Animals, Humans, Letters to the Editor, Loss function, 030304 developmental biology, Aged, TET2, Prevention, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), AD, Odds ratio, Alzheimer’s Disease Neuroimaging Initiative, medicine.disease, Brain Disorders, 030104 developmental biology, Alzheimer, Dementia, ALS, 030217 neurology & neurosurgery
Abstract

We conducted genome sequencing to search for rare variation contributing to early onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions).Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p=6.5×10−8, genome-wide corrected p=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only p=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5–3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2–3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0–5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

Published
2019

33. Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Ca

Author

Hugo, Jimenez, Minghui, Wang, Jacquelyn W, Zimmerman, Michael J, Pennison, Sambad, Sharma, Trevor, Surratt, Zhi-Xiang, Xu, Ivan, Brezovich, Devin, Absher, Richard M, Myers, Barry, DeYoung, David L, Caudell, Dongquan, Chen, Hui-Wen, Lo, Hui-Kuan, Lin, Dwayne W, Godwin, Michael, Olivier, Anand, Ghanekar, Kui, Chen, Lance D, Miller, Yijian, Gong, Myles, Capstick, Ralph B, D'Agostino, Reginald, Munden, Philippe, Merle, Alexandre, Barbault, Arthur W, Blackstock, Herbert L, Bonkovsky, Guang-Yu, Yang, Guangxu, Jin, Liang, Liu, Wei, Zhang, Kounosuke, Watabe, Carl F, Blackman, and Boris C, Pasche

Subjects
Carcinoma, Hepatocellular, Magnetic Field Therapy, Liver Neoplasms, Calcium Channel Blockers, Xenograft Model Antitumor Assays, Calcium Channels, T-Type, Disease Models, Animal, Mice, Treatment Outcome, Organ Specificity, Gene Knockdown Techniques, Neoplastic Stem Cells, Commentary, Animals, Humans, Calcium, RNA, Small Interfering, Radiometry
Abstract

Administration of amplitude modulated 27·12 MHz radiofrequency electromagnetic fields (AM RF EMF) by means of a spoon-shaped applicator placed on the patient's tongue is a newly approved treatment for advanced hepatocellular carcinoma (HCC). The mechanism of action of tumour-specific AM RF EMF is largely unknown.Whole body and organ-specific human dosimetry analyses were performed. Mice carrying human HCC xenografts were exposed to AM RF EMF using a small animal AM RF EMF exposure system replicating human dosimetry and exposure time. We performed histological analysis of tumours following exposure to AM RF EMF. Using an agnostic genomic approach, we characterized the mechanism of action of AM RF EMF.Intrabuccal administration results in systemic delivery of athermal AM RF EMF from head to toe at levels lower than those generated by cell phones held close to the body. Tumour shrinkage results from differentiation of HCC cells into quiescent cells with spindle morphology. AM RF EMF targeted antiproliferative effects and cancer stem cell inhibiting effects are mediated by CaIntrabuccally-administered AM RF EMF is a systemic therapy that selectively block the growth of HCC cells. AM RF EMF pronounced inhibitory effects on cancer stem cells may explain the exceptionally long responses observed in several patients with advanced HCC. FUND: Research reported in this publication was supported by the National Cancer Institute's Cancer Centre Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Centre (BP) and by funds from the Charles L. Spurr Professorship Fund (BP). DWG is supported by R01 AA016852 and P50 AA026117.

Published
2019

34. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Laura M. Thornton, Paul Lichtenstein, Verneri Anttila, Diego Albani, Josep Antoni Ramos-Quiroga, Roger A.H. Adan, Monika Schlögelhofer, Stephen Sanders, Enrique Castelao, Klaus Berger, Nina Dalkner, Urs Heilbronner, Engilbert Sigurdsson, Pablo Mir, Fuquan Zhang, James T.R. Walters, Patrick F. Sullivan, Fragiskos Gonidakis, F. Kyle Satterstrom, Sara Marsal, Per Hoffmann, Amy Perry, Valentina Ciullo, Beate Herpertz-Dahlmann, Catharina Lavebratt, Kieran C. Murphy, Tammy Hedderly, Hyun Ju Hong, Evald Saemundsen, Sascha B. Fischer, Hailiang Huang, Andrew D. Grotzinger, Nienke Vulink, Murray B. Stein, Mark A. Frye, Laura J. Scott, David Curtis, Todd Lencz, Janiece E. DeSocio, Richard A. Belliveau, Eduard Vieta, Andrea Dietrich, Wade H. Berrettini, Kenneth S. Kendler, Marquis P. Vawter, Paul S. Nestadt, Michael E. Talkowski, Manuel Mattheisen, Ingrid Agartz, Elisa Docampo, Bernhard T. Baune, Stefan Ehrlich, Jolanta Lissowska, Felecia Cerrato, Terje Nærland, Robin M. Murray, Jennifer Reichert, Annette M. Hartmann, Hannelore Ehrenreich, Howard J. Edenberg, Katherine A. Halmi, Qingqin S. Li, Peristera Paschou, Marie Bækvad-Hansen, Esther Walton, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Frank Bellivier, Jungeun Song, D. Blake Woodside, Young Shin Kim, Jochen Seitz, Jacques Pantel, Palmiero Monteleone, Erika L. Nurmi, Rodney J. Scott, Kang Sim, Ekaterina A. Khramtsova, Udo Dannlowski, Rolf Adolfsson, Danielle Posthuma, Melissa J. Green, Laura Ibanez-Gomez, Jakob Grove, Elvira Bramon, Gregory L. Hanna, Cynthia M. Bulik, Yiran Guo, Stephan Ripke, Mary M. Robertson, Harald N. Aschauer, Adebayo Anjorin, Joanna Martin, Bertram Müller-Myhsok, Deborah Kaminská, Jose Guzman-Parra, Benedetta Nacmias, Erik G. Jönsson, Jonathan R. I. Coleman, Douglas F. Levinson, Hamdi Mbarek, Gun Peggy Knudsen, Karin Egberts, Mette Nyegaard, Patrik K. E. Magnusson, Mark Adams, Douglas Blackwood, Elisabeth B. Binder, Marcus Ising, Anna R. Docherty, Jim van Os, Nese Direk, Lina Martinsson, Maria Arranz, Christel M. Middeldorp, Stefan Kloiber, Sintia Iole Belangero, Eske M. Derks, Ingrid Melle, Erlend Bøen, Jan Haavik, Federica Piras, Unna N. Danner, Anil K. Malhotra, Gerome Breen, Stephen V. Faraone, Amanda B Zheutlin, Timothy Poterba, Stephan Ruhrmann, Inge Joa, Ulrik Fredrik Malt, Sarah E. Bergen, Federica Tozzi, Lauren A. Weiss, Hana Papezova, Dominic Holland, Elliot S. Gershon, Jaakko Kaprio, Merete Nordentoft, Scott D. Gordon, Christopher Pittenger, Keun-Ah Cheon, Jennifer Jordan, Philip Gorwood, Myrna M. Weissman, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Isobel Heyman, Eun-Young Shin, Christie L. Burton, Katherine Gordon-Smith, Sietske G. Helder, Peter Nagy, Till F. M. Andlauer, Yunpeng Wang, Young Key Kim, Kate Langley, Søren Dalsgaard, Richard Delorme, Torbjørn Elvsåshagen, Bennett L. Leventhal, Giovanni Gambaro, Christos Androutsos, Jennifer Tübing, Marion Roberts, Annelie Nordin Adolfsson, Hakon Hakonarson, Dorothy E. Grice, Vaughan J. Carr, Konstantinos Tziouvas, Stephanie Zerwas, Cathy L. Barr, Michael Conlon O'Donovan, Per Qvist, Beate St Pourcain, Samuel Kuperman, Leila Karhunen, Jack Samuels, Markus M. Nöthen, Martien J H Kas, Alfonso Tortorella, Mikael Landén, Jennifer Crosbie, Marco A. Grados, Joanna M. Biernacka, Paul D. Arnold, Irene A. Malaty, Jurjen J. Luykx, Nicholas Bass, Naomi R. Wray, Catharina A. Hartman, Christina M. Hultman, Michael S. Okun, Brandon Wormley, Michael Bauer, Daniel J. Smith, Ian Jones, Kathryn Roeder, Brien P. Riley, Caroline M. Nievergelt, Katrin Gade, Sarah Kittel-Schneider, Roy H. Perlis, James R. Mitchell, Ziarih Hawi, James Lee, Liz Forty, William E. Bunney, Thomas Damm Als, Catherine Schaefer, Digby Quested, Matteo Cassina, Anna C. Koller, Patrick Turley, Agnes A. Steixner, Anu Raevuori, Assen Jablensky, Peter Holmans, Dong-Ho Song, S. Evelyn Stewart, Jan K. Buitelaar, Fernando S. Goes, Alexander Münchau, Ayman H. Fanous, Nicolas Ramoz, James B. Potash, Monica Gratacos Mayora, Tobias Banaschewski, Céline S. Reinbold, Renata Rizzo, Arianna Di Florio, Lenka Foretova, Gianfranco Spalletta, Aarno Palotie, Eleftheria Zeggini, Lawrence W. Brown, Julie K. O'Toole, Lynn E. DeLisi, Ulrich Schall, Mary Roberson, Barbara J. Coffey, Bryan J. Mowry, Murray J. Cairns, Dan J. Stein, Glyn Lewis, Marta Ribasés, C. Robert Cloninger, Bettina Konte, John B. Vincent, Duncan S. Palmer, Radhika Kandaswamy, Christine Ladd-Acosta, Lars Alfredsson, Frank Visscher, Ulrike Schmidt, Aiden Corvin, Susan L. Santangelo, Brenda W.J.H. Penninx, David J. Porteous, Tetsuya Ando, Arne E. Vaaler, Bru Cormand, Laura Carlberg, Claire Churchhouse, Manfred Stuhrmann, Niamh Mullins, Christine Søholm Hansen, Cathy L. Budman, Hartmut Imgart, Dan E. Arking, James J. McGough, Michael Gill, Christel Depienne, Roland Burghardt, Antonio Julià, Anders M. Dale, Sven Sandin, Katharina Domschke, Maria Grigoroiu-Serbanescu, Susana Jiménez-Murcia, Marianne Giørtz Pedersen, Zsanett Tarnok, Gisli Baldursson, Michele T. Pato, David M. Hougaard, Thorgeir E. Thorgeirsson, Katharina Bey, Kerstin J. Plessen, Margaret A. Richter, Ole A. Andreassen, Claudine Laurent-Levinson, Leonid Padyukov, Jacques Mallet, Daniela Degortes, John R. Kelsoe, Robert D. Levitan, Andreas Reif, Chaim Huyser, Derek W. Morris, Sina Wanderer, William Byerley, Edna Grünblatt, E.J.C. de Geus, Hyejung Won, Josephine Elia, Rudolf Uher, Jay A. Tischfield, Andreas Karwautz, Gustavo Turecki, Pieter J. Hoekstra, Dorret I. Boomsma, Jacob Rosenthal, Daniele Cusi, Michael C. Neale, Sara Mostafavi, Gwyneth Zai, F. Anthony O'Neill, Gary Donohoe, Karola Rehnström, Harry Brandt, Helena Gaspar, Francis J. McMahon, H-Erich Wichmann, Andrew W. Bergen, Giovanni Coppola, Lea K. Davis, Lenka Slachtova, Olav B. Smeland, Erin C. Dunn, Nicholas G. Martin, Allan L. Naarden, Jo Knight, Cristina Sánchez-Mora, Masashi Ikeda, Lorraine Southam, Sandro Sorbi, Barbara Franke, Martin Schalling, Russell Schachar, Yen-Chen Anne Feng, Kirsten R. Müller-Vahl, André Scherag, Zhaozhong Zhu, Eric A. Storch, Páll Magnússon, David Cohen, Olafur O Gudmundsson, Harvey S. Singer, Brian Kelly, Jonas Bybjerg-Grauholm, Blanca Garcia-Delgar, Thomas Hansen, Carmel M. Loughland, Christine Lochner, Stacy Steinberg, Martin Woods, Jorge A. Quiroz, Raquel Rabionet, Alden Y. Huang, Janice M. Fullerton, María Soler Artigas, Hans J. Grabe, Philip Asherson, Margit Burmeister, Alicia R. Martin, Martin A. Kennedy, Janet Treasure, Anders D. Børglum, Eva C. Schulte, Andreas Hartmann, Frans Henskens, Youl-Ri Kim, Jens Treutlein, Joanna Hauser, Manfred M. Fichter, Damiaan Denys, Ann E. Pulver, Kelly L. Klump, Paul Sandor, Michael Wagner, Philippe Courtet, Sandra Van der Auwera, Susanne Lucae, Eystein Stordal, Michel G. Nivard, Maurizio Clementi, Astrid Morer, Philip B. Mitchell, Huda Akil, Edwin H. Cook, Jennifer L. Moran, Donald W. Black, Jeremiah M. Scharf, Jana Strohmaier, Colm McDonald, Meg M.-J. Wang, Richard M. Myers, Stephanie Godard, Pablo V. Gejman, Athanasios Maras, Marcella Rietschel, Nancy G. Buccola, Konstantinos Hatzikotoulas, Dalila Pinto, Jouke-Jan Hottenga, Kari Stefansson, James S. Sutcliffe, Andres Metspalu, Amaia Hervás, Joel Gelernter, Wolfgang Herzog, Paula Rovira, Gunnar Morken, Tara Murphy, Mark Weiser, Vincent Millischer, Frank Dudbridge, Dan Rujescu, Vladimir Bencko, Valdo Ricca, Kimberly Chambert, Guy A. Rouleau, James J. Crowley, Thomas G. Schulze, Toni-Kim Clarke, Triinu Peters, Gudrun Wagner, Daniel A. Geller, Henry R. Kranzler, G. Bragi Walters, Vera Golimbet, Clement C. Zai, Nigel Williams, Andreas Birgegård, Joseph D. Buxbaum, Elliot M. Tucker-Drob, Jerome C. Foo, Tracey L. Petryshen, Daniel P. Howrigan, Hunna J. Watson, Franziska Degenhardt, Peter R. Schofield, Jesper Buchhave Poulsen, Stefan Herms, Johannes Hebebrand, Mario Maj, George Kirov, Fabrizio Piras, Sara McDevitt, James T. McCracken, Carol A. Mathews, Michael John Owen, Peter Falkai, Donald L. Gilbert, Enda M. Byrne, Fernando Fernández-Aranda, Csaba Barta, Stéphane Jamain, Jubao Duan, Dongmei Yu, Danielle C. Cath, Ole Mors, Sigrun Hope, Laramie E. Duncan, Alan R. Sanders, Sang-Yun Oh, Carsten Bøcker Pedersen, Henning Tiemeier, Roseann E. Peterson, Raymond K. Walters, Margarita C T Slof-Op 't Landt, Madeline Alexander, Stephanie Le Hellard, Ina Giegling, Annemarie A. van Elburg, Steven P. Hamilton, Vesna Boraska Perica, Thomas V. Fernandez, Danielle M. Dick, Francesco Bettella, Roel A. Ophoff, Grant W. Montgomery, Gerald Nestadt, Nakao Iwata, Jessica H. Baker, Walter H. Kaye, Jeremy M. Silverman, Mark J. Daly, Robert A. King, Sarah E. Medland, Anastasios Konstantinidis, Robert D. Oades, Samuel H. Zinner, Steven Crawford, Daniel H. Geschwind, Patrick W. L. Leung, Martin Alda, Marie Navratilova, Pak C. Sham, Paul A. Tooney, Tian Ge, Veit Roessner, Martin Preisig, Thomas Werge, Eli A. Stahl, David A. Collier, Stephanie H. Witt, Dermot Walsh, Miquel Casas, Anna Keski-Rahkonen, Jane H. Christensen, Silvia De Rubeis, Giorgio Pistis, Sven Cichon, Bruno Etain, Dominique Campion, O. Joseph Bienvenu, Christian Dina, Manolis Kogevinas, Thomas Espeseth, Benjamin M. Neale, Ditte Demontis, Klaus-Peter Lesch, Marina Mitjans, Tiffany A. Greenwood, Marcos Madruga-Garrido, Sibylle G. Schwab, Oedegaard Ketil Joachim, Hreinn Stefansson, Sara A. Paciga, Monica Forzan, Dieter B. Wildenauer, Lena Backlund, A. Jeremy Willsey, Carlos N. Pato, Nicholas John Craddock, Inge A. Meijer, Sandra K. Loo, Filip Rybakowski, Tracey D. Wade, Scott J. Crow, Bernard Lerer, Valsamma Eapen, Esben Agerbo, Andrew M. McIntosh, Luis Augusto Rohde, Susan L. McElroy, Stephan Zipfel, Peter P. Zandi, Cathryn M. Lewis, Lars Klareskog, Martin Begemann, Phil Lee, Richard Anney, Mark A. Bellgrove, Lisa Jones, Andreas J. Forstner, Agnieszka Słopień, Hilary Coon, Dong Li, Alessandro Serretti, Carsten Horn, Christos Pantelis, Ryan L. Collins, David M. Howard, Lucía Colodro-Conde, Pippa A. Thomson, Martin Hautzinger, Alysa E. Doyle, Julie Hagstrøm, Oliver S. P. Davis, Karen S. Mitchell, Jordan W. Smoller, Michael Strober, John I. Nurnberger, Andrea G. Ludolph, Monika Budde, Anna Maaser, Lambertus Klei, Aribert Rothenberger, Yulia Worbe, Fabian Streit, James L. Kennedy, Barbara E. Stranger, Ashley Dumont, Jianxin Shi, Dale R. Nyholt, Craig Johnson, Jonna Kuntsi, Yun-Joo Koh, Loes M. Olde Loohuis, Robert B. Freedman, Anke Hinney, Susanne Walitza, Enrico Domenici, Margarita Rivera, Sodahm Kook, Erica Greenberg, Tetyana Zayats, Josef Frank, Gary A. Heiman, Andrew McQuillin, Abraham Reichenberg, Piotr M. Czerski, Humberto Nicolini, Lee P.H., Anttila V., Won H., Feng Y.-C.A., Rosenthal J., Zhu Z., Tucker-Drob E.M., Nivard M.G., Grotzinger A.D., Posthuma D., Wang M.M.-J., Yu D., Stahl E.A., Walters R.K., Anney R.J.L., Duncan L.E., Ge T., Adolfsson R., Banaschewski T., Belangero S., Cook E.H., Coppola G., Derks E.M., Hoekstra P.J., Kaprio J., Keski-Rahkonen A., Kirov G., Kranzler H.R., Luykx J.J., Rohde L.A., Zai C.C., Agerbo E., Arranz M.J., Asherson P., Baekvad-Hansen M., Baldursson G., Bellgrove M., Belliveau R.A., Buitelaar J., Burton C.L., Bybjerg-Grauholm J., Casas M., Cerrato F., Chambert K., Churchhouse C., Cormand B., Crosbie J., Dalsgaard S., Demontis D., Doyle A.E., Dumont A., Elia J., Grove J., Gudmundsson O.O., Haavik J., Hakonarson H., Hansen C.S., Hartman C.A., Hawi Z., Hervas A., Hougaard D.M., Howrigan D.P., Huang H., Kuntsi J., Langley K., Lesch K.-P., Leung P.W.L., Loo S.K., Martin J., Martin A.R., McGough J.J., Medland S.E., Moran J.L., Mors O., Mortensen P.B., Oades R.D., Palmer D.S., Pedersen C.B., Pedersen M.G., Peters T., Poterba T., Poulsen J.B., Ramos-Quiroga J.A., Reif A., Ribases M., Rothenberger A., Rovira P., Sanchez-Mora C., Satterstrom F.K., Schachar R., Artigas M.S., Steinberg S., Stefansson H., Turley P., Walters G.B., Werge T., Zayats T., Arking D.E., Bettella F., Buxbaum J.D., Christensen J.H., Collins R.L., Coon H., De Rubeis S., Delorme R., Grice D.E., Hansen T.F., Holmans P.A., Hope S., Hultman C.M., Klei L., Ladd-Acosta C., Magnusson P., Naerland T., Nyegaard M., Pinto D., Qvist P., Rehnstrom K., Reichenberg A., Reichert J., Roeder K., Rouleau G.A., Saemundsen E., Sanders S.J., Sandin S., St Pourcain B., Stefansson K., Sutcliffe J.S., Talkowski M.E., Weiss L.A., Willsey A.J., Agartz I., Akil H., Albani D., Alda M., Als T.D., Anjorin A., Backlund L., Bass N., Bauer M., Baune B.T., Bellivier F., Bergen S.E., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boen E., Budde M., Bunney W., Burmeister M., Byerley W., Byrne E.M., Cichon S., Clarke T.-K., Coleman J.R.I., Craddock N., Curtis D., Czerski P.M., Dale A.M., Dalkner N., Dannlowski U., Degenhardt F., Di Florio A., Elvsashagen T., Etain B., Fischer S.B., Forstner A.J., Forty L., Frank J., Frye M., Fullerton J.M., Gade K., Gaspar H.A., Gershon E.S., Gill M., Goes F.S., Gordon S.D., Gordon-Smith K., Green M.J., Greenwood T.A., Grigoroiu-Serbanescu M., Guzman-Parra J., Hauser J., Hautzinger M., Heilbronner U., Herms S., Hoffmann P., Holland D., Jamain S., Jones I., Jones L.A., Kandaswamy R., Kelsoe J.R., Kennedy J.L., Joachim O.K., Kittel-Schneider S., Kogevinas M., Koller A.C., Lavebratt C., Lewis C.M., Li Q.S., Lissowska J., Loohuis L.M.O., Lucae S., Maaser A., Malt U.F., Martin N.G., Martinsson L., McElroy S.L., McMahon F.J., McQuillin A., Melle I., Metspalu A., Millischer V., Mitchell P.B., Montgomery G.W., Morken G., Morris D.W., Muller-Myhsok B., Mullins N., Myers R.M., Nievergelt C.M., Nordentoft M., Adolfsson A.N., Nothen M.M., Ophoff R.A., Owen M.J., Paciga S.A., Pato C.N., Pato M.T., Perlis R.H., Perry A., Potash J.B., Reinbold C.S., Rietschel M., Rivera M., Roberson M., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Sigurdsson E., Smeland O.B., Stordal E., Streit F., Strohmaier J., Thorgeirsson T.E., Treutlein J., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Wang Y., Witt S.H., Zandi P., Adan R.A.H., Alfredsson L., Ando T., Aschauer H., Baker J.H., Bencko V., Bergen A.W., Birgegard A., Perica V.B., Brandt H., Burghardt R., Carlberg L., Cassina M., Clementi M., Courtet P., Crawford S., Crow S., Crowley J.J., Danner U.N., Davis O.S.P., Degortes D., DeSocio J.E., Dick D.M., Dina C., Docampo E., Egberts K., Ehrlich S., Espeseth T., Fernandez-Aranda F., Fichter M.M., Foretova L., Forzan M., Gambaro G., Giegling I., Gonidakis F., Gorwood P., Mayora M.G., Guo Y., Halmi K.A., Hatzikotoulas K., Hebebrand J., Helder S.G., Herpertz-Dahlmann B., Herzog W., Hinney A., Imgart H., Jimenez-Murcia S., Johnson C., Jordan J., Julia A., Kaminska D., Karhunen L., Karwautz A., Kas M.J.H., Kaye W.H., Kennedy M.A., Kim Y.-R., Klareskog L., Klump K.L., Knudsen G.P.S., Landen M., Le Hellard S., Levitan R.D., Li D., Lichtenstein P., Maj M., Marsal S., McDevitt S., Mitchell J., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., O'Toole J.K., Padyukov L., Pantel J., Papezova H., Rabionet R., Raevuori A., Ramoz N., Reichborn-Kjennerud T., Ricca V., Roberts M., Rujescu D., Rybakowski F., Scherag A., Schmidt U., Seitz J., Slachtova L., Slof-Op't Landt M.C.T., Slopien A., Sorbi S., Southam L., Strober M., Tortorella A., Tozzi F., Treasure J., Tziouvas K., van Elburg A.A., Wade T.D., Wagner G., Walton E., Watson H.J., Wichmann H.-E., Woodside D.B., Zeggini E., Zerwas S., Zipfel S., Adams M.J., Andlauer T.F.M., Berger K., Binder E.B., Boomsma D.I., Castelao E., Colodro-Conde L., Direk N., Docherty A.R., Domenici E., Domschke K., Dunn E.C., Foo J.C., de. Geus E.J.C., Grabe H.J., Hamilton S.P., Horn C., Hottenga J.-J., Howard D., Ising M., Kloiber S., Levinson D.F., Lewis G., Magnusson P.K.E., Mbarek H., Middeldorp C.M., Mostafavi S., Nyholt D.R., Penninx B.W., Peterson R.E., Pistis G., Porteous D.J., Preisig M., Quiroz J.A., Schaefer C., Schulte E.C., Shi J., Smith D.J., Thomson P.A., Tiemeier H., Uher R., van der Auwera S., Weissman M.M., Alexander M., Begemann M., Bramon E., Buccola N.G., Cairns M.J., Campion D., Carr V.J., Cloninger C.R., Cohen D., Collier D.A., Corvin A., DeLisi L.E., Donohoe G., Dudbridge F., Duan J., Freedman R., Gejman P.V., Golimbet V., Godard S., Ehrenreich H., Hartmann A.M., Henskens F.A., Ikeda M., Iwata N., Jablensky A.V., Joa I., Jonsson E.G., Kelly B.J., Knight J., Konte B., Laurent-Levinson C., Lee J., Lencz T., Lerer B., Loughland C.M., Malhotra A.K., Mallet J., McDonald C., Mitjans M., Mowry B.J., Murphy K.C., Murray R.M., O'Neill F.A., Oh S.-Y., Palotie A., Pantelis C., Pulver A.E., Petryshen T.L., Quested D.J., Riley B., Sanders A.R., Schall U., Schwab S.G., Scott R.J., Sham P.C., Silverman J.M., Sim K., Steixner A.A., Tooney P.A., van Os J., Vawter M.P., Walsh D., Weiser M., Wildenauer D.B., Williams N.M., Wormley B.K., Zhang F., Androutsos C., Arnold P.D., Barr C.L., Barta C., Bey K., Bienvenu O.J., Black D.W., Brown L.W., Budman C., Cath D., Cheon K.-A., Ciullo V., Coffey B.J., Cusi D., Davis L.K., Denys D., Depienne C., Dietrich A., Eapen V., Falkai P., Fernandez T.V., Garcia-Delgar B., Geller D.A., Gilbert D.L., Grados M.A., Greenberg E., Grunblatt E., Hagstrom J., Hanna G.L., Hartmann A., Hedderly T., Heiman G.A., Heyman I., Hong H.J., Huang A., Huyser C., Ibanez-Gomez L., Khramtsova E.A., Kim Y.K., Kim Y.-S., King R.A., Koh Y.-J., Konstantinidis A., Kook S., Kuperman S., Leventhal B.L., Lochner C., Ludolph A.G., Madruga-Garrido M., Malaty I., Maras A., McCracken J.T., Meijer I.A., Mir P., Morer A., Muller-Vahl K.R., Munchau A., Murphy T.L., Naarden A., Nagy P., Nestadt G., Nestadt P.S., Nicolini H., Nurmi E.L., Okun M.S., Paschou P., Piras F., Pittenger C., Plessen K.J., Richter M.A., Rizzo R., Robertson M., Roessner V., Ruhrmann S., Samuels J.F., Sandor P., Schlogelhofer M., Shin E.-Y., Singer H., Song D.-H., Song J., Spalletta G., Stein D.J., Stewart S.E., Storch E.A., Stranger B., Stuhrmann M., Tarnok Z., Tischfield J.A., Tubing J., Visscher F., Vulink N., Wagner M., Walitza S., Wanderer S., Woods M., Worbe Y., Zai G., Zinner S.H., Sullivan P.F., Franke B., Daly M.J., Bulik C.M., McIntosh A.M., O'Donovan M.C., Zheutlin A., Andreassen O.A., Borglum A.D., Breen G., Edenberg H.J., Fanous A.H., Faraone S.V., Gelernter J., Mathews C.A., Mattheisen M., Mitchell K.S., Neale M.C., Nurnberger J.I., Ripke S., Santangelo S.L., Scharf J.M., Stein M.B., Thornton L.M., Walters J.T.R., Wray N.R., Geschwind D.H., Neale B.M., Kendler K.S., Smoller J.W., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Epidemiology and Data Science, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, APH - Digital Health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Kas lab, Adult Psychiatry, Child Psychiatry, ANS - Complex Trait Genetics, Aarno Palotie / Principal Investigator, Jaakko Kaprio / Principal Investigator, Centre of Excellence in Complex Disease Genetics, Genetic Epidemiology, Department of Public Health, University Management, Anna Keski-Rahkonen / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, HUS Psychiatry, Institute for Molecular Medicine Finland, Research Programs Unit, Genomics of Neurological and Neuropsychiatric Disorders, Biological Psychology, Complex Trait Genetics, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Lee, P. H., Anttila, V., Won, H., Feng, Y. -C. A., Rosenthal, J., Zhu, Z., Tucker-Drob, E. M., Nivard, M. G., Grotzinger, A. D., Posthuma, D., Wang, M. M. -J., Yu, D., Stahl, E. A., Walters, R. K., Anney, R. J. L., Duncan, L. E., Ge, T., Adolfsson, R., Banaschewski, T., Belangero, S., Cook, E. H., Coppola, G., Derks, E. M., Hoekstra, P. J., Kaprio, J., Keski-Rahkonen, A., Kirov, G., Kranzler, H. R., Luykx, J. J., Rohde, L. A., Zai, C. C., Agerbo, E., Arranz, M. J., Asherson, P., Baekvad-Hansen, M., Baldursson, G., Bellgrove, M., Belliveau, R. A., Buitelaar, J., Burton, C. L., Bybjerg-Grauholm, J., Casas, M., Cerrato, F., Chambert, K., Churchhouse, C., Cormand, B., Crosbie, J., Dalsgaard, S., Demontis, D., Doyle, A. E., Dumont, A., Elia, J., Grove, J., Gudmundsson, O. O., Haavik, J., Hakonarson, H., Hansen, C. S., Hartman, C. A., Hawi, Z., Hervas, A., Hougaard, D. M., Howrigan, D. P., Huang, H., Kuntsi, J., Langley, K., Lesch, K. -P., Leung, P. W. L., Loo, S. K., Martin, J., Martin, A. R., Mcgough, J. J., Medland, S. E., Moran, J. L., Mors, O., Mortensen, P. B., Oades, R. D., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Peters, T., Poterba, T., Poulsen, J. B., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Rothenberger, A., Rovira, P., Sanchez-Mora, C., Satterstrom, F. K., Schachar, R., Artigas, M. S., Steinberg, S., Stefansson, H., Turley, P., Walters, G. B., Werge, T., Zayats, T., Arking, D. E., Bettella, F., Buxbaum, J. D., Christensen, J. H., Collins, R. L., Coon, H., De Rubeis, S., Delorme, R., Grice, D. E., Hansen, T. F., Holmans, P. A., Hope, S., Hultman, C. M., Klei, L., Ladd-Acosta, C., Magnusson, P., Naerland, T., Nyegaard, M., Pinto, D., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Roeder, K., Rouleau, G. A., Saemundsen, E., Sanders, S. J., Sandin, S., St Pourcain, B., Stefansson, K., Sutcliffe, J. S., Talkowski, M. E., Weiss, L. A., Willsey, A. J., Agartz, I., Akil, H., Albani, D., Alda, M., Als, T. D., Anjorin, A., Backlund, L., Bass, N., Bauer, M., Baune, B. T., Bellivier, F., Bergen, S. E., Berrettini, W. H., Biernacka, J. M., Blackwood, D. H. R., Boen, E., Budde, M., Bunney, W., Burmeister, M., Byerley, W., Byrne, E. M., Cichon, S., Clarke, T. -K., Coleman, J. R. I., Craddock, N., Curtis, D., Czerski, P. M., Dale, A. M., Dalkner, N., Dannlowski, U., Degenhardt, F., Di Florio, A., Elvsashagen, T., Etain, B., Fischer, S. B., Forstner, A. J., Forty, L., Frank, J., Frye, M., Fullerton, J. M., Gade, K., Gaspar, H. A., Gershon, E. S., Gill, M., Goes, F. S., Gordon, S. D., Gordon-Smith, K., Green, M. J., Greenwood, T. A., Grigoroiu-Serbanescu, M., Guzman-Parra, J., Hauser, J., Hautzinger, M., Heilbronner, U., Herms, S., Hoffmann, P., Holland, D., Jamain, S., Jones, I., Jones, L. A., Kandaswamy, R., Kelsoe, J. R., Kennedy, J. L., Joachim, O. K., Kittel-Schneider, S., Kogevinas, M., Koller, A. C., Lavebratt, C., Lewis, C. M., Li, Q. S., Lissowska, J., Loohuis, L. M. O., Lucae, S., Maaser, A., Malt, U. F., Martin, N. G., Martinsson, L., Mcelroy, S. L., Mcmahon, F. J., Mcquillin, A., Melle, I., Metspalu, A., Millischer, V., Mitchell, P. B., Montgomery, G. W., Morken, G., Morris, D. W., Muller-Myhsok, B., Mullins, N., Myers, R. M., Nievergelt, C. M., Nordentoft, M., Adolfsson, A. N., Nothen, M. M., Ophoff, R. A., Owen, M. J., Paciga, S. A., Pato, C. N., Pato, M. T., Perlis, R. H., Perry, A., Potash, J. B., Reinbold, C. S., Rietschel, M., Rivera, M., Roberson, M., Schalling, M., Schofield, P. R., Schulze, T. G., Scott, L. J., Serretti, A., Sigurdsson, E., Smeland, O. B., Stordal, E., Streit, F., Strohmaier, J., Thorgeirsson, T. E., Treutlein, J., Turecki, G., Vaaler, A. E., Vieta, E., Vincent, J. B., Wang, Y., Witt, S. H., Zandi, P., Adan, R. A. H., Alfredsson, L., Ando, T., Aschauer, H., Baker, J. H., Bencko, V., Bergen, A. W., Birgegard, A., Perica, V. B., Brandt, H., Burghardt, R., Carlberg, L., Cassina, M., Clementi, M., Courtet, P., Crawford, S., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., Degortes, D., Desocio, J. E., Dick, D. M., Dina, C., Docampo, E., Egberts, K., Ehrlich, S., Espeseth, T., Fernandez-Aranda, F., Fichter, M. M., Foretova, L., Forzan, M., Gambaro, G., Giegling, I., Gonidakis, F., Gorwood, P., Mayora, M. G., Guo, Y., Halmi, K. A., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Imgart, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Julia, A., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kaye, W. H., Kennedy, M. A., Kim, Y. -R., Klareskog, L., Klump, K. L., Knudsen, G. P. S., Landen, M., Le Hellard, S., Levitan, R. D., Li, D., Lichtenstein, P., Maj, M., Marsal, S., Mcdevitt, S., Mitchell, J., Monteleone, P., Monteleone, A. M., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., O'Toole, J. K., Padyukov, L., Pantel, J., Papezova, H., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Roberts, M., Rujescu, D., Rybakowski, F., Scherag, A., Schmidt, U., Seitz, J., Slachtova, L., Slof-Op't Landt, M. C. T., Slopien, A., Sorbi, S., Southam, L., Strober, M., Tortorella, A., Tozzi, F., Treasure, J., Tziouvas, K., van Elburg, A. A., Wade, T. D., Wagner, G., Walton, E., Watson, H. J., Wichmann, H. -E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Adams, M. J., Andlauer, T. F. M., Berger, K., Binder, E. B., Boomsma, D. I., Castelao, E., Colodro-Conde, L., Direk, N., Docherty, A. R., Domenici, E., Domschke, K., Dunn, E. C., Foo, J. C., D, e. Geus E. J. C., Grabe, H. J., Hamilton, S. P., Horn, C., Hottenga, J. -J., Howard, D., Ising, M., Kloiber, S., Levinson, D. F., Lewis, G., Magnusson, P. K. E., Mbarek, H., Middeldorp, C. M., Mostafavi, S., Nyholt, D. R., Penninx, B. W., Peterson, R. E., Pistis, G., Porteous, D. J., Preisig, M., Quiroz, J. A., Schaefer, C., Schulte, E. C., Shi, J., Smith, D. J., Thomson, P. A., Tiemeier, H., Uher, R., van der Auwera, S., Weissman, M. M., Alexander, M., Begemann, M., Bramon, E., Buccola, N. G., Cairns, M. J., Campion, D., Carr, V. J., Cloninger, C. R., Cohen, D., Collier, D. A., Corvin, A., Delisi, L. E., Donohoe, G., Dudbridge, F., Duan, J., Freedman, R., Gejman, P. V., Golimbet, V., Godard, S., Ehrenreich, H., Hartmann, A. M., Henskens, F. A., Ikeda, M., Iwata, N., Jablensky, A. V., Joa, I., Jonsson, E. G., Kelly, B. J., Knight, J., Konte, B., Laurent-Levinson, C., Lee, J., Lencz, T., Lerer, B., Loughland, C. M., Malhotra, A. K., Mallet, J., Mcdonald, C., Mitjans, M., Mowry, B. J., Murphy, K. C., Murray, R. M., O'Neill, F. A., Oh, S. -Y., Palotie, A., Pantelis, C., Pulver, A. E., Petryshen, T. L., Quested, D. J., Riley, B., Sanders, A. R., Schall, U., Schwab, S. G., Scott, R. J., Sham, P. C., Silverman, J. M., Sim, K., Steixner, A. A., Tooney, P. A., van Os, J., Vawter, M. P., Walsh, D., Weiser, M., Wildenauer, D. B., Williams, N. M., Wormley, B. K., Zhang, F., Androutsos, C., Arnold, P. D., Barr, C. L., Barta, C., Bey, K., Bienvenu, O. J., Black, D. W., Brown, L. W., Budman, C., Cath, D., Cheon, K. -A., Ciullo, V., Coffey, B. J., Cusi, D., Davis, L. K., Denys, D., Depienne, C., Dietrich, A., Eapen, V., Falkai, P., Fernandez, T. V., Garcia-Delgar, B., Geller, D. A., Gilbert, D. L., Grados, M. A., Greenberg, E., Grunblatt, E., Hagstrom, J., Hanna, G. L., Hartmann, A., Hedderly, T., Heiman, G. A., Heyman, I., Hong, H. J., Huang, A., Huyser, C., Ibanez-Gomez, L., Khramtsova, E. A., Kim, Y. K., Kim, Y. -S., King, R. A., Koh, Y. -J., Konstantinidis, A., Kook, S., Kuperman, S., Leventhal, B. L., Lochner, C., Ludolph, A. G., Madruga-Garrido, M., Malaty, I., Maras, A., Mccracken, J. T., Meijer, I. A., Mir, P., Morer, A., Muller-Vahl, K. R., Munchau, A., Murphy, T. L., Naarden, A., Nagy, P., Nestadt, G., Nestadt, P. S., Nicolini, H., Nurmi, E. L., Okun, M. S., Paschou, P., Piras, F., Pittenger, C., Plessen, K. J., Richter, M. A., Rizzo, R., Robertson, M., Roessner, V., Ruhrmann, S., Samuels, J. F., Sandor, P., Schlogelhofer, M., Shin, E. -Y., Singer, H., Song, D. -H., Song, J., Spalletta, G., Stein, D. J., Stewart, S. E., Storch, E. A., Stranger, B., Stuhrmann, M., Tarnok, Z., Tischfield, J. A., Tubing, J., Visscher, F., Vulink, N., Wagner, M., Walitza, S., Wanderer, S., Woods, M., Worbe, Y., Zai, G., Zinner, S. H., Sullivan, P. F., Franke, B., Daly, M. J., Bulik, C. M., Mcintosh, A. M., O'Donovan, M. C., Zheutlin, A., Andreassen, O. A., Borglum, A. D., Breen, G., Edenberg, H. J., Fanous, A. H., Faraone, S. V., Gelernter, J., Mathews, C. A., Mattheisen, M., Mitchell, K. S., Neale, M. C., Nurnberger, J. I., Ripke, S., Santangelo, S. L., Scharf, J. M., Stein, M. B., Thornton, L. M., Walters, J. T. R., Wray, N. R., Geschwind, D. H., Neale, B. M., Kendler, K. S., and Smoller, J. W.

Subjects
Netherlands Twin Register (NTR), cross-disorder genetics, Medizin, Genome-wide association study, Tourette syndrome, functional genomics, gene expression, genetic architecture, genetic correlation, GWAS, neurodevelopment, pleiotropy, psychiatric disorders, Psychiatric genetics, 0302 clinical medicine, Pleiotropy, functional genomic, WIDE ASSOCIATION, cross-disorder genetic, 0303 health sciences, Mental Disorders, Genetic Pleiotropy, HUMAN BRAIN, INSIGHTS, Autism spectrum disorder, Schizophrenia, DISEASES, GENETIC CORRELATIONS, medicine.medical_specialty, Neurogenesis, Quantitative Trait Loci, BF, Biology, GENOTYPE IMPUTATION, Psychiatric geneticscross-disorder geneticspsychiatric disorderspleiotropyneurodevelopmentGWASgenetic correlationgene expressiongenetic architecturefunctional genomics, Article, General Biochemistry, Genetics and Molecular Biology, psychiatric disorder, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, TRANSCRIPTOME, Psychiatry, 030304 developmental biology, Gwas, Psychiatric Genetics, Cross-disorder Genetics, Functional Genomics, Gene Expression, Genetic Architecture, Genetic Correlation, Neurodevelopment, Psychiatric Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, medicine.disease, Genetic architecture, DEMETHYLASE, RC0321, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Published
2019

35. Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

Author

Ethan G. Geier, Mathieu Bourdenx, Jennifer S. Yokoyama, Anna Karydas, Suzee E. Lee, Salvatore Spina, J. Nicholas Cochran, Giovanni Coppola, Lea T. Grinberg, Deepika Dokuru, Ana Maria Cuervo, Ji Hye Hwang, Richard M. Myers, Nadia J. Storm, Victoria Van Berlo, Alissa L. Nana, Yadong Huang, Maureen E. Balestra, Bruce L. Miller, Antonio Diaz, Luke W. Bonham, Daniel W. Sirkis, Eliana Marisa Ramos, Silvia P. Russo, and William W. Seeley

Subjects
0301 basic medicine, Male, Pathology, Aging, Neurodegenerative, Alzheimer's Disease, 0302 clinical medicine, C9orf72, Risk Factors, Medicine, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Related Dementias (ADRD), Neurodegeneration, Frontotemporal lobar degeneration, Middle Aged, Neuronal ceroid lipofuscinosis, Frontotemporal Dementia (FTD), Frontotemporal Dementia, Neurological, Intercellular Signaling Peptides and Proteins, Female, Frontotemporal dementia, medicine.medical_specialty, Clinical Sciences, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Rare Diseases, Pick Disease of the Brain, Neuronal Ceroid-Lipofuscinoses, Clinical Research, mental disorders, Autophagy, Genetics, Acquired Cognitive Impairment, Dementia, Humans, Genetic Testing, Allele, Genetic Association Studies, Aged, Neurology & Neurosurgery, business.industry, Prevention, Case-control study, Neurosciences, nutritional and metabolic diseases, Membrane Transport Proteins, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, nervous system diseases, Brain Disorders, 030104 developmental biology, Mutation, Neurology (clinical), Frontotemporal Lobar Degeneration, business, Lysosomes, 030217 neurology & neurosurgery
Abstract

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observedan increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

Published
2019

36. Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis

Author

Carlos Tomás Roura, José Antonio Pinto, Benjamín Fernández-Gutiérrez, J.L. Sánchez-Carazo, E. J. Herrera, Mireia López-Corbeto, G Salvador, David Moreno, Juan D. Cañete, Josep M. Mercader, Daniel Roig, Jordi Gratacós, Alfredo Willisch Domínguez, Rubén Queiro, Ricardo Blanco, Andrea Pluma, Raimon Sanmartí, Devin Absher, Santos Castañeda, Lluís Puig, Carlos M. González, Mercedes Alperi-López, Santiago Muñoz-Fernández, Jesús Rodríguez, Josep Lluís Gelpí, Jesús Tornero, E. Daudén, Sílvia Bonàs-Guarch, Laia Codó, Pablo de la Cueva, J.J. Pérez-Venegas, Isidoro González-Álvaro, Andrés C. García-Montero, José Luis López-Estebaranz, Francisco J. Blanco, Carolina Pérez-García, Paloma Vela, David Torrents, Sara Marsal, Simón Ángel Sánchez-Fernández, Juan Carlos Torre-Alonso, Cesar Diaz-Torne, Hèctor Corominas, Antonio Julià, Núria Palau, E. Rubio, Antonio Gonzalez, Francisco Vanaclocha, Carlos Ferrándiz, Alejandro Olivé Marqués, Pedro Zarco, Adrià Aterido, Carlos Montilla, Eduardo Fonseca, Raül Tortosa, Emilia Fernández, Alba Erra, José Antonio Mosquera, María López-Lasanta, Julio A. Ramirez, Antonio Fernández Nebro, Richard M. Myers, and Víctor M. Martínez-Taboada

Subjects
0301 basic medicine, Oncology, Male, Inflammatory arthritis, Estudio de asociación del genoma completo, Drug repurposing, Genome-wide association study, urologic and male genital diseases, Arthritis, Rheumatoid, Cohort Studies, 0302 clinical medicine, Immunology and Allergy, Glycosaminoglycans, glycosaminoglycan, psoriatic arthritis, genome-wide association study, Rheumatoid arthritis, Psoriatic arthritis, Cohort, Female, Signal Transduction, Adult, medicine.medical_specialty, Farmacología, Immunology, N-Acetylglucosaminyltransferases, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rheumatology, Internal medicine, Psoriasis, Genetic variation, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetic association, 030203 arthritis & rheumatology, drug repurposing, Artritis, business.industry, Arthritis, Psoriatic, drug repurposing, genetics, genome-wide association study, glycosaminoglycan, psoriatic arthritis, medicine.disease, Genética, genetics, 030104 developmental biology, Glycosaminoglycan, Spain, Case-Control Studies, North America, Artritis psoriásica, business, Genome-Wide Association Study
Abstract

ObjectivePsoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA.MethodsWe performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case–control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA.ResultsWe identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDRConclusionThese findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.

Published
2019

37. Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction

Author

ON Gill, Delpech, David Asboe, David F. Bibby, Juan Ledesma, Richard M. Myers, Alison E Brown, Amin S. Hassan, Caroline A. Sabin, Gary Murphy, David Dunn, Peter Kirwan, Jean L. Mbisa, Anton Pozniak, Anna Tostevin, and S Kirk

Subjects
Male, 0301 basic medicine, Microbiology (medical), Genotype, Anti-HIV Agents, Population, HIV Infections, Drug resistance, law.invention, 03 medical and health sciences, Mutation Rate, Acquired immunodeficiency syndrome (AIDS), Risk Factors, law, Drug Resistance, Viral, Prevalence, Consensus sequence, Cluster Analysis, Humans, Medicine, Public Health Surveillance, Mutation frequency, education, Clade, Articles and Commentaries, Phylogeny, education.field_of_study, business.industry, Genetic Variation, High-Throughput Nucleotide Sequencing, medicine.disease, Virology, United Kingdom, 030104 developmental biology, Infectious Diseases, Transmission (mechanics), Mutation, Mutation (genetic algorithm), HIV-1, Female, business
Abstract

BACKGROUND: Drug-resistant minority variants (DRMinVs) detected in patients who recently acquired human immunodeficiency virus type 1 (HIV-1) can be transmitted, generated de novo through virus replication, or technical errors. The first form is likely to persist and result in treatment failure, while the latter two could be stochastic and transient. METHODS: Ultradeep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the United Kingdom was performed to detect DRMinVs at a mutation frequency between 2% and 20%. Sequence alignments including >110 000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD), linked to epidemiological and clinical data from the HIV and AIDS Reporting System, were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events. RESULTS: Drug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n = 48; 72.7%) and DRMinV (n = 63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harbored the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (P < .00001, Fisher exact test). Evidence of likely direct transmission of DRMajVs was observed for 25/66 (37.9%), whereas none were observed for the DRMinVs (P < .00001). CONCLUSIONS: Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals.

Published
2018

38. Enhanced surveillance of HIV-1 drug resistance in recently infected MSM in the UK

Author

Jean L. Mbisa, Patricia A. Cane, Richard M. Myers, Adamma Aghaizu, Jennifer Tosswill, Nigel Field, David F. Bibby, Ross J Harris, Valerie Delpech, Emma Cunningham, Yuen-Ting Chan, O Noel Gill, and Gary Murphy

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), Adolescent, Genotype, HIV Infections, Drug resistance, Biology, Polymerase Chain Reaction, Serology, law.invention, Men who have sex with men, Young Adult, 03 medical and health sciences, law, Drug Resistance, Viral, Humans, Pharmacology (medical), Clinical significance, Avidity, Homosexuality, Male, Mutation frequency, Polymerase chain reaction, Aged, Pharmacology, Sequence Analysis, DNA, Middle Aged, Virology, United Kingdom, 030104 developmental biology, Infectious Diseases, pol Gene Products, Human Immunodeficiency Virus, Epidemiological Monitoring, HIV-1
Abstract

To determine the prevalence of inferred low-frequency HIV-1 transmitted drug resistance (TDR) in MSM in the UK and its predicted effect on first-line therapy.The HIV-1 pol gene was amplified from 442 newly diagnosed MSM identified as likely recently infected by serological avidity testing in 2011-13. The PCR products were sequenced by next-generation sequencing with a mutation frequency threshold of2% and TDR mutations defined according to the 2009 WHO surveillance drug resistance mutations list.The majority (75.6%) were infected with subtype B and 6.6% with rare complex or unique recombinant forms. At a mutation frequency threshold of20%, 7.2% (95% CI 5.0%-10.1%) of the sequences had TDR and this doubled to 15.8% (95% CI 12.6%-19.6%) at2% mutation frequency (P 0.0001). The majority (26/42, 62%) of low-frequency variants were against PIs. The most common mutations detected at20% and 2%-20% mutation frequency differed for each drug class, these respectively being: L90M (n = 7) and M46IL (n = 10) for PIs; T215rev (n = 9) and D67GN (n = 4) for NRTIs; and K103N (n = 5) and G190E (n = 2) for NNRTIs. Combined TDR was more frequent in subtype B than non-B (OR = 0.38; 95% CI = 0.17-0.88; P = 0.024) and had minimal predicted effect on recommended first-line therapies.The data suggest differences in the types of low-frequency compared with majority TDR variants that require a better understanding of the origins and clinical significance of low-frequency variants. This will better inform diagnostic and treatment strategies.

Published
2016

39. Decoding transcriptional enhancers: Evolving from annotation to functional interpretation

Author

Mark Mackiewicz, Daniel Savic, Krysta L. Engel, Andrew A. Hardigan, and Richard M. Myers

Subjects
0301 basic medicine, Genetics, Regulation of gene expression, Models, Genetic, Embryonic Development, Molecular Sequence Annotation, Cell Biology, Computational biology, Biology, Genome, Article, 03 medical and health sciences, Multicellular organism, Enhancer Elements, Genetic, 030104 developmental biology, Gene Expression Regulation, Genome editing, Animals, Humans, Disease, Enhancer, Functional genomics, Transcription factor, Gene, Developmental Biology
Abstract

Deciphering the intricate molecular processes that orchestrate the spatial and temporal regulation of genes has become an increasingly major focus of biological research. The differential expression of genes by diverse cell types with a common genome is a hallmark of complex cellular functions, as well as the basis for multicellular life. Importantly, a more coherent understanding of gene regulation is critical for defining developmental processes, evolutionary principles and disease etiologies. Here we present our current understanding of gene regulation by focusing on the role of enhancer elements in these complex processes. Although functional genomic methods have provided considerable advances to our understanding of gene regulation, these assays, which are usually performed on a genome-wide scale, typically provide correlative observations that lack functional interpretation. Recent innovations in genome editing technologies have placed gene regulatory studies at an exciting crossroads, as systematic, functional evaluation of enhancers and other transcriptional regulatory elements can now be performed in a coordinated, high-throughput manner across the entire genome. This review provides insights on transcriptional enhancer function, their role in development and disease, and catalogues experimental tools commonly used to study these elements. Additionally, we discuss the crucial role of novel techniques in deciphering the complex gene regulatory landscape and how these studies will shape future research.

Published
2016

40. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Ssang-Taek Lim, Helger G. Yntema, Tara Funari, Alexander P.A. Stegmann, Daniel G. MacArthur, Jung-Hyun Kim, Bert B.A. de Vries, Alyson Krokosky, Joost Nicolai, Sha Tang, Serge Romana, Megan T. Cho, Joris A. Veltman, Berivan Baskin, Vandana Shashi, Clesson Turner, Deepali N. Shinde, Maja Hempel, Franco Laccone, Lisenka E.L.M. Vissers, Richard M. Myers, Grazia M.S. Mancini, Daniëlle G.M. Bosch, Eun-Young Erin Ahn, Tamison Jewett, Ganka Douglas, Margot R.F. Reijnders, Eun Young Park, Axel Neu, Dong-Er Zhang, Joshua K. Stone, Davor Lessel, Connie T.R.M. Stumpel, Helga Rehder, Christopher T. Gordon, Luis Rohena, Laurie B. Owen, Dima El-Khechen, Jana Behunova, Tim M. Strom, Julie Vogt, Andrea H. Seeley, Kirsty McWalter, Nuria C. Bramswig, Margje Sinnema, Marlène Rio, Natalie Hauser, Rebecca L. Belmonte, Servi J. C. Stevens, Kristin Lindstrom, Han G. Brunner, Fanny Kortüm, Kelly Schoch, Amber Begtrup, Kristine K. Bachman, Paula A. Bubulya, Stephanie L. Santoro, Jos M. T. Draaisma, Dagmar Wieczorek, Xu Yao, David L. Stachura, Slavé Petrovski, Gregory R. Wilson, David Traver, Clinical Genetics, Genetica & Celbiologie, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), and MUMC+: DA Klinische Genetica (5)

Subjects
0301 basic medicine, Male, Developmental Disabilities, Medizin, Haploinsufficiency, Bioinformatics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Intellectual disability, FLNA, Genetics(clinical), Eye Abnormalities, Zebrafish, Genetics (clinical), Genetics, Gene knockdown, Genes, Essential, biology, Brain, Syndrome, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Pedigree, DNA-Binding Proteins, RNA splicing, Female, Heterozygote, RNA Splicing, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Minor Histocompatibility Antigens, 03 medical and health sciences, Metabolic Diseases, Intellectual Disability, Report, medicine, Animals, Humans, RNA, Messenger, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], RNA, medicine.disease, biology.organism_classification, Spine, 030104 developmental biology, Mutation, Head, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 167701.pdf (Publisher’s version ) (Open Access) The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Published
2016

41. Advancements in Next-Generation Sequencing

Author

Richard M. Myers and Shawn Levy

Subjects
0301 basic medicine, Genome, Human, Research areas, business.industry, Genome scale, High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, Biology, Data science, DNA sequencing, Biotechnology, 03 medical and health sciences, 030104 developmental biology, Genetics, Humans, business, Molecular Biology, Exome, Genetics (clinical), Pace
Abstract

The term next-generation sequencing is almost a decade old, but it remains the colloquial way to describe highly parallel or high-output sequencing methods that produce data at or beyond the genome scale. Since the introduction of these technologies, the number of applications and methods that leverage the power of genome-scale sequencing has increased at an exponential pace. This review highlights recent concepts, technologies, and methods from next-generation sequencing to illustrate the breadth and depth of the applications and research areas that are driving progress in genomics.

Published
2016

42. RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4

Author

Katherine C. Sexton, Sara J. Cooper, Martin J. Heslin, Nicholas S. Davis, Donald J. Buchsbaum, Ryne C. Ramaker, James Posey, Edward W Greeno, John D. Christein, Patsy G. Oliver, Selwyn M. Vickers, Jason Gertz, William E. Grizzle, Marie K. Kirby, Bobbi E Johnston, and Richard M. Myers

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Time Factors, RNA-Seq, Kaplan-Meier Estimate, Adenocarcinoma, Deoxycytidine, 03 medical and health sciences, 0302 clinical medicine, ANGPTL4, Internal medicine, Gene expression, Genetics, medicine, Angiopoietin-Like Protein 4, Humans, RNA, Messenger, Research Articles, Aged, Cell Proliferation, Sequence Analysis, RNA, business.industry, Gene Expression Profiling, RNA, Genomic signature, General Medicine, Middle Aged, medicine.disease, Survival Analysis, Gemcitabine, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, 030104 developmental biology, ROC Curve, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Cohort, Molecular Medicine, Female, business, Angiopoietins, medicine.drug
Abstract

Background Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. Results RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line. Conclusions Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy.

Published
2016

43. A genome-wide association study identifiesSLC8A3as a susceptibility locus for ACPA-positive rheumatoid arthritis

Author

Víctor M. Martínez-Taboada, S. Louis Bridges, Sara Marsal, Alba Erra, Arnald Alonso, Laia Codó, Josep Lluís Gelpí, Antonio Fernández-Nebro, Antonio Julià, Jaume Bertranpetit, I. González, Devin Absher, Richard M. Myers, Jesús Tornero, Joan Maymó, Mercedes Alperi-López, Antonio Gonzalez, Alejandro Olivé, Luis Rodriguez Rodriguez, Francisco J. Blanco, Juan D. Cañete, Hèctor Corominas, Raül Tortosa, Simón Ángel Sánchez-Fernández, Andrés C. García-Montero, and María López-Lasanta

Subjects
rheumatoid arthritis, Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), genetic risk, Peptides, Cyclic, Polymorphism, Single Nucleotide, Sodium-Calcium Exchanger, White People, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Risk Factors, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Pharmacology (medical), anti-citrullinated protein antibodies, Gene, Autoantibodies, joint erosions, 030203 arthritis & rheumatology, Genetics, genome-wide association study, biology, business.industry, Anti–citrullinated protein antibody, Odds ratio, Middle Aged, medicine.disease, 030104 developmental biology, Genetic Loci, Case-Control Studies, Rheumatoid arthritis, Cohort, biology.protein, Female, business, Genome-Wide Association Study
Abstract

OBJECTIVE RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. METHODS A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. RESULTS In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. CONCLUSIONS SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.

Published
2016

44. Evolving New Skeletal Traits by cis -Regulatory Changes in Bone Morphogenetic Proteins

Author

Jeremy Schmutz, David M. Kingsley, Vahan B. Indjeian, Jane Grimwood, Garrett A. Roberts Kingman, Felicity C. Jones, Richard M. Myers, and Catherine A. Guenther

Subjects
Fish Proteins, 0301 basic medicine, Transposable element, Transgene, Quantitative Trait Loci, Fresh Water, Locus (genetics), Growth Differentiation Factor 6, Quantitative trait locus, Biology, Bone morphogenetic protein, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, 03 medical and health sciences, Species Specificity, Animals, Humans, Seawater, Enhancer, Skeleton, Genetics, Comparative genomics, Biochemistry, Genetics and Molecular Biology(all), Adaptation, Physiological, Biological Evolution, Smegmamorpha, Enhancer Elements, Genetic, 030104 developmental biology, GDF6, Vertebrates
Abstract

Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone-size differences in sticklebacks map to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor-plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form.

Published
2016

45. Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure

Author

Roda P. Konadhode, Jing Liu, Heidi Salisbury, Jeffrey Brandimarto, Matthew T. Wheeler, Euan A. Ashley, Aleksandra Pavlovic, Rupak Mukherjee, Porama Koy Thanaporn, Ching Shang, Devin Absher, Thomas E. Scammell, Daniel Sedehi, Thomas P. Cappola, Thomas Quertermous, Marco V Perez, Stephen Pan, Clint L. Miller, Frederick E. Dewey, Richard M. Myers, and Khin Chan

Subjects
Cardiac function curve, Adult, Male, Candidate gene, medicine.medical_specialty, Genome-wide association study, Article, Cohort Studies, Hypocretin (orexin) receptor 2, Mice, Orexin Receptors, Internal medicine, medicine, Animals, Humans, Aged, Genetics, Heart Failure, Ejection fraction, business.industry, Stroke Volume, Middle Aged, medicine.disease, Orexin receptor, Minor allele frequency, Disease Models, Animal, Heart failure, Cardiology, Female, business, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function. Objectives This study sought to identify genetic variations associated with response to HF therapy. Methods This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography. Results Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10−5). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model. Conclusions A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.

Published
2015
Full Text
View/download PDF

46. aRNApipe: a balanced, efficient and distributed pipeline for processing RNA-seq data in high-performance computing environments

Author

Brittany N. Lasseigne, Kelly L. Williams, Brian S. Roberts, Sara Marsal, Sara J. Cooper, Richard M. Myers, Josh Nielsen, Arnald Alonso, Bobbi E Johnston, Andrew A. Hardigan, and Ryne C. Ramaker

Subjects
0301 basic medicine, Statistics and Probability, Genotyping Techniques, Computer science, Distributed computing, RNA-Seq, Biochemistry, Genome, Computing Methodologies, Workflow, 03 medical and health sciences, Software, Humans, Molecular Biology, business.industry, Sequence Analysis, RNA, Alternative splicing, RNA, Modular design, Supercomputer, Pipeline (software), Applications Notes, Computer Science Applications, Computational Mathematics, Identification (information), Alternative Splicing, 030104 developmental biology, Computational Theory and Mathematics, business, Sequence Analysis
Abstract

Summary The wide range of RNA-seq applications and their high-computational needs require the development of pipelines orchestrating the entire workflow and optimizing usage of available computational resources. We present aRNApipe, a project-oriented pipeline for processing of RNA-seq data in high-performance cluster environments. aRNApipe is highly modular and can be easily migrated to any high-performance computing (HPC) environment. The current applications included in aRNApipe combine the essential RNA-seq primary analyses, including quality control metrics, transcript alignment, count generation, transcript fusion identification, alternative splicing and sequence variant calling. aRNApipe is project-oriented and dynamic so users can easily update analyses to include or exclude samples or enable additional processing modules. Workflow parameters are easily set using a single configuration file that provides centralized tracking of all analytical processes. Finally, aRNApipe incorporates interactive web reports for sample tracking and a tool for managing the genome assemblies available to perform an analysis. Availability and documentation https://github.com/HudsonAlpha/aRNAPipe; DOI: 10.5281/zenodo.202950 Supplementary information Supplementary data are available at Bioinformatics online.

Published
2017

47. De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Author

Patricia G Wheeler, Anya Revah-Politi, Viktor Stranecky, Alejandro Iglesias, James W. Wheless, Anna C.E. Hurst, Nicholas Stong, Parisa Hemati, Ryne C. Ramaker, Zdenek Sedlacek, Caroline Nava, Matthew B. Neu, Yves Lacassie, Cyril Mignot, Jan Prchal, Richard M. Myers, Marketa Havlovicova, Jeremy W. Prokop, Darina Prchalova, Rebecca Willaert, Zöe Powis, Susan M. Hiatt, Dwight K. C. Yim, Mariya Kozenko, Andrew A. Hardigan, Gregory M. Cooper, Lauren Brick, Boris Keren, Sharon F. Suchy, Miroslava Hancarova, Ingrid M. Wentzensen, Gregory S. Barsh, and Marlène Rio

Subjects
0301 basic medicine, Proband, Models, Molecular, Cancer Research, Mutation rate, GTP', Protein Conformation, Hydrolases, Developmental Disabilities, Glycobiology, GTPase, QH426-470, medicine.disease_cause, Biochemistry, Database and Informatics Methods, 0302 clinical medicine, Medicine and Health Sciences, Missense mutation, Small GTPase, Public and Occupational Health, Genome Sequencing, Enzyme-Linked Immunoassays, Child, Genetics (clinical), Genetics, education.field_of_study, Mutation, 0303 health sciences, Guanosine, Nucleosides, Phenotype, RALA, Glycosylamines, Recombinant Proteins, Enzymes, Phenotypes, Bioassays and Physiological Analysis, Developmental disabilities--Genetic aspects, Perspective, Metabolic Pathways, Guanosine Triphosphate, Anatomy, Sequence Analysis, Research Article, Signal Transduction, Genotype, Bioinformatics, Disabilities, Population, Mutation, Missense, Biology, Research and Analysis Methods, Guanosine Diphosphate, Mitochondrial Proteins, 03 medical and health sciences, Amino Acid Sequence Analysis, Intellectual Disability, medicine, Humans, Protein Interaction Domains and Motifs, Allele, education, Immunoassays, Molecular Biology Techniques, Sequencing Techniques, Gene, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, Enzyme Assays, Facies, Biology and Life Sciences, Proteins, Human Genetics, Guanosine Triphosphatase, 030104 developmental biology, Metabolism, Genetic Loci, FOS: Biological sciences, Face, Genetics of Disease, ras Proteins, Immunologic Techniques, Enzymology, ral GTP-Binding Proteins, Biochemical Analysis, Head, 030217 neurology & neurosurgery
Abstract

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10−11) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases., Author summary While many causes of developmental disabilities have been identified, a large number of affected children cannot be diagnosed despite extensive medical testing. Previously unknown genetic factors are likely to be the culprits in many of these cases. Using DNA sequencing, and by sharing information among many doctors and researchers, we have identified a set of individuals with developmental problems who all have changes to the same gene, RALA. The affected individuals all have similar symptoms, including intellectual disability, speech delay (or no speech), and problems with motor skills like walking. In nearly all of these cases (10 of 11), the genetic change found in the child was not inherited from either parent. The locations and biological properties of these changes suggest that they are likely to disrupt the normal functions of RALA. Functional experiments also show that the genetic changes found in these individuals alter two key functions of RALA. Together, we have provided evidence that genetic changes in RALA can cause developmental disabilities. These results will allow doctors and researchers to identify additional children with the same condition, providing a clinical diagnosis to these families and leading to new research opportunities.

Published
2018

48. Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

Author

Jedidiah Carlson, Adam E. Locke, Matthew Flickinger, Matthew Zawistowski, Shawn Levy, Richard M. Myers, Michael Boehnke, Hyun Min Kang, Laura J. Scott, Jun Z. Li, Sebastian Zöllner, and The BRIDGES Consortium

Subjects
0301 basic medicine, Mutation rate, Guanine, Science, General Physics and Astronomy, Genomics, Context (language use), Biology, Polymorphism, Single Nucleotide, Genome, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, Cytosine, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Mutation Rate, Humans, Histone code, lcsh:Science, Germ-Line Mutation, 030304 developmental biology, Genetics, Base Composition, 0303 health sciences, Replication timing, Deoxyribonucleases, Multidisciplinary, Genome, Human, Genetic Variation, General Chemistry, DNA Methylation, Histone Code, 030104 developmental biology, CpG site, Mutation (genetic algorithm), CpG Islands, lcsh:Q, Human genome, Hypersensitive site, 030217 neurology & neurosurgery
Abstract

Precise estimates of the single-nucleotide mutation rate and its variability are essential to the study of human genome evolution and genetic diseases. Here we use ~36 million singleton variants observed in 3,716 whole-genome sequences to characterize the heterogeneity of germline mutation rates across the genome. Adjacent-nucleotide context is the strongest predictor of mutability, with mutation rates varying by >650-fold depending on the identity of three bases upstream or downstream of the mutated site. Histone modifications, replication timing, recombination rate, and other local genomic features further modify mutability; magnitude and direction of this modification varies with the sequence context. Compared to estimates based on common variants used in previous approaches, singleton-based estimates provide a more accurate prediction of the mutation patterns seen in an independent dataset of ~46,000 de novo mutations; and incorporating the effects of genomic features further improves the prediction. The effects of sequence contexts, genomic features, and their interactions reported here capture the most refined portrait to date of the germline mutation patterns in humans.

Published
2018

49. Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles

Author

David E. Gray, Brittany N. Lasseigne, James Holt, Bryan A. Moyers, Gregory M. Cooper, Michelle L. Thompson, James M.J. Lawlor, David S. Geldmacher, Jennifer S. Yokoyama, Michelle D. Amaral, J. Scott Newberry, Emily C. McKinley, Erik D. Roberson, Jeremy W. Prokop, Elizabeth A. Worthey, Meagan Cochran, Ethan G. Geier, Marissa Natelson Love, J. Nicholas Cochran, and Richard M. Myers

Subjects
Male, Aging, Apolipoprotein E4, Penetrance, Neurodegenerative, Alzheimer's Disease, frontotemporal dementia, 0302 clinical medicine, Risk Factors, Odds Ratio, 2.1 Biological and endogenous factors, Family history, Genetics, 0303 health sciences, Chromosome Mapping, General Medicine, Middle Aged, 3. Good health, Neurological, Medical genetics, Female, Alzheimer's disease, Research Article, Frontotemporal dementia, medicine.medical_specialty, Genomics, DNA sequencing, 03 medical and health sciences, Alzheimer Disease, Clinical Research, Acquired Cognitive Impairment, medicine, Humans, Dementia, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Aged, 030304 developmental biology, Base Sequence, Whole Genome Sequencing, C9orf72 Protein, business.industry, Prevention, Human Genome, Neurosciences, Genetic Variation, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, Brain Disorders, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41–76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in APP, C9orf72, CSF1R, and MAPT. Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2–5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2. All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE ε4 alleles. One patient had two APOE ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.

Published
2019

50. Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies

Author

Gemma L. Carvill, Krysta L. Engel, Aishwarya Ramamurthy, J. Nicholas Cochran, Jolien Roovers, Hannah Stamberger, Nicholas Lim, Amy L. Schneider, Georgie Hollingsworth, Dylan H. Holder, Brigid M. Regan, James Lawlor, Lieven Lagae, Berten Ceulemans, E. Martina Bebin, John Nguyen, Gregory S. Barsh, Sarah Weckhuysen, Miriam Meisler, Samuel F. Berkovic, Peter De Jonghe, Ingrid E. Scheffer, Richard M. Myers, Gregory M. Cooper, Heather C. Mefford, Pasquale Striano, Federico Zara, Ingo Helbig, Rikke S. Møller, Sarah von Spiczak, Hiltrud Muhle, Hande Caglayan, Katalin Sterbova, Dana Craiu, Dorota Hoffman, Anna-Elina Lehesjoki, Kaja Selmer, Christel Depienne, Johannes Lemke, Carla Marini, Renzo Guerrini, Bernd Neubauer, Tiina Talvik, Eric Leguern, Peter de Jonghe, and EuroEPINOMICS Rare Epilepsy Syndro

Subjects
0301 basic medicine, Male, SPLICE VARIANTS, PROTEIN, Epilepsies, Myoclonic, Sodium Channels, Transcriptome, Epilepsy, Exon, poison exon, 0302 clinical medicine, SCN1A, NEURONAL SODIUM-CHANNEL, BRAIN, Child, Genetics (clinical), Exome sequencing, Genetics, Genetics & Heredity, noncoding, Exons, Middle Aged, genome sequencing, Female, REGULATOR, Life Sciences & Biomedicine, Adult, Biology, 03 medical and health sciences, alternative splicing, Dravet syndrome, Report, medicine, Humans, Gene, Science & Technology, variant interpretation, Alternative splicing, epilepsy, Genetic Variation, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, 030104 developmental biology, DE-NOVO MUTATIONS, Neurodevelopmental Disorders, Human genome, Human medicine, 030217 neurology & neurosurgery
Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1-3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:6 pages:1022-1029 ispartof: location:United States status: published

Published
2018

Catalog

Books, media, physical & digital resources
See catalog results