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1. Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis

Author

Patrick R. Lawler, MD, MPH, Garen Manvelian, PhD, Alida Coppi, PhD, Amy Damask, PhD, Michael N. Cantor, MD, Manuel A. R. Ferreira, PhD, Charles Paulding, PhD, Nilanjana Banerjee, PhD, Dadong Li, PhD, Susan Jorgensen, MS, Richa Attre, PhD, David J. Carey, PhD, Kristi Krebs, PhD, Lili Milani, PhD, Kristian Hveem, MD, Jan K. Damås, PhD, Erik Solligård, PhD, Stefan Stender, MD, Anne Tybjærg-Hansen, MD, Børge G. Nordestgaard, MD, Tamara Hernandez-Beeftink, PhD, Tormod Rogne, MD, Carlos Flores, PhD, Jesús Villar, MD, Keith R. Walley, MD, Vincent X. Liu, MD, Alison E. Fohner, PhD, Luca A. Lotta, MD, Christos A. Kyratsous, PhD, Mark W. Sleeman, PhD, Michel Scemama, MD, Richard DelGizzi, MS, Robert Pordy, MD, Julie E. Horowitz, PhD, Aris Baras, MD, Greg S. Martin, MD, Philippe Gabriel Steg, MD, Gregory G. Schwartz, MD, Michael Szarek, PhD, and Shaun G. Goodman, MD

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN:. Genetic and clinical epidemiology, and experimental models. SETTING:. Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS:. Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS:. Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS:. Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67–1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS:. PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Published
2023
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2. Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure

Author

Joel T. Rämö, Tuomo Kiiskinen, Richard Seist, Kristi Krebs, Masahiro Kanai, Juha Karjalainen, Mitja Kurki, Eija Hämäläinen, Paavo Häppölä, Aki S. Havulinna, Heidi Hautakangas, FinnGen, Reedik Mägi, Priit Palta, Tõnu Esko, Andres Metspalu, Matti Pirinen, Konrad J. Karczewski, Samuli Ripatti, Lili Milani, Konstantina M. Stankovic, Antti Mäkitie, Mark J. Daly, and Aarno Palotie

Subjects
Science
Abstract

Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.

Published
2023
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3. Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes

Author

Michael Dannemann, Yuri Milaneschi, Danat Yermakovich, Victoria Stiglbauer, Hanna Maria Kariis, Kristi Krebs, Manuel A. Friese, Christian Otte, Estonian Biobank Research Team, Kelli Lehto, Brenda W. J. H. Penninx, Janet Kelso, and Stefan M. Gold

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets. Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans

Published
2022
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4. ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma

Author

Kavita Praveen, Gaurang C. Patel, Lauren Gurski, Ariane H. Ayer, Trikaladarshi Persaud, Matthew D. Still, Lawrence Miloscio, Tavé Van Zyl, Silvio Alessandro Di Gioia, Ben Brumpton, Kristi Krebs, Bjørn Olav Åsvold, Esteban Chen, Venkata R. M. Chavali, Wen Fury, Harini V. Gudiseva, Sarah Hyde, Eric Jorgenson, Stephanie Lefebvre, Dadong Li, Alexander Li, James Mclninch, Brijeshkumar Patel, Jeremy S. Rabinowitz, Rebecca Salowe, Claudia Schurmann, Anne-Sofie Seidelin, Eli Stahl, Dylan Sun, Tanya M. Teslovich, Anne Tybjærg-Hansen, Cristen Willer, Scott Waldron, Sabrina Walley, Hua Yang, Sarthak Zaveri, Regeneron Genetics Center, GHS-RGC DiscovEHR Collaboration, Estonian Biobank Research Team, Ying Hu, Kristian Hveem, Olle Melander, Lili Milani, Stefan Stender, Joan M. O’Brien, Marcus B. Jones, Gonçalo R. Abecasis, Michael N. Cantor, Jonathan Weyne, Katia Karalis, Aris Economides, Giusy Della Gatta, Manuel A. Ferreira, George D. Yancopoulos, Aris Baras, Carmelo Romano, and Giovanni Coppola

Subjects
Biology (General), QH301-705.5
Abstract

Rare variant association data from human genetics combined with in vitro and in vivo functional validation highlight ANGPTL7 as a promising therapeutic target for intraocular pressure reduction, and protection from glaucoma.

Published
2022
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5. Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis

Author

Sanni E. Ruotsalainen, Ida Surakka, Nina Mars, Juha Karjalainen, Mitja Kurki, Masahiro Kanai, Kristi Krebs, Sarah Graham, Pashupati P. Mishra, Binisha H. Mishra, Juha Sinisalo, Priit Palta, Terho Lehtimäki, Olli Raitakari, Estonian Biobank Research Team, Lili Milani, The Biobank Japan Project, Yukinori Okada, FinnGen, Aarno Palotie, Elisabeth Widen, Mark J. Daly, and Samuli Ripatti

Subjects
Biology (General), QH301-705.5
Abstract

A genome-wide association study identifies MFGE8 as protective against coronary atherosclerosis in European and East Asian populations.

Published
2022
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6. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good

Author

Kristi Krebs and Lili Milani

Subjects
Pharmacogenetics, Pharmacogenomics, PGx, Implementation of pharmacogenetics, Translation into the clinic, Clinical decision support, Medicine, Genetics, QH426-470
Abstract

Abstract The field of pharmacogenomics (PGx) is gradually shifting from the reactive testing of single genes toward the proactive testing of multiple genes to improve treatment outcomes, reduce adverse events, and decrease the burden of unnecessary costs for healthcare systems. Despite the progress in the field of pharmacogenomics, its implementation into routine care has been slow due to several barriers. However, in recent years, the number of studies on the implementation of PGx has increased, all providing a wealth of knowledge on different solutions for overcoming the obstacles that have been emphasized over the past years. This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.

Published
2019
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7. Harnessing the Power of Electronic Health Records and Genomics for Drug Discovery

Author

Kristi Krebs and Lili Milani

Subjects
Pharmacology, Toxicology
Abstract

A long-standing recognition that information from human genetics studies has the potential to accelerate drug discovery has led to decades of research on how to leverage genetic and phenotypic information for drug discovery. Established simple and advanced statistical methods that allow the simultaneous analysis of genotype and clinical phenotype data by genome- and phenome-wide analyses, colocalization analyses with quantitative trait loci data from transcriptomics and proteomics data sets from different tissues, and Mendelian randomization are essential tools for drug development in the postgenomic era. Numerous studies have demonstrated how genomic data provide opportunities for the identification of new drug targets, the repurposing of drugs, and drug safety analyses. With an increase in the number of biobanks that enable linking in-depth omics data with rich repositories of phenotypic traits via electronic health records, more powerful ways for the evaluation and validation of drug targets will continue to expand across different disciplines of clinical research.

Published
2023

8. Pharmacogenomics in Stroke and Cardiovascular Disease: State of the Art

Author

Stephanie Ross, Kristi Krebs, Guillaume Paré, and Lili Milani

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

There is considerable interindividual variability in the response to antiplatelet and anticoagulant therapies, and this variation may be attributable to genetic variants. There has been an increased understanding of the genetic architecture of stroke and cardiovascular disease, which has been driven by advancements in genomic technologies and this has raised the possibility of more targeted pharmaceutical treatments. Pharmacogenetics promises to use a patient’s genetic profile to treat those who are more likely to benefit from a particular intervention by selecting the best possible therapy. Although there are numerous studies indicating strong evidence for the effect of specific genotypes on the outcomes of vascular drugs, the adoption of pharmacogenetic testing in clinical practice has been slow. This resistance may stem from sometimes conflicting findings among pharmacogenetic studies, a lack of stroke-specific randomized controlled trials to test the effectiveness of genetically-guided therapies, and the practical and cost-effective implementation of genetic testing within the clinic. Thus, this review provides an overview of the genetic variants that influence the individual responses to aspirin, clopidogrel, warfarin and statins and the different methods for pharmacogenetic testing and guidelines for clinical implementation for stroke patients.

Published
2023

9. Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure

Author

Kristi Krebs, Masahiro Kanai, and Tuomo Kiiskinen

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p −8) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.

Published
2023

10. Associations between attention-deficit hyperactivity disorder genetic liability and ICD-10 medical conditions in adults: Utilizing electronic health records in a Phenome-Wide Association Study

Author

Kristi Krebs, Elis Haan, and Isabell Brikell

Abstract

BackgroundAttention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults and little is known about the medical comorbidities in undiagnosed adult individuals with high ADHD liability. In this study we investigated associations between ADHD genetic liability and electronic health record (EHR)-based ICD-10 diagnoses across all diagnostic categories, in individuals without ADHD diagnosis history.MethodsWe used data from the Estonian Biobank cohort (N=111,261) and generated polygenic risk scores (PRS) for ADHD (PRSADHD) based on the latest ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRSADHDand 1,515 EHR-based ICD-10 diagnoses in the full and sex-stratified sample. We compared the observed significant ICD-10 associations to associations with: 1) ADHD diagnosis and 2) questionnaire-based high ADHD risk analyses.ResultsAfter Bonferroni correction (p=3.3×10−5) we identified 80 medical conditions associated with PRSADHD. The strongest evidence was seen with chronic obstructive pulmonary disease (OR=1.15, CI=1.11-1.18), obesity (OR=1.13, CI=1.11-1.15), and type 2 diabetes (OR=1.11, CI=1.09-1.14). Sex-stratified analysis generally showed similar associations in males and females. Out of all identified associations, 40% and 78% were also observed using ADHD diagnosis or questionnaire-based ADHD, respectively, as the predictor.ConclusionsOverall our findings indicate that ADHD genetic liability is associated with an increased risk of a substantial number of medical conditions in undiagnosed individuals. These results highlight the need for timely detection and improved management of ADHD symptoms in adults.

Published
2022

12. Lessons learned during the process of reporting individual genomic results to participants of a population-based biobank

Author

Liis Leitsalu, Anu Reigo, Marili Palover, Tiit Nikopensius, Kristi Läll, Kristi Krebs, Sulev Reisberg, Reedik Mägi, Mart Kals, Helene Alavere, Margit Nõukas, Anneli Kolk, Ivi Normet, Mari-Liis Tammesoo, Ene Käärik, Mairo Puusepp, Kristjan Metsalu, Annely Allik, Lili Milani, Krista Fischer, Neeme Tõnisson, and Andres Metspalu

Subjects
Genetics, Genetics (clinical)
Abstract

The return of individual genomic results (ROR) to research participants is still in its early phase, and insight on how individuals respond to ROR is scarce. Studies contributing to the evidence base for best practices are crucial before these can be established. Here, we describe a ROR procedure conducted at a population-based biobank, followed by surveying the responses of almost 3000 participants to a range of results, and discuss lessons learned from the process, with the aim of facilitating large-scale expansion. Overall, participants perceived the information that they received with counseling as valuable, even when the reporting of high risks initially caused worry. The face-to-face delivery of results limited the number of participants who received results. Although the participants highly valued this type of communication, additional means of communication need to be considered to improve the feasibility of large-scale ROR. The feedback collected sheds light on the value judgements of the participants and on potential responses to the receipt of genetic risk information. Biobanks in other countries are planning or conducting similar projects, and the sharing of lessons learned may provide valuable insight and aid such endeavors.

Published
2022

13. Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy

Author

Kristi Krebs, Jonas Bovijn, Neil Zheng, Maarja Lepamets, Jenny C. Censin, Tuuli Jürgenson, Dage Särg, Erik Abner, Triin Laisk, Yang Luo, Line Skotte, Frank Geller, Bjarke Feenstra, Wei Wang, Adam Auton, Soumya Raychaudhuri, Tõnu Esko, Andres Metspalu, Sven Laur, Dan M. Roden, Wei-Qi Wei, Michael V. Holmes, Cecilia M. Lindgren, Elizabeth J. Phillips, Reedik Mägi, Lili Milani, João Fadista, Michelle Agee, Stella Aslibekyan, Robert K. Bell, Katarzyna Bryc, Sarah K. Clark, Sarah L. Elson, Kipper Fletez-Brant, Pierre Fontanillas, Nicholas A. Furlotte, Pooja M. Gandhi, Karl Heilbron, Barry Hicks, David A. Hinds, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K. Litterman, Marie K. Luff, Jennifer C. McCreight, Matthew H. McIntyre, Kimberly F. McManus, Joanna L. Mountain, Sahar V. Mozaffari, Priyanka Nandakumar, Elizabeth S. Noblin, Carrie A.M. Northover, Jared O’Connell, Aaron A. Petrakovitz, Steven J. Pitts, G. David Poznik, J. Fah Sathirapongsasuti, Anjali J. Shastri, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Robert J. Tunney, Vladimir Vacic, Xin Wang, Amir S. Zare, Institute for Molecular Medicine Finland, and University of Helsinki

Subjects
0301 basic medicine, Genome-wide association study, Human leukocyte antigen, HYPERSENSITIVITY REACTIONS, FREQUENCY, BIOBANK, MECHANISMS, PTPN22, 03 medical and health sciences, 0302 clinical medicine, MANAGEMENT, Genetics, medicine, SNP, Allele, METAANALYSIS, Genetics (clinical), business.industry, 1184 Genetics, developmental biology, physiology, ADVERSE DRUG-REACTIONS, POLYMORPHISM, HLA-B, 3. Good health, HLA, Penicillin, 030104 developmental biology, 030220 oncology & carcinogenesis, Pharmacogenomics, Immunology, T-CELLS, business, medicine.drug
Abstract

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

Published
2020

14. Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Author

Natalia Trpchevska, Maxim B. Freidin, Linda Broer, Berthe C. Oosterloo, Shuyang Yao, Yitian Zhou, Barbara Vona, Charles Bishop, Argyro Bizaki-Vallaskangas, Barbara Canlon, Fabio Castellana, Daniel I. Chasman, Stacey Cherny, Kaare Christensen, Maria Pina Concas, Adolfo Correa, Ran Elkon, Jonas Mengel-From, Yan Gao, Anne B.S. Giersch, Giorgia Girotto, Alexander Gudjonsson, Vilmundur Gudnason, Nancy L. Heard-Costa, Ronna Hertzano, Jacob v.B. Hjelmborg, Jens Hjerling-Leffler, Howard J. Hoffman, Jaakko Kaprio, Johannes Kettunen, Kristi Krebs, Anna K. Kähler, Francois Lallemend, Lenore J. Launer, I-Min Lee, Hampton Leonard, Chuan-Ming Li, Hubert Lowenheim, Patrik K.E. Magnusson, Joyce van Meurs, Lili Milani, Cynthia C. Morton, Antti Mäkitie, Mike A. Nalls, Giuseppe Giovanni Nardone, Marianne Nygaard, Teemu Palviainen, Sheila Pratt, Nicola Quaranta, Joel Rämö, Elmo Saarentaus, Rodolfo Sardone, Claudia L. Satizabal, John M. Schweinfurth, Sudha Seshadri, Eric Shiroma, Eldad Shulman, Eleanor Simonsick, Christopher Spankovich, Anke Tropitzsch, Volker M. Lauschke, Patrick F. Sullivan, Andre Goedegebure, Christopher R. Cederroth, Frances M.K. Williams, Andries Paul Nagtegaal, Andres Metspalu, Mari Nelis, Reedik Mägi, Tõnu Esko, Tampere University, Clinical Medicine, Department of Otology and Oral Diseases, Institute for Molecular Medicine Finland, HUS Head and Neck Center, Clinicum, Korva-, nenä- ja kurkkutautien klinikka, Genetic Epidemiology, Genomics of Neurological and Neuropsychiatric Disorders, Complex Disease Genetics, Trpchevska, Natalia, Freidin, Maxim B, Broer, Linda, Oosterloo, Berthe C, Yao, Shuyang, Zhou, Yitian, Vona, Barbara, Bishop, Charle, Bizaki-Vallaskangas, Argyro, Canlon, Barbara, Castellana, Fabio, Chasman, Daniel I, Cherny, Stacey, Christensen, Kaare, Concas, Maria Pina, Correa, Adolfo, Elkon, Ran, Mengel-From, Jona, Gao, Yan, Giersch, Anne B S, Girotto, Giorgia, Gudjonsson, Alexander, Gudnason, Vilmundur, Heard-Costa, Nancy L, Hertzano, Ronna, Hjelmborg, Jacob V B, Hjerling-Leffler, Jen, Hoffman, Howard J, Kaprio, Jaakko, Kettunen, Johanne, Krebs, Kristi, Kähler, Anna K, Lallemend, Francoi, Launer, Lenore J, Lee, I-Min, Leonard, Hampton, Li, Chuan-Ming, Lowenheim, Hubert, Magnusson, Patrik K E, van Meurs, Joyce, Milani, Lili, Morton, Cynthia C, Mäkitie, Antti, Nalls, Mike A, Nardone, Giuseppe Giovanni, Nygaard, Marianne, Palviainen, Teemu, Pratt, Sheila, Quaranta, Nicola, Rämö, Joel, Saarentaus, Elmo, Sardone, Rodolfo, Satizabal, Claudia L, Schweinfurth, John M, Seshadri, Sudha, Shiroma, Eric, Shulman, Eldad, Simonsick, Eleanor, Spankovich, Christopher, Tropitzsch, Anke, Lauschke, Volker M, Sullivan, Patrick F, Goedegebure, Andre, Cederroth, Christopher R, Williams, Frances M K, Nagtegaal, Andries Paul, Internal Medicine, and Otorhinolaryngology and Head and Neck Surgery

Subjects
basal cells, hair cells, cochlea, spindle cell, ARHL, GWAS, genetics, hearing loss, root cells, spindle cells, stria vascularis, Animals, Cochlea, Genome-Wide Association Study, Humans, Mice, Stria Vascularis, Deafness, Hearing Loss, basal cell, hair cell, Hair-cells, Heritability, otorhinolaryngologic diseases, Genetics, Pathogenicity, Gwas data, Deafne, Ld score regression, Ganglion neurons, Genetics (clinical), Animal, 1184 Genetics, developmental biology, physiology, hearing lo, Stria Vasculari, Inner, 3142 Public health care science, environmental and occupational health, root cell, Differentiation, Degeneration, 3111 Biomedicine, genetic, Noise, Human
Abstract

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss. publishedVersion

Published
2022

15. 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. 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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

16. Response to comment on 'Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics'

Author

Kristi Krebs, Jenny C Censin, Sara L. Pulit, Ruth Boxall, Iona Y Millwood, Teresa Ferreira, Chia-Yen Chen, Robin G. Walters, Reedik Mägi, Benjamin M. Neale, Kuang Lin, Liming Li, Jonas Bovijn, Lili Milani, Samantha Laber, Craig A. Glastonbury, George Davey Smith, Cecilia M. Lindgren, Zhengming Chen, and Michael V. Holmes

Subjects
Cardiovascular safety, business.industry, MEDLINE, Human Genetics, General Medicine, Bioinformatics, Human genetics, Clinical trial, chemistry.chemical_compound, chemistry, Cardiovascular Diseases, Meta-analysis, Medicine, Sclerostin, Humans, business
Abstract

Triangulation of evidence from clinical trials and human genetics suggests a potential excess risk of cardiovascular disease events arising from therapeutic inhibition of sclerostin.

Published
2021

17. Genome-wide association study identifies new locus associated with OCD

Author

Danielle Posthuma, Bernie Devlin, Edna Grünblatt, Ying Wang, Daniele Cusi, Stephan Ruhrmann, Steven A. Rasmussen, Michael S. Breen, Julia Klawohn, Ana Gabriela Hounie, Aline S. Sampaio, Cristina Barlassina, Marta Ribasés, Jackson G. Thorp, Cynthia M. Bulik, Marco A. Grados, Dan J. Stein, Abby Fyer, Vladimir Coric, Martha J. Falkenstein, Stephanie Le Hellard, Behrang Mahjani, Nathaniel McGregor, Homero Vallada, Miguel Casas, Laurent F. Thomas, Janice Krasnow, Abraham Reichenberg, Donald W. Black, Gwyneth Zai, Norbert Kathmann, Manuel Mattheisen, Nicholas G. Martin, Jason W. Krompinger, Josep Antoni Ramos-Quiroga, Judith Becker Nissen, Helga Ask, Damiaan Denys, Carolina Cappi, Euripedes Constantino Miguel, O. Joseph Bienvenu, Bengt T. Fundin, Lisa Osiecki, Karin J. H. Verweij, Paul Sandor, Jeremy Veenstra-VanderWeele, Maureen Mulhern, Sarah E. Medland, David M. Hougaard, Lauren Erdman, Jan Haavik, James L. Kennedy, Christopher P. Walker, Jurjen J. Luykx, Tim B. Bigdeli, Ian M. Hickie, Nienke Vulink, Maurizio Turiel, Peter Falkai, Enda M. Byrne, Valentina Ciullo, Daniel A. Geller, Liang Kung-Yee, Miriam A. Schiele, Lambertus Klei, Götz Berberich, Thomas Werge, Brion S. Maher, Christie L. Burton, Julia M. Sealock, Sandra Meier, Bernadette Cullen, Stephan Ripke, Dorothy E. Grice, Richard Delorme, Ted Reichborn-Kjennerud, Dongmei Yu, Danielle C. Cath, Lili Milani, Abdel Abdellaoui, Andres Metspalu, María Soler Artigas, Maria Conceição do Rosário, Ole Mors, Brian P. Brennan, Barbara E. Stranger, Ann E. Pulver, Nora I. Strom, Joseph D. Buxbaum, Hans J. Grabe, Jens R. Wendland, Michael H. Bloch, Srdjan Djurovic, Raquel Rabionet, Angel Carracedo, Carlos N. Pato, Erika L. Nurmi, Janet L. Sobell, Kevin S. O’Connell, Michael Wagner, David R. Rosenberg, Jonathan R. I. Coleman, Jeremiah M. Scharf, Kerry J. Ressler, Jaakko Kaprio, Edwin H. Cook, Scott L. Rauch, Federica Piras, Merete Nordentoft, Christian Rück, Fabrizio Piras, John-Anker Zwart, Jason A. Elias, Christopher Pittenger, Lea K. Davis, Margaret A. Richter, Evonne McArthur, Bendik S. Winsvold, Yin Yao, James J. Crowley, David L. Pauls, Rosa Bosch, Xavier Estivil, Matthew Halvorsen, Adrian Camarena, Nancy L. Pedersen, Pino Alonso, Eric A. Storch, Bjarne Hansen, Helena Brentani, James T. McCracken, Jan Maerten Smit, Donald Hucks, Alexandra Havdahl, Gerome Breen, Christina M. Hultman, Benjamin M. Neale, Gregory L. Hanna, Mikael Landén, Christine Lochner, Dirk J.A. Smit, Fabio Macciardi, Carol A. Mathews, Nuria Lanzagorta, Laura G. Sloofman, Cristina Rodriguez-Fontenla, Michael A. Jenike, Michele T. Pato, Marion Leboyer, Humberto Nicolini, Anders D. Børglum, Maria Cristina Cavallini, Wei Guo, Benjamin D. Greenberg, Maiken Elvestad Gabrielsen, Magdalena Janecka, Mark A. Riddle, Paul S. Nestadt, Beatriz Camarena, Valsamma Eapen, Susanne Walitza, Jack Samuels, Fernando S. Goes, Nicole C.R. McLaughlin, S. Evelyn Stewart, Jennifer Reichert, Sven Sandin, Gerd Kvale, Katharina Domschke, Ole A. Andreassen, Elles de Schipper, Paul D. Arnold, Kristi Krebs, Zachary Gerring, Teemu Palviainen, Kathleen D. Askland, Alfredo Ramirez, James A. Knowles, Laura Bellodi, Kristen Hagen, Julia Boberg, Thomas V. Fernandez, Gerald Nestadt, John Piacentini, Jakob Grove, Eske M. Derks, Preben Bo Mortensen, Elinor K. Karlsson, Gianfranco Spalletta, David Mataix-Cols, Katharina Bey, and Jonas Bybjerg-Grauholm

Subjects
Genetics, business.industry, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Heritability, behavioral disciplines and activities, humanities, Genetic architecture, Anorexia nervosa (differential diagnoses), mental disorders, medicine, Anxiety, SNP, medicine.symptom, business
Abstract

Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.

Published
2021

20. Genetic and Functional Characterization of ANGPTL7 as a Therapeutic Target for Glaucoma

Author

Scott Waldron, Alexander H. Li, Joan O'Brien, Katia Karalis, Stefanie Lefebvre, Gaurang Patel, Silvio Alessandro Di Gioia, Kristi Krebs, Hua Yang, Dadong Li, Ariane Ayer, Wen Fury, Ying Hu, Eric Jorgenson, James McIninch, Olle Melander, Giusy Della Gatta, Trikaladarshi Persaud, Ben Michael Brumpton, Claudia Schurmann, Stefan Stender, Eli A. Stahl, Michael N. Cantor, Venkata Gudiseva, Aris Baras, Marcus B. Jones, Dylan Sun, Jonathan Weyne, Manuel A. R. Ferreira, Tavé van Zyl, Lauren Gurski, Rebecca Salowe, Esteban Chen, Sarah Hyde, Gonçalo R. Abecasis, Kavita Praveen, Anne Tybjærg-Hansen, Giovanni Coppola, Matthew Still, Venkata Chavali, Tanya M. Teslovich, Lili Milani, Aris N. Economides, Sabrina Walley, Sarthak Zaveri, Kristian Hveem, Jeremey Rabinowitz, Carmelo Romano, Lawrence Miloscio, Bjørn Olav Åsvold, Brijeshkumar Patel, Cristen J. Willer, Anne-Sofie Seidelin, and George D. Yancopoulos

Subjects
genetic structures, business.industry, medicine, Glaucoma, sense organs, Computational biology, medicine.disease, business, eye diseases
Abstract

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing mAngptl7 levels via injection into mouse eyes increases the IOP. We also show that acute gene silencing via siRNA knockdown of Angptl7 in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

Published
2021

21. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good

Author

Lili Milani and Kristi Krebs

Subjects
lcsh:QH426-470, Computer science, Clinical Decision-Making, Treatment outcome, lcsh:Medicine, Review, Clinical decision support system, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, Genetics, Humans, Implementation of pharmacogenetics, Precision Medicine, PGx, Molecular Biology, Routine care, 030304 developmental biology, Translation into the clinic, 0303 health sciences, lcsh:R, Clinical decision support, Adversary, Decision Support Systems, Clinical, 3. Good health, lcsh:Genetics, Treatment Outcome, Risk analysis (engineering), Pharmacogenetics, 030220 oncology & carcinogenesis, Pharmacogenomics, Molecular Medicine, Delivery of Health Care, Healthcare system
Abstract

The field of pharmacogenomics (PGx) is gradually shifting from the reactive testing of single genes toward the proactive testing of multiple genes to improve treatment outcomes, reduce adverse events, and decrease the burden of unnecessary costs for healthcare systems. Despite the progress in the field of pharmacogenomics, its implementation into routine care has been slow due to several barriers. However, in recent years, the number of studies on the implementation of PGx has increased, all providing a wealth of knowledge on different solutions for overcoming the obstacles that have been emphasized over the past years. This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.

Published
2019

22. TU34. ASSOCIATION BETWEEN DEPRESSION DIAGNOSIS, POLYGENIC RISK FOR DEPRESSION AND ANTIHYPERTENSIVE MEDICATION NON-PERSISTENCE

Author

Urmo Võsa, Jana Lass, Kristi Krebs, Kelli Lehto, Hanna Kariis, Tuuli Jürgenson, Aet Saar, Lili Milani, and Silva Kasela

Subjects
Pharmacology, Persistence (psychology), medicine.medical_specialty, business.industry, Psychiatry and Mental health, Neurology, Internal medicine, Medicine, Pharmacology (medical), Polygenic risk score, Neurology (clinical), Association (psychology), business, Biological Psychiatry, Depression (differential diagnoses), Antihypertensive medication
Published
2021

23. TU5. PHENOME-WIDE ASSOCIATION STUDY BETWEEN ADHD POLYGENIC RISK AND ELECTRONIC HEALTH RECORD ICD-10 DIAGNOSIS CODES IN THE ESTONIAN BIOBANK

Author

Kelli Lehto, Elis Haan, Kristi Krebs, and Urmo Võsa

Subjects
Pharmacology, medicine.medical_specialty, business.industry, ICD-10, Phenome, Biobank, Estonian, language.human_language, Psychiatry and Mental health, Neurology, Electronic health record, Family medicine, medicine, language, Pharmacology (medical), Polygenic risk score, Neurology (clinical), Diagnosis code, Association (psychology), business, Biological Psychiatry
Published
2021

24. Lifelong genetically lowered sclerostin and risk of cardiovascular disease

Author

Michael V. Holmes, Samantha Laber, Benjamin M. Neale, Jenny C Censin, Z Chen, Kuang Lin, Robin G. Walters, Kristi Krebs, Reedik Mägi, Jonas Bovijn, Iona Y. Millwood, Ruth Boxall, Cecilia M. Lindgren, Liheng Li, Lili Milani, Sara L. Pulit, Teresa Ferreira, Craig A. Glastonbury, and Chiao-Lin Chen

Subjects
0303 health sciences, business.industry, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Appendix, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Medicine, Sclerostin, business, 030304 developmental biology
Abstract

BackgroundInhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events.MethodsWe used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab.ResultsMeta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2·98; 95% confidence interval [CI], 1·18 to 7·55; P=0·017). Scaled to the equivalent dose of romosozumab (210mg/month; 0·09 g/cm2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0·59; 95% CI, 0·54-0·66; P= 1·4×10−24), and osteoporosis (OR, 0·43; 95% CI, 0·36-0·52; P=2·4×10−18). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1·18; 95% CI, 1·06-1·32; P=0·003) and type 2 diabetes (OR 1·15; 95% CI, 1·05-1·27; P=0·003), higher systolic blood pressure (1·3mmHg; 95% CI 0·8-1·9; P=5·9×10−6) and waist-to-hip-ratio adjusted for BMI (0·05 SDs; 95% CI, 0·02 to 0·08; P=8·5×10−4).ConclusionsGenetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.

Published
2021

25. 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

26. Rare genetic variability in human drug target genes modulates drug response and can guide precision medicine

Author

Barbora Svobodova, Jan Korabecny, Gunnar Schulte, Volker M. Lauschke, Tuuli Jürgenson, Kristi Krebs, Yitian Zhou, Souren Mkrtchian, Yi Wang, Ainoleena Turku, Stefano Gastaldello, Lili Milani, and Gabriel Herras Arribas

Subjects
Multidisciplinary, Pharmacotherapy, Drug disposition, business.industry, Drug target, Drug response, Medicine, Genetic variability, business, Precision medicine, Bioinformatics, Gene
Abstract

Interindividual variability in drug response constitutes a major concern in pharmacotherapy. While polymorphisms in genes involved in drug disposition have been extensively studied, drug target variability remains underappreciated. By mapping the genomic variability of all human drug target genes onto high-resolution crystal structures of drug target complexes, we identified 1094 variants localized within 6 Å of drug-binding pockets and directly affecting their geometry, topology, or physicochemical properties. We experimentally show that binding site variants affect pharmacodynamics with marked drug- and variant-specific differences. In addition, we demonstrate that a common

Published
2021
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27. Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure

Author

Antti Mäkitie, Tuomo Kiiskinen, Juha Karjalainen, Samuli Ripatti, A. Metspalu, Tõnu Esko, Lili Milani, Kurki M, Joel T. Rämö, Masahiro Kanai, Eija Hämäläinen, Reedik Mägi, Paavo Häppölä, Hautakangas H, Matti Pirinen, Kristi Krebs, Mark J. Daly, Aki S. Havulinna, Priit Palta, A. Palotie, and Konrad J. Karczewski

Subjects
Genetics, 0303 health sciences, education.field_of_study, Population, Genome-wide association study, Locus (genetics), Biology, Heritability, medicine.disease, Biobank, Genome, 03 medical and health sciences, 0302 clinical medicine, medicine, Otosclerosis, Family history, 030223 otorhinolaryngology, education, 030304 developmental biology
Abstract

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood and treatment options are limited. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 2,413 cases and 762,382 controls. We identify 15 novel risk loci (p < 5*10−8) and replicate the regions of RELN and two previously reported candidate genes (TGFB1 and MEPE). Implicated genes in many loci are essential for bone remodelling or mineralization. Otosclerosis is genetically correlated with height and fracture risk, and the association loci overlap with severe skeletal disorders. Our results highlight TGFβ1 signalling for follow-up mechanistic studies.

Published
2020

28. Genome-wide association study of over 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, HUNT All-In Psychiatry, 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
Genetics, 0303 health sciences, Druggability, Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, medicine, Bipolar disorder, Synaptic signaling, Prefrontal cortex, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD 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 eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2020

29. 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

30. Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics

Author

Zhengming Chen, Lili Milani, Kristi Krebs, Michael V. Holmes, Jenny C Censin, George Davey Smith, Chia-Yen Chen, Craig A. Glastonbury, Iona Y Millwood, Teresa Ferreira, Robin G. Walters, Reedik Mägi, Jonas Bovijn, Ruth Boxall, Cecilia M. Lindgren, Benjamin M. Neale, Sara L. Pulit, Liming Li, Samantha Laber, and Kuang Lin

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Bone density, Osteoporosis, Romosozumab, 030204 cardiovascular system & hematology, Lower risk, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, business.industry, General Medicine, medicine.disease, Clinical trial, 030104 developmental biology, chemistry, Meta-analysis, Sclerostin, business
Abstract

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase III randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab [210 mg/month; 0.09 g/cm2 higher bone mineral density (BMD)], the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab), and with a higher risk of myocardial infarction (MI) and/or coronary revascularization and major adverse cardiovascular events (MACE). The same variants were also associated with increased risk of type 2 diabetes mellitus (T2D) and higher systolic blood pressure (SBP) and central adiposity. Taken together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

Published
2020

31. Global Frequencies of Clinically Important HLA Alleles and Their Implications For the Cost‐Effectiveness of Preemptive Pharmacogenetic Testing

Author

Lili Milani, Yitian Zhou, Volker M. Lauschke, and Kristi Krebs

Subjects
medicine.medical_specialty, Asia, Genotype, Cost effectiveness, Allopurinol, Cost-Benefit Analysis, Human leukocyte antigen, 030226 pharmacology & pharmacy, Drug Hypersensitivity, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Abacavir, medicine, Humans, Pharmacology (medical), Genetic Testing, Intensive care medicine, Genotyping, Alleles, Genetic testing, Pharmacology, medicine.diagnostic_test, business.industry, Cost-effectiveness analysis, medicine.disease, Dideoxynucleosides, Pharmacogenomic Testing, 3. Good health, Europe, Carbamazepine, Pharmacogenetics, 030220 oncology & carcinogenesis, business, Adverse drug reaction, medicine.drug
Abstract

Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01, HLA-B*15:02, HLA-A*31:01, and HLA-B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing of HLA-B*57:01 in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA-B*15:02 is only cost-effective across most of East and South Asia, whereas HLA-A*31:01 testing is likely to be cost-effective globally. Testing of HLA-B*58:01 is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.

Published
2020
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32. W57. MENTAL HEALTH DATA COLLECTION IN THE ESTONIAN BIOBANK: INSTRUMENTS, METHODOLOGY AND PRELIMINARY RESULTS

Author

Triinu Ojalo, Elis Haan, Kelli Lehto, Helene Alavere, Lili Milani, Kristi Krebs, and Helen Uusberg

Subjects
Pharmacology, medicine.medical_specialty, Computer-assisted web interviewing, medicine.disease, Mental health, Comorbidity, Biobank, Psychiatry and Mental health, Eating disorders, Social support, Neurology, medicine, Anxiety, Pharmacology (medical), Neurology (clinical), medicine.symptom, Psychology, Psychiatry, Biological Psychiatry, Psychiatric genetics
Abstract

Background: Background: Common psychiatric disorders are clinically heterogeneous and often display many overlapping symptoms as well as comorbidity across psychiatric disorders, hence complicating the genetic investigation of these disorders. To facilitate new discoveries and gain better understanding of the genetics of psychiatric problems, large well-phenotyped biobank samples are greatly needed. The Estonian Biobank (EstBB;N=200,000) is a data-rich national biobank that joins genomic, biomarker, electronic health record (EHR), national registry and questionnaire data to significantly advance the current knowledge of the genetic underpinnings of complex and rare diseases. We aimed to expand the EstBB database with rich phenotypic questionnaire-based information on a broad set of symptoms of common psychiatric disorders and related phenotypes. Methods: Methods: We compiled an online questionnaire “Wellbeing and mental health” which included self-report brief screening instruments to capture a broad range of symptoms on current and/or lifetime depression, anxiety disorders, mania, post-traumatic stress disorder, eating disorders, attention deficit/hyperactivity disorder, psychotic experiences, suicidal thoughts and behavior, cognition, substance (ab)use, problematic gambling and related risk- and protective factors, such as childhood adversity, stressful life events, social support, lifestyle, sociodemographic factors and life satisfaction. In addition, the participants were asked about the side effects, discontinuation and switching of medications prescribed for a mental health problem in their lifetime. Since the start of the data collection coincided with the peak of the second COVID-19 wave in Estonia, we included items related to current perceived stress, burnout and change in mental health during the pandemic. When selecting instruments, preference was given based on 1) reliability and validity of the instruments;2) whether an Estonian adaptation and/or validation has been conducted;3) application in other large biobanks (e.g. the UK Biobank) for future harmonization or replication;4) short length. Results: Results: The invitations to participate in the online mental health study were e-mailed out to all living EstBB participants with available e-mail addresses (N=184,622), followed by two e-mail reminders. The active data collection phase spanned over three months from March to May 2021. The preliminary response rate was 46.7% (N = 86,222) out of all who were contacted. We will present preliminary results on the comparison of respondents and non-respondents based on demographic data, psychiatric diagnoses in EHR and psychiatric polygenic risk scores. Discussion: Discussion: We have significantly expanded the EstBB resource with phenotypic information on a broad range of psychiatric symptoms and related phenotypes to facilitate future research in psychiatric genetics. Disclosure: Nothing to disclose.

Published
2021

33. Genetic variation in the Estonian population : pharmacogenomics study of adverse drug effects using electronic health records

Author

Mart Kals, Maido Remm, Tarmo Puurand, Jaak Vilo, Tõnu Esko, Volker M. Lauschke, Lili Milani, Tõnis Tasa, Andres Metspalu, Toomas Haller, Kristi Krebs, and Reedik Mägi

Subjects
Estonia, Candidate gene, medicine.medical_specialty, Pharmacogenomic Variants, Population, Anti-Inflammatory Agents, Mutation, Missense, Computational biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Mutation Rate, Loss of Function Mutation, Genetics, Medicine, Electronic Health Records, Humans, Allele, education, Genetics (clinical), Genetic association, Medicinsk genetik, 0303 health sciences, education.field_of_study, business.industry, 030305 genetics & heredity, 16. Peace & justice, Biobank, 3. Good health, Pharmacogenomics, Medical genetics, business, Medical Genetics, Pharmacogenetics, alpha Catenin
Abstract

Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel loss-of-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.

Published
2019

34. Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations : challenges and solutions

Author

Jaak Vilo, Volker M. Lauschke, Sulev Reisberg, Mart Kals, Lili Milani, Kristjan Metsalu, Kristi Krebs, Reedik Mägi, and Maarja Lepamets

Subjects
Estonia, 0301 basic medicine, medicine.medical_specialty, Databases, Factual, Genotype, Pharmacogenomic Variants, Computational biology, preemptive pharmacogenetic testing, 030105 genetics & heredity, Article, DNA sequencing, genotyping array, 03 medical and health sciences, Electronic Health Records, Humans, Medicine, Genetic Testing, Precision Medicine, Genotyping, Genetics (clinical), Exome sequencing, biobank participants, Biological Specimen Banks, Oligonucleotide Array Sequence Analysis, pharmacogenetics, Medicinsk genetik, pharmacogenomics, business.industry, Sequence Analysis, DNA, Biobank, Pharmacogenomic Testing, Phenotype, 030104 developmental biology, Pharmacogenetics, Pharmacogenomics, Medical genetics, business, Medical Genetics, Algorithms
Abstract

Purpose: Biomedical databases combining electronic medical records and phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype-phenotype associations. Methods: We developed and tested algorithms for translation of preexisting genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. Results: Our most striking result was that the performance of genotyping arrays is similar to that of genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants. Conclusion: We find that microarrays are a cost-effective solution for creating preemptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.

Published
2019

35. Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions

Author

Mart Kals, Volker M. Lauschke, Reedik Mägi, Sulev Reisberg, Jaak Vilo, Kristi Krebs, Lili Milani, and Kristjan Metsalu

Subjects
Whole genome sequencing, 0303 health sciences, business.industry, Medical record, Computational biology, 16. Peace & justice, 030226 pharmacology & pharmacy, Biobank, 03 medical and health sciences, 0302 clinical medicine, Genotype, Medicine, Medical prescription, business, Genotyping, Exome sequencing, Pharmacogenetics, 030304 developmental biology
Abstract

PurposeBiomedical databases combining electronic medical records, phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype-phenotype associations.MethodsWe developed and tested algorithms for translation of pre-existing genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by whole genome sequencing, whole exome sequencing and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia.ResultsOur most striking result was that the performance of genotyping arrays is similar to that of whole genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants.ConclusionWe find that microarrays are a cost-effective solution for creating pre-emptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.

Published
2018

36. Expression of FLNa in human melanoma cells regulates the function of integrin α1β1 and phosphorylation and localisation of PKB/AKT/ERK1/2 kinases

Author

Grethel Simonlatser, Teet Velling, Kristi Krebs, and Anu Ruusmann

Subjects
Histology, Filamins, Integrin, Pathology and Forensic Medicine, Collagen receptor, Integrin alpha1beta1, Cell Movement, Cell Line, Tumor, Cell Adhesion, FLNA, Humans, Phosphorylation, Cell adhesion, Extracellular Signal-Regulated MAP Kinases, Protein kinase B, Melanoma, biology, Epidermal Growth Factor, Kinase, Cell Biology, General Medicine, Cell biology, Fibronectin, Protein Transport, biology.protein, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt
Abstract

FLNa is a ubiquitous cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and functions as a signalling intermediate. We investigated FLNa's role in the function of integrin-type collagen receptors, EGF-EGFR signalling and regulation of PKB/Akt and ERK1/2. Using FLNa-deficient M2 human melanoma cells, and same cells expressing EGFP-FLNa (M2F) or its Ig-like repeats 1-8+24, 8-15+24 and 16-24, we found that in M2F and M2 8-15+24 cells, EGF induced the increased phosphorylation of PKB/Akt and ERK1/2. In M2F cells EGF induced the localisation of these kinases to cell nucleus and lamellipodia, respectively, and the ERK1/2 phosphorylation-dependent co-immunoprecipitation of FLNa with ERK1/2. Only M2F and M2 8-15+24 cells adhered to and spread on type I collagen whereas on fibronectin all cells behaved similarly. α1β1 and α2β1 were the integrin-type collagen receptors expressed on these cells with primarily α1β1 localising to focal contacts and affecting cell adhesion and migration in a manner dependent on FLNa or its Ig-like repeats 8-15. Our results suggest a role for FLNa repeats 8-15 in the α1-subunit-dependent regulation of integrin α1β1 function, EGF-EGFR signalling to PKB/Akt and ERK1/2, identify ERK1/2 in EGF-induced FLNa-associated protein complexes, and show that the function of different integrins is subjected to differential regulation by FLNa.

Published
2015

37. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Stéphanie Debette, Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Masaru Koido, Quentin Le Grand, Frederick Kamanu, Mingyang Shi, Yunye He, Marios Georgakis, Ilana Caro, Kristi Krebs, Felix Vaura, Naomi Habib, Bendik Winsvold, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Kuang Lin, Marianne Nygaard, Ganesh Chauhan, Hampton Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria Knol, Tetsuro Ago, Philippe Amouyel, Christopher Anderson, Nicole Armstrong, Mark Bakker, Traci Bartz, Joshua Bis, Constance Bordes, Sigrid Borte, Anael Cain, Paul Ridker, Zhengming Chen, Michael Chong, John Cole, Rafael de Cid, Matthias Endres, Leslie Ferreira, Natalie Gasca, Vilmundur Gudnason, Jun Hata, Aki Havulinna, Jemma Hopewell, Hyacinth Hyacinth, Michael Inouye, Mina Jacob, Christina Jeon, Christina Jern, Masahiro Kamouchi, Keith Keene, Takanari Kitazono, Steven Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore Launer, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh Markus, Nicholas Marston, Thomas Meitinger, Braxton Mitchell, Felipe Montellano, Takayuki Morisaki, Thomas Mosley, Mike Nalls, Børge Nordestgaard, Martin O'Donnell, Yukinori Okada, Guillaume Pare, Annette Peters, Bruce Psaty, Stephen Rich, Jonathan Rosand, Marc Sabatine, Ralph Sacco, Danish Saleheen, Else Charlotte Sandset, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia Satizabal, Carsten Schmidt, Atsushi Shimizu, Nicholas Smith, Daniel Strbian, Yoichi Sutoh, Kozo Tanno, Steffen Tiedt, Nuria Torres-Aguila, David-Alexandre Trégouët, Stella Trompet, Anil Tuladhar, Anne Tybjærg-Hansen, Marion van Vugt, Riina Vibo, Kerri Wiggins, Daniel Woo, Huichun Xu, Qiong Yang, Mark Lathrop, Iona Millwood, Christian Gieger, Toshiharu Ninomiya, Hans Grabe, J Wouter Jukema, Ina Rissanen, Sudha Seshadri, William Longstreth, Daniel Chasman, Joanna Howson, Marguerite Irvin, Hieab Adams, Sylvia Wasssertheil-Smoller, Kaare Christensen, M. Arfan Ikram, Tatjana Rundek, Jerome Rotter, Moeen Riaz, Eleanor Simonsick, Janika Kõrv, Paulo França, Myriam Fornage, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank-Erik de Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte Ruigrok, Peter Heuschmann, Keum Jung, John-Anker Zwart, Teemu Niiranen, Christian Ruff, Israel Fernández-Cadenas, Robin Walters, Lili Milani, Yoichiro Kamatani, and Martin Dichgans

Abstract

Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control individuals of five ancestries from population- and clinic-based studies, nearly doubling the number of cases in previous stroke GWAS. We identified association signals at 89 independent loci, of which 61 were novel. Effect sizes were overall highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis using a novel machine-learning approach,3 transcriptome and proteome-wide association analyses revealed putative causal genes (e.g. SH3PXD2A and FURIN) and variants (e.g. at GRK5 and NOS3). Using a novel three-pronged approach,4 we provided genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWAS with vascular risk factor GWAS (iPGS) showed strong prediction of ischemic stroke risk in European and, for the first time, East-Asian populations.5,6 The iPGS performed better than stroke PGS alone and better than previous best iPGS, in Europeans and East-Asians. Transferability of European-specific iPGS to East-Asians was limited. Stroke genetic risk scores were predictive of ischemic stroke independent of clinical risk factors in 52,600 clinical trial participants with cardiometabolic disease and performed considerably better than previous scores, both in Europeans and East-Asians. Altogether our results provide critical insight to inform biology, reveal potential drug targets for intervention, and provide genetic risk prediction tools across ancestries for targeted prevention.

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38. Ennetava farmakogeneetilise testimise vajalikkus ning potentsiaal Eesti tervishoiusüsteemis

Author

Ranne, Pauliine, MSc, Kristi Krebs, juhendaja, Ph.D, Lili Milani, juhendaja, Tartu Ülikool. Loodus- ja täppisteaduste valdkond, and Tartu Ülikool. Molekulaar- ja rakubioloogia instituut

Subjects
CPIC, ADR, bakalaureusetööd, meditsiin, farmakogeneetika
Abstract

Bakalaureusetöö annab ülevaate farmakogeneetikaalastest avastustest ning nende rakendamise võimalustest meditsiinis. Lisaks uuritakse töös Eesti Geenivaramu andmete põhjal, milliseid varasemalt tõestatud geneetilise seosega ravimeid Eestis väljakirjutatakse ning kui paljudel biopanga doonoritel on geenivariandid, mis mõjutavad nende ravimite normaalset omastamist. Selle põhjal näitab töö ennetava farmakogeneetilise testimise kasutuselevõtu võimalikku kasulikkust ravimite väljakirjutamisel ka Eesti tervishoiusüsteemis.

Published
2017

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