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El. knyga: Psychiatric Genomics

Edited by , Edited by (Professor and Killam Chair in Mood Disorders, Department of Psychiatry, Dalhousie Un), Edited by (Laboratory of Pharmacogenetics, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia)
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Psychiatric Genomics presents and synthesizes available knowledge in the field of psychiatric genomics, offering methodologies to advance new research and aid clinical translation. After providing an introduction to genomics and psychiatry, international experts discuss the genomic basis of schizophrenia, bipolar disorder, depression, personality disorders, anxiety disorders, addictions, eating disorders, and sleep disorders, among other disorders. In addition, recommendations for next steps in clinical implementation and drug discovery are discussed in-depth, with chapters dedicated to pharmacogenomics and antipsychotics, antidepressants and mood stabilizers, adverse drug reactions, implementation of pharmacogenomics in psychiatric clinics, and ethical issues.

Finally, methods sections provide a solid grounding in research approaches and computational analytics, from using animal models in psychiatric genomics and accessing biobanks, to employing computational analysis, genome-wide association studies (GWAS), brain pathophysiology, and endophenotypes in psychiatric research.

  • Thoroughly examines the genetic mechanisms underlying a broad range of psychiatric disorders
  • Offers genomic methodologies and analytical approaches supporting new research and clinical translation, including personalized diagnosis and treatment models
  • Features chapter contributions from international leaders in the field
List of contributors
xv
About the editors xxi
Preface xxv
Chapter 1 Genomics and psychiatry: a historical overview
1(16)
Alessandra G. Ferrera
John I. Nurnberger
Introduction
1(1)
The Middle Ages
2(1)
The 18th century
3(1)
Era of enlightenment
3(1)
The 19th century
4(1)
The 20th century
5(1)
Twin studies
6(1)
Adoption studies
7(1)
Modem family studies
8(1)
DNA sequencing
8(1)
21st century
9(1)
Human genome project
9(1)
Genome-wide association studies
9(1)
Consortia
10(1)
Lessons learned from history
11(2)
References
13(4)
Chapter 2 Schizophrenia genomics
17(26)
Niamh M. Ryan
Cathal Ormond
Philip Brady
Elizabeth A. Heron
Aiden Corvin
Introduction
17(1)
Schizophrenia heritability
18(1)
Molecular genetics before genomics
18(1)
Defining the phenotype
19(1)
Genome-wide association studies
19(2)
Rare structural risk variants
21(2)
Genome sequencing studies
23(2)
Lessons learned from schizophrenia genomics
25(1)
Genetic architecture
25(1)
Diagnostics
26(1)
Localizing risk genes
27(1)
Molecular mechanisms and pathways
28(1)
Drug discovery
29(1)
Personalized treatment
30(1)
Conclusion
31(1)
References
32(11)
Chapter 3 Genetics of bipolar disorder
43(20)
Kevin S. O'Connell
Olav B. Smeland
Ole A. Andreassen
Introduction
43(1)
Family and adoption studies
43(1)
Twin studies
44(1)
Molecular genetics
44(1)
Linkage and candidate gene studies
45(1)
Genome-wide association studies
45(1)
GWAS in BD
45(1)
Genetic architecture of BD
46(1)
Recent GWAS of BD
46(2)
Genetic overlap between BD and other traits and disorders
48(2)
Polygenic analytical approaches
50(2)
From genetic loci to disease mechanisms
52(1)
Rare genetic variants in BD
53(1)
Potential clinical implications of BD genetics
53(1)
Conclusion
54(1)
Acknowledgments
55(1)
Competing financial interests
55(1)
References
55(8)
Chapter 4 Genetics of depression
63(4)
Marin M. Jukic
Genetic factors affecting the onset of depression
63(2)
Conclusions
65(1)
References
66(1)
Chapter 5 Genetics of personality disorders
67(18)
Nicolas Ramoz
Introduction
67(1)
International classification of personality disorders
67(2)
Heritability of personality disorders
69(2)
First evidence of genetic predisposition in personality disorders
71(1)
Candidate gene studies
71(2)
Meta-analysis of candidate gene studies in personality disorders
73(1)
Interaction between gene and environmental factors in personality disorders
74(1)
Comorbid disorders and traits, environment, and genetic factors in personality disorders
75(1)
Genome-wide associations studies in personality disorders
76(1)
Neuroticism and personality phenotypes
76(3)
Temperamental behaviors
79(1)
Antisocial phenotype
80(1)
GWAS in borderline personality disorder
80(1)
Conclusions
81(1)
References
82(3)
Chapter 6 Genomics and epigenomics of anxiety and obsessive-compulsive disorders
85(20)
Angelika Erhardt
Manuel Mattheisen
Jurgen Deckert
Clinical genetics, molecular genetics, gene-environment interactions and epigenetics of anxiety disorders
85(1)
Epidemiology and clinical genetics
85(1)
Molecular genetics
86(3)
Gene--environment interactions and epigenetics
89(3)
Epidemiology, clinical genetics, molecular genetics, gene-environment interactions and epigenetics of obsessive-compulsive disorders
92(1)
Molecular genetics
92(1)
Gene--environment interactions and epigenetics
92(1)
Therapy (epi)genetics of anxiety and OCDs
93(1)
Conclusion
94(1)
References
95(10)
Chapter 7 Neurogenetics of alcohol use disorder a subset of reward deficiency syndrome: candidate genes to be or not to be?
105(56)
Kenneth Blum
Jean Lud Cadet
Panayotis K. Thanos
David Baron
Asmita Mishrekar
Raymond Brewer
Abdalla Bowirrat
Marcelo Febo
Mark S. Gold
Introduction--a historical overview
105(1)
The genetics of alcoholism
106(1)
Finding the first alcohol gene
107(2)
Understanding polygenic inheritance of alcoholism and links to opioids
109(1)
GARS case--controls and targeted endophenotypes for alcohol abuse and alcoholism
110(34)
Importance of genome wide association studies: convergence to candidates
144(1)
Conclusion
144(2)
Acknowledgments
146(1)
Author contribution
146(1)
Funding
146(1)
Conflict of interest
147(1)
References
147(14)
Chapter 8 Pharmacogenomics and antipsychotics: efficacy and adverse drug reactions
161(28)
Evangelia Eirini Tsermpini
Tea Terzi
Blanka Kores Plesnicar
Vita Dolzan
Introduction
161(1)
Pharmacogenetics of antipsychotics metabolizing enzymes and drug targets
162(1)
Pharmacogenes involved in antipsychotic metabolism and transport
163(3)
Pharmacogenomics of antipsychotic efficacy
166(1)
Candidate gene studies of treatment response
166(1)
Genomic studies of antipsychotic efficacy
167(2)
Epigenetics of treatment response
169(1)
Pharmacogenetics of antipsychotic-induced adverse drug reactions
170(1)
Tardive dyskinesia
171(1)
Clozapine-induced agranulocytosis and neutropenia
172(1)
Antipsychotic-induced weight gain
173(1)
Pharmacogenetic-based treatment guidelines for antipsychotics
174(2)
Pharmacogenomic testing
176(1)
Clinical implementation studies
177(1)
Conclusions
178(1)
References
179(10)
Chapter 9 Pharmacogenomics and antidepressants: efficacy and adverse drug reactions
189(14)
Joseph F. Goldberg
Charles B. Nemeroff
Financial disclosures (last 3 years)
189(1)
Cautionary statements
190(1)
Safety versus efficacy, and pharmacokinetics versus pharmacodynamics
190(5)
Pharmacokinetic pharmacogenomics and efficacy
195(1)
Pharmacodynamic pharmacogenomics and efficacy
196(1)
Antidepressant efficacy trials using combinatorial pharmacogenomic panels
197(2)
Clinical implications and future directions
199(1)
Conclusions
199(1)
References
200(3)
Chapter 10 Pharmacogenomics and mood stabilizers: efficacy and adverse drug reactions
203(20)
Claudia Pisanu
Alessio Squassina
Introduction
203(1)
Pharmacogenomics of lithium
204(1)
Lithium response: candidate-gene studies
204(6)
Lithium response: from candidate gene to genome-wide association studies
210(4)
Lithium-induced adverse drug reactions
214(1)
Pharmacogenomics of other mood stabilizers
214(1)
Response to other mood stabilizers
214(1)
Adverse drug reactions induced by other mood stabilizers
215(1)
Discussion
215(1)
References
216(7)
Chapter 11 Balancing prevention and respect: the ethical stakes of a psychiatric genomics lens for mental disorder and intellectual disability
223(18)
Camillia Kong
Introduction
223(3)
Conceptual framing and ethical orientation: points of divergence
226(3)
Challenging projections of suffering
229(5)
Responding to the ethical stakes
234(2)
Conclusion
236(1)
Acknowledgment
237(1)
References
237(4)
Chapter 12 Genetic animal models for psychiatric disorders
241(28)
Young Zhou
James N. Samsom
Albert H.C. Wong
Genetic evidence, epidemiology, and genetic animal models
241(1)
Identifying candidate genes for modeling
241(1)
Modeling candidate genes in animal systems
242(1)
Schizophrenia
243(1)
Disrupted-in-schizophrenia 1 (DISCI)
243(2)
Neuregulin-1 (NRG1) and receptor tyrosine-protein kinase erbB-4 (ErbB4)
245(2)
Dysbindin (DTNBP1)
247(1)
Reelin (RELN)
247(1)
Bipolar disorder
248(1)
CLOCK
248(3)
Ankyrin G (ANK3)
251(1)
Dopamine transporter
252(1)
Glycogen synthase kinase 3
253(1)
Major depressive disorder
253(1)
Serotonin transporter
253(2)
Stress-related genes in depression
255(1)
Conclusion
256(1)
References
256(13)
Chapter 13 Psychiatric genomics: brain pathophysiology and genetic factors
269(20)
Jessica Qian
Nzaar Al-Chalabi
Yin Wang
Amarachukwu Igblom
Ali Bani Fatemi
Vincenzo De Luca
Introduction
269(1)
Autism spectrum disorders
269(1)
Pathophysiology of autism spectrum disorders
270(1)
Genetics of autism spectrum disorders
271(1)
Attention deficit hyperactivity disorder
271(1)
Pathophysiology of attention deficit hyperactivity disorder
272(1)
Genetics of attention deficit hyperactivity disorder
272(1)
Antisocial personality disorder
273(1)
Pathophysiology of antisocial personality disorder
273(1)
Genetics of antisocial personality disorder
273(1)
Schizophrenia
274(1)
Pathophysiology of schizophrenia
274(1)
Major depressive disorder
275(1)
Pathophysiology of major depressive disorder
276(1)
Genetics of major depressive disorder
277(1)
Bipolar disorder
277(1)
Pathophysiology of bipolar disorder
277(1)
Genetics of bipolar disorder
278(1)
Generalized anxiety disorder
278(1)
Pathophysiology of generalized anxiety disorder
278(1)
Genetics of generalized anxiety disorder
279(1)
Panic disorder
279(1)
Pathophysiology of panic disorder
280(1)
Genetics of panic disorder
280(1)
Conclusions
280(1)
References
281(8)
Chapter 14 Integration with systems biology approaches and -omics data to characterize risk variation
289(28)
Hannah Young
Manna Cote
Laura M. Huckins
Introduction
289(1)
Functional annotation of noncoding regions
289(1)
Annotations from experimental data
290(1)
QTL analysis
291(1)
Context-specific genetic regulation
292(1)
Cell-type QTLs
293(1)
Context-specific QTLs
294(3)
Mapping GWAS to QTLs
297(2)
Multi-QTL methods
299(3)
Annotation of variants to gene pathways
302(1)
Gene-set databases
302(1)
Gene-set analysis
303(1)
Gene networks
304(1)
Network-based variant interpretation
304(2)
Conclusion/Future Directions
306(1)
References
306(11)
Chapter 15 Usage of biobank data for psychiatric genomics and promotion of precision psychiatry
317(24)
Lea K. Davis
Jessica Kiri Dennis
Introduction to biobanks
317(4)
Psychiatric genomics in a biobank setting
321(1)
Contextualizing the limitations of biobanks for psychiatric genomics
321(2)
Algorithmic phenotyping
323(2)
Evaluation of algorithmic phenotyping
325(1)
Chart review
325(1)
Automated phenotyping
326(2)
Major impact of biobanks on psychiatric genomics research
328(1)
Applications to genome-wide association studies
328(1)
Phenome-wide and lab-wide association studies
329(1)
Practicing the implementation of precision psychiatry
330(2)
Ethical considerations
332(1)
Future directions
333(1)
References
334(7)
Chapter 16 Shared heritability among psychiatric disorders and traits
341(20)
Kevin S. O'Connell
Guy Hindley
Olav B. Smeland
Alexey Shadrin
Yunpeng Wang
Oleksandr Frei
Ole A. Andreassen
Heritability
341(2)
Shared heritability, genetic overlap, and pleiotropy
343(2)
Evaluating genetic overlap
345(1)
Polygenic risk scores
345(1)
Genetic correlation
346(1)
Overlap beyond genetic correlation
347(3)
Identifying specific shared loci
350(1)
Mendelian randomization
351(1)
Rare variant genetic overlap
352(1)
Implications for psychiatry
353(1)
Conclusion
353(1)
Acknowledgments
354(1)
Competing financial interests
354(1)
References
354(7)
Chapter 17 Endophenotypes in psychiatric genomics: a selective review of their status and a call to action
361(17)
Caroline K. Diehl
Brigitte Rockstroh
Cindy M. Yee
Gregory A. Miller
Introduction and context: The endophenotype construct
361(1)
Progress in identifying genomic endophenotypes
362(1)
Schizophrenia endophenotypes
362(2)
Mood disorder endophenotypes
364(1)
Transdiagnostic endophenotypes
364(1)
Animal studies of endophenotypes
365(1)
Questioning the clinical utility of endophenotypes
366(1)
Advancing a dimensional understanding of psychopathology
367(4)
Clinical translation of endophenotypes
371(1)
The role of nongenomic studies
371(1)
Endophenotypes and clinical prediction
372(1)
Race and racism in psychiatric genomics
373(5)
Conclusions 378(1)
Acknowledgment 378(1)
References 379(6)
Index 385
Dr. Evangelia Eirini Tsermpini is a postdoctoral researcher at the Laboratory of Pharmacogenetics, Faculty of Medicine, University of Ljubljana in Slovenia, since September 2021. She obtained her Ph.D. in 2016 from the Department of Pharmacy of the University of Patras, where she worked in the Laboratory of Pharmacogenomics and Personalized Therapy under the supervision of Professor George Patrinos. After her Ph.D., she worked as an academic scholar at the Departments of Medicine and Pharmacy of the University of Patras, and a senior research scientist and group leader at the Laboratory of Pharmacogenomics and Personalized Therapy at the Department of Pharmacy of the University of Patras, until July 2021. She was a visiting scholar at the Division of Pharmacotherapy and Experimental Therapeutics of the UNC Eshelman School of Pharmacy at the University of North Carolina, a research associate at RIKEN, Genomic Research Center for Integrative Medical Sciences in Japan, as well as at the Department of Neuroscience and Clinical Pharmacology, University of Cagliari, in Italy. Her field of expertise is psychiatric genomics, pharmacogenomics, transcriptomics and epigenomics. Her research is related to identifying genetic biomarkers associated with the development of schizophrenia, bipolar disorder, depression, alcohol use disorder and psychiatric drugs response. Other research interests include discovering and assessing miRNAs biomarkers for early diagnosis of schizophrenia and antipsychotic response and investigating leukocyte telomere length in mental disorders. Furthermore, from 2016 and until 2021 she was actively involved in the First European Implementation study, funded by the European Commission. Dr. Tsermpini has received twice the first prize for the high quality of research during her Ph.D. She has published 28 scientific articles, six chapters in international peer-reviewed journals and textbooks, and many abstracts in international conference proceedings. She is a reviewer for several scientific journals and an evaluator in grant evaluation committees. Martin Alda, MD, FRCPC is a Professor of Psychiatry and Killam Chair in Mood Disorders at Dalhousie University in Halifax, Canada. An active clinician, Dr. Alda works as the head of the Mood Disorders Program at the QEII Health Sciences Centre in Halifax. After graduating from the medical school at Charles University in Prague, he trained in psychiatry at Charles University and at the University of Ottawa. Dr. Aldas work has been at the junction of clinical and basic research, investigating genetic and neurobiological markers of mood disorders and response to treatment. His clinical, genetic, pharmacogenetic, and brain imaging studies are based on carefully characterized prospective clinical samples and their aim is to develop methods of personalized treatment in psychiatry. George P. Patrinos is a Professor of Pharmacogenomics and Pharmaceutical Biotechnology in the University of Patras (Greece), Department of Pharmacy, and Head of Division of Pharmacology and Biosciences of the same department and holds adjunct Full Professorships at Erasmus MC, Faculty of Medicine, and Health Sciences, Rotterdam (the Netherlands), and the United Arab Emirates University, College of Medicine, Department of Genetics and Genomics, Al-Ain (UAE). Also, from 2018 until the end of 2024, he was Chair of the Global Genomic Medicine Collaborative (G2MC). He served 12.5 years as a full member and Greeces National representative in the CHMP Pharmacogenomics Working Party of the European Medicines Agency (EMA). George has more than 340 publications in peer-reviewed scientific journals, some of them in leading scientific journals, such as The Lancet, Nature Genetics, Nature Reviews Genetic, Nucleic Acids Research, Genes & Development. He has also coauthored and coedited more than 15 textbooks, among which the renowned textbook Molecular Diagnostics, published by Academic Press, now in its 3rd edition, while he is the editor of Translational and Applied Genomics book series, published by Elsevier. Furthermore, he serves as the Editor-In-Chief of the prestigious Pharmacogenomics Journal (TPJ), published by Nature Publishing Group, Associate Editor, and member of the editorial board of several scientific journals, and advisory and evaluation committees. Apart from that, George is the main coorganizer of the Golden Helix Conferences, an international meeting series on Pharmacogenomics and Genomic Medicine with more than 50 conferences organized in more than 25 countries worldwide.