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Principles of Psychiatric Genetics
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    Lei, Man-Kit Simons, Ronald L. Edmond, Mary Bond Simons, Leslie Gordon and Cutrona, Carolyn E. 2014. The effect of neighborhood disadvantage, social ties, and genetic variation on the antisocial behavior of African American women: A multilevel analysis. Development and Psychopathology, Vol. 26, Issue. 4pt1, p. 1113.

    Al Eissa, Mariam M. Fiorentino, Alessia Sharp, Sally I. O'Brien, Niamh L. Wolfe, Kate Giaroli, Giovanni Curtis, David Bass, Nicholas J. and McQuillin, Andrew 2018. Exome sequence analysis and follow up genotyping implicates rare ULK1 variants to be involved in susceptibility to schizophrenia. Annals of Human Genetics, Vol. 82, Issue. 2, p. 88.

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    Principles of Psychiatric Genetics
    • Online ISBN: 9781139025997
    • Book DOI: https://doi.org/10.1017/CBO9781139025997
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Book description

Disorders of behavior represent some of the most common and disabling diseases affecting humankind; however, despite their worldwide distribution, genetic influences on these illnesses are often overlooked by families and mental health professionals. Psychiatric genetics is a rapidly advancing field, elucidating the varied roles of specific genes and their interactions in brain development and dysregulation. Principles of Psychiatric Genetics includes 22 disorder-based chapters covering, amongst other conditions, schizophrenia, mood disorders, anxiety disorders, Alzheimer's disease, learning and developmental disorders, eating disorders and personality disorders. Supporting chapters focus on issues of genetic epidemiology, molecular and statistical methods, pharmacogenetics, epigenetics, gene expression studies, online genetic databases and ethical issues. Written by an international team of contributors, and fully updated with the latest results from genome-wide association studies, this comprehensive text is an indispensable reference for psychiatrists, neurologists, psychologists and anyone involved in psychiatric genetic studies.

Reviews

'A magnificent and timely contribution. I especially enjoyed Dan Geschwind's chapter on autism.'

Solomon Snyder - University Distinguished Service Professor of Neuroscience, Pharmacology and Psychiatry, The Johns Hopkins University School of Medicine

'It is highly suitable as a starting point for those who find themselves on the continuum between practising clinicians and specialists in biological psychiatry.'

Source: Psychological Medicine

'The contributing authors are all prominent, expert members of their fields … Principles of Psychiatric Genetics … is a demonstration of how much the field has progressed and an indication toward a promising future.'

Source: American Journal of Psychiatry

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Contents


Page 1 of 2


  • Chapter 7 - Functional validation of candidate genetic susceptibility factors for major mental illnesses
    pp 69-78
  • View abstract

    Summary

    Genetic epidemiology focuses on how genetic factors and their interactions with other risk factors increase vulnerability to, or protection against, disease. The investigations in genetic epidemiology are typically based on a combination of study designs including family, twin, and adoption studies. Migrant studies are perhaps the most powerful study design to identify environmental and cultural risk factors. This chapter presents a summary of relative risks derived from controlled family studies of selected psychiatric disorders such as schizophrenia, anxiety disorders, substance use disorders and mood disorders. Two factors which contribute to the complexity of the patterns of inheritance of psychiatric disorders are lack of validity of classification of psychiatric disorders and complexity of the pathways from genotypes to psychiatric phenotypes. The chapter reviews the role of the tools of epidemiology in ongoing and future studies designed to identify genes underlying mental disorders.
  • Chapter 8 - Epigeneticmechanisms in drug addiction and depression
    pp 79-89
  • View abstract

    Summary

    This chapter describes the basic principles behind the most widely used human genetic strategies to identify inherited disease susceptibility factors. There are many extensions and modifications to the basis linkage and linkage disequilibrium (LD) mapping approaches. The chapter describes the intuitions and basic strategies behind a few of the more widely used extensions. There are also a number of issues that plague linkage and LD mapping strategies for identifying genetic variants that influence disease susceptibility. The chapter discusses a few of these issues and notes that all of them are well-recognized by the genetics community and that concerted efforts to deal with them in various ways have been made. Advances in DNA sequencing technologies have facilitated studies of rare variants, as these technologies can be used to exhaustively identify all forms of variation, common and rare, in a genomic region for a group of individuals.
  • Chapter 9 - Panicdisorder
    pp 90-111
  • View abstract

    Summary

    This chapter outlines methods for studying the genetic basis of psychiatric disorders. The two types of methods, single nucleotide polymorphism (SNP) genotyping and sequencing, are focused on characterizing two different types of variants predisposing to disease: common and rare. The chapter provides a technical overview of two technologies that have been used in the majority of linkage studies and population-based genome-wide association studies (GWAS): Illumina BeadArray Mapping arrays and Affymertrix Gene-Chip Arrays. While there are many potential applications of these technologies, the chapter focuses on those involving sequencing DNA for the purpose of identifying the genetic basis of disease, specifically dividing this section into targeted methods and genome-wide approaches. The chapter provides an overview of features for all three commercially available platforms (SOLiD, GA and 454). Analysis of next-generation sequencing data falls into three categories: alignment/assembly; quality control; and variant calling.
  • Chapter 10 - The genetics of the phobic disorders and generalized anxiety disorder
    pp 112-120
  • View abstract

    Summary

    The use of databases and computational methods to sort out the potential functional significance of a gene or variation implicated in a linkage or association is now relatively easy and is becoming more commonplace. This chapter describes databases and available computational-based functional analysis tools that can facilitate understanding of the biological meaningfulness of an association involving a specific genomic region, gene, or specific variation. DNA sequence data must be dealt with at some level in any genetic investigation. For example, translating DNA or RNA sequences in protein sequences is a basic task in sequence analysis. Sequence alignments are a robust tool used for many purposes, the most common of which is the identification of similar stretches of sequence across DNA or protein regions. An emerging set of resources and databases for gene expression analysis of relevance to genetic studies of neuropsychiatric diseases are "expression quantitative trait locus" or "eQTL" resources.
  • Chapter 11 - Genetic contributions to obsessive–compulsive disorder (OCD) and OCD-related disorders
    pp 121-133
  • View abstract

    Summary

    Gene expression studies in psychiatric disorders have proven to be a useful partner to classic genetics approaches, and combined approaches such as convergent functional genomics (CFG) may provide shortcuts to the discovery of genes and overall understanding of the neurobiology involved. The combined approach has been applied with some success to bipolar disorder, alcoholism, and schizophrenia. For complete understanding of the illness, the analyses then need to be pursued at a biological pathway and mechanistic level, integrating environmental effects as key modulators of gene expression and phenotype manifestation. Progress in quantitative profiling of psychiatric phenotypes, and borrowing of concepts and paradigms from other medical fields that are farther along, such as cancer genetics and genomics, are exciting areas of advance for the near future. A (r)evolution in medical nosology in general, and psychiatric nosology in particular, will occur as a result of such studies.
  • Chapter 12 - Post-traumaticstress disorder
    pp 134-144
  • View abstract

    Summary

    This chapter describes the recent developments in the field of psychiatric pharmacogenetics. Most pharmacogenetic studies of antidepressants have focused predominantly on treatment response, perhaps also due to the fact that most current antidepressants are well tolerated and fairly safe. Pharmacotherapy is the treatment of choice for psychotic symptoms of mental conditions such as schizophrenia, bipolar disorder, and psychotic depression. Antipsychotic drugs are traditionally divided into two groups: typical (first-generation) antipsychotics, with strong affinity for the dopamine receptor, and atypical (second-generation) antipsychotics, with multiple receptor targets. Anticonvulsant drugs are widely used in the management of behavioral disorders, including bipolar disorder, mood disorders, and impulse control disorders. While psychiatry has entered the new area of pharmacogenetics, it is important to remember that this new technology will only provide additional information on one aspect of the complex and personal history of psychiatric patients.
  • Chapter 13 - Antisocialbehavior: gene–environment interplay
    pp 145-159
  • View abstract

    Summary

    This chapter reviews how functions of genetic susceptibility factors can be validated, specifically using disrupted in schizophrenia 1 (DISC1) as an example. Studies at multiple levels, from protein chemistry, cell biology, animal study, to clinical work provide comprehensive understanding of the functions of susceptibility factors. Once genetic studies identify candidate susceptibility factors for the diseases, functions of such proteins can be tested in cells by modulating expression of the target molecules or by expressing their genetic variants. The chapter describes rodent models with manipulations for genetic susceptibility factors of mental illnesses in greater detail. A series of studies by Weinberger and associates has pioneered the possible correlation of brain dysfunction with genetic variations in susceptibility factors associated with mental illnesses. To identify mechanistic links from genetic factors to the phenotypes, especially those observed during brain development and maturation, a combination of human studies with animal experiments is expected.
  • Chapter 14 - Learning disabilities
    pp 160-167
  • View abstract

    Summary

    Focusing on drug addiction and depression, this chapter discusses the molecular machinery underlying epigenetic mechanisms and describes how their dysregulation may contribute to the chronic psychiatric disorders. While the epigenetic studies are ongoing for a variety of substance abuse models, the chapter focuses on the psychostimulants cocaine and amphetamine because these studies are more mature. One of the most challenging obstacles for depression research has been the development of an animal model that accurately recapitulates the symptoms of human depression. Brain-derived neurotrophic factor (BDNF) plays a critical role in the development of the social defeat phenotype and its reversal by antidepressant treatment. While extremely exciting, epigenetic research in psychiatry is still in its infancy, and far more research is needed to identify both the dysregulated genes and chromatin modifications responsible for individual psychiatric diseases and their improvement during effective therapy.
  • Chapter 15 - Attention-deficit hyperactivity disorder
    pp 168-182
  • View abstract

    Summary

    This chapter discusses the diagnosis and epidemiology of panic disorder (PD). Genetic studies, while instrumental, cannot alone address the etiological complexities of most psychiatric disorders. The chapter turns to two integrative approaches that combine genetics with other clinical or biological methods to target the underlying mechanisms. First, it discusses exploiting the relationship between psychiatric and non-psychiatric medical manifestations (the expanded spectrum approach). This approach is particularly relevant to PD, where the panic attacks are accompanied by a range of physiological responses that may be central to the etiology. Second, the chapter describes neurobiological phenotypes, and in particular, on using measures of brain structure and function to identify genetic variation, and studies the mechanisms via which genes can impact behavior. The chapter concludes with an overview of imaging genetic studies of PD, and particularly, of how data from imaging studies can be used to enhance the tractability of genetic targets.
  • Chapter 16 - Autism and autism spectrum disorders
    pp 183-195
  • View abstract

    Summary

    Genetic epidemiology can address a number of questions of practical importance for a search for genes for phobic disorders. With the genetics of the phobic disorders established, studies are beginning to ask more specifically what constitutes the additive genetic component. Genome searches have been reported for agoraphobia, simple phobia, social phobia, and for a broad phenotype that includes these three phobias in addition to other anxiety disorders. Genetic epidemiology indicates that finding genes for the phobic disorders will require samples with considerable statistical power since the heritability's of these disorders are modest. Twin studies indicate that the familial transmission of generalized anxiety disorder (GAD) is due to genes. With regard to GAD, additive genes shared with panic disorder and agoraphobia accounted for 20% of the total variance of GAD; indeed, this shared variance component made up 87% of its additive genetic variance.
  • Chapter 17 - The genetics of bipolar disorder
    pp 196-211
  • View abstract

    Summary

    This chapter reviews the investigations that have indicated likely contributions of chromosomal risk regions, specific candidate genes and gene pathway networks to obsessive-compulsive disorder (OCD) etiology. As with other genetically complex medical disorders, methodological approaches in psychiatric genetics are shifting to genome-wide association studies (GWAS), which make more comprehensive single nucleotide polymorphism (SNP)-based assessments possible. Numerous gene products seem highly relevant to neurotransmitter system pathways and developmental sequences important in OCD, but only relatively few have been investigated. These include glutamate, dopamine, serotonin, and other systems, neurotrophic factor genes and their affiliated receptors, and genes indirectly implicated via comorbid disorders or suggested from animal models of OCD and OCD-related behaviors. Many models of behavioral changes resembling OCD-related features such as perseveration, compulsive grooming, food-restriction-induced compulsive wheel running, or drinking have been reported. OCD seems likely to be genotypically and phenotypically heterogeneous.
  • Chapter 18 - Thegenetics of major depression
    pp 212-229
  • View abstract

    Summary

    This chapter provides some background about post-traumatic stress disorder (PTSD) and reviews the evidence for the role of genetic factors as a diathesis for PTSD. There are three approaches that have traditionally been used to investigate the presence of genetic influences on psychopathology: family studies, twin studies, and adoption studies. There have been a number of case-control association studies conducted to try to identify genetic variants that are related to a vulnerability to develop PTSD following exposure to trauma. There have been a number of twin studies that have examined possible genetic influences that contribute to the comorbidity of PTSD with other mental disorders. An area that is likely to play an increasingly important role in understanding how genes influence psycho-pathology in general and PTSD in particular is epigenetics. The cutting-edge research design for gene discovery is currently the genome-wide association studies (GWAS).
  • Chapter 19 - The genetics of schizophrenia
    pp 230-261
  • View abstract

    Summary

    This chapter reviews the evidence for genetic and environmental influences, both specified and unspecified in antisocial behavior. It discusses heritability of both adult and child mental disorders in DSM-IV-TR, for which antisocial behavior is central to their diagnosis. The chapter also reviews heritability of the related externalizing disorders. It highlights some of the most exciting new directions in this field, which aim to unpack the genetic and environmental black boxes in antisocial behavior, and provides the complexities of the gene-environment interplay in antisocial development. Evidence of genetic influences on antisocial behavior does not implicate that individuals exhibiting antisocial behavior are immune or resistant to interventions. Future research with combined approaches from behavior genetics and neuroscience will lead to better understanding of specific genes that result in structural and functional brain impairments that in turn give rise to antisocial, violent, and psychopathic behavior.
  • Chapter 20 - The genetics of anorexia and bulimia nervosa
    pp 262-271
  • View abstract

    Summary

    Rather than being separate and distinct, learning disabilities are often comorbid in children, suggesting that there may be overlaps in deficits and etiologies. Through the identification of genes influencing processes that are important to learning, new developments in genetic analysis may help define alternate ways of conceptualizing different types of learning disabilities based on the genes and endophenotypes that are involved in each one. There has been evidence since the turn of the last century that reading disability (RD) occurs in families, and twin studies have shown heritabilities around 0.56. Although the definitions of RD and language impairment (LI) are based on measures that are very different, the disorders share some similarities; the heritabilities for deficits are similar, males are affected more often than females, and young children with LI are at greater risk for RD. Molecular genetic studies support common genetic influences on RD and speech sound disorder (SSD).
  • Chapter 21 - Genetics and common human obesity
    pp 272-278
  • View abstract

    Summary

    The initial search for attention-deficit hyperactivity disorder (ADHD) genes was hypothesis driven and focused on genes involved in neurotransmission, based on evidence from effective pharmacotherapeutic agents, animal model, and neuroimaging studies. Candidate genes, linkage, and genome-wide analyses studies (GWAS) have identified several gene variants involved in neurotransmission which confer a modest risk for ADHD. It is also possible that few common variants conferring risk for ADHD exist in the European population and that very large samples will be necessary to identify them. Structural variant studies are indicating that ADHD genetic risk is likely to be transmitted largely by rare variants that collectively disrupt a sizable constellation of genes, presumably with related functions. This is supported by animal genetic models which also implicate numerous genes involved in complex interactions between neural pathways. Epigenetic factors, environmental factors, and gene regulatory elements most likely also play a role in ADHD genetics.
  • Chapter 22 - Alcoholism
    pp 279-286
  • View abstract

    Summary

    All of the major linkage studies relied on the qualitative diagnosis of autism for their analysis. Their results strongly suggest that individual common genetic risk factors are not likely to cause the entire core deficits required for the broad diagnosis of autism or autism spectrum disorders (ASD). Thus, it is necessary to define more precise intermediate phenotypes or endophenotypes that comprise components of the disorder that might be more closely related to a few single genes of small effect size. Endophenotypes are heritable traits characteristic of the disorder and are present in relatives of affected individuals more frequently than in the unrelated general population. The vast majority of association studies have involved the assessment of single candidate genes whose selection was based either on biological hypotheses or on published linkage regions. Similar to other complex genetic diseases, identifying significant genome-wide linkage and association signals in autism has been challenging.
  • Chapter 23 - Nicotine dependence
    pp 287-296
  • View abstract

    Summary

    This chapter reviews the family studies supporting the role of genetics and recent molecular genetic results. Mapping studies using linkage and association methods have had modest success to date despite difficulties in replication between studies. Linkage studies have shown the best support for chromosomal regions: 6q, 8q, 9p, 13q, 14q, and 22q. Several candidate genes first identified in studies of schizophrenia have shown reproducible association in bipolar disorder. Genome-wide association studies (GWAS) have been successful in identifying a few genes with small effects on risk. The data overall suggest a high level of both genic and allelic heterogeneity, as well as, a complex mode of inheritance. The coming availability of economical whole genome sequencing promises availability of complete genomic information. This, and large samples now being collected, may provide the datasets necessary to unravel the genetic complexities of this illness.
  • Chapter 24 - Human molecular genetics of opioid addiction
    pp 297-305
  • View abstract

    Summary

    In addition to subjects with recurrent major depressive disorder (MDD), individuals with only a single episode of major depression were considered affected, as were those with bipolar disorder. One approach to potentially improving genetic linkage signals is to attempt to reduce genetic heterogeneity through reducing clinical heterogeneity. Studies of gene expression in MDD have been carried out in brain samples and in white blood cell samples from MDD patients, as well as in experimental cell lines and in mouse models. As with the genetics of MDD, the genetics of antidepressant response is likely to involve large numbers of genetic variations acting jointly to influence the phenotype. Epigenetic studies should advance our understanding of the mechanisms that underlie gene expression. Pharmacogenetic studies could also provide exciting clinical benefits from genetic investigations of MDD. Understanding of the basic processes would guide the search for novel treatments of MDD.

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