428429CHAPTER 12

Genetic Elements of Behavioral Disorders

Christine E. Kasper

The genetics of cognitive abilities, mental functioning, social attitudes, psychological interests, psychiatric disorders, learning disorders, behavior, addiction, mood, and personality traits have long been of interest to geneticists. This interest has been complicated by the complexity of brain function as well as the social, ethical, legal, and political implications of research in this area. Also complicating the study is the tendency for such conditions to be too broadly defined, thus perhaps diluting the gene associations. For example, it is more fruitful to look for a specific type of genetic variation connected with a more narrowly defined communication disorder such as expressive, mixed, phonologic, and so on, rather than the broadly used term. Genomic research into the various psychiatric and behavioral disorders has rapidly progressed and it is now evident that the precision of genomic findings does not clearly match standard behaviorally based systems such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). In reality, behavioral disorders are more akin to continuums of genetic, cognitive, behavioral, personality, and environmental factors rather than a one-gene–one-disease phenomenon. The recognition that clinical diagnostic categories do not correlate with the biology of behavioral and psychiatric illnesses represents a new and radical change in this field of study. To this end, the National Institute for Mental Health (NIMH) has developed a new framework based on genomic findings that should flexibly expand as new research clarifies the underlying biology of mental health illnesses. The Research Domain Criteria (RDoC) project of the NIMH seeks to “Develop, for research purposes, new ways of classifying mental disorders based on behavioral dimensions and neurobiological measures” (National Institute of Mental Health, 2015). RDoC uses cutting edge research approaches in genetics, neuroscience, and behavioral science to study the problems of mental illness, studied independently from the classification systems by which patients are currently grouped. While rapidly progressing, the RDoC remains at this time a framework of psychiatric classification to guide research rather than one for immediate clinical use. However, the classification of behavioral and psychiatric disorders into groups based on genetics and similar traits between groups points clearly to these disorders having similar biologic origins and manifesting as more of a continuum of disorder from fundamental behavioral components 430rather than discrete clinical phenomena. RDoC also seeks to study the full range of variation, from normal to abnormal, as well as using genetics and brain imaging point to the biological measures that will help explain the heterogeneity of symptoms. It is anticipated that important translational and interdisciplinary work of this nature will soon transform clinical practice in the fields of behavior and psychiatric disorder by leading to precision diagnoses.

GENETICS AND MENTAL HEALTH

The observations that disorders affecting mental health and behaviors tend to run in families have been historically claimed as support for genetic contributions to illness. Biological families tend to share their genes, their cultural heritage, and their living environment, which includes similar exposure to pathogens, diet, stressors, toxins, dynamic family interactions, patterns of behavior, and other parameters. Given recent research and genomic studies by the NIMH at the National Institutes of Health, we now know that this is true for some psychopathology. Disorders known to be due to a single gene error (e.g., Lesch–Nyhan syndrome), uniparental disomy (e.g., Prader–Willi syndrome), or a chromosomal variation (e.g., Klinefelter syndrome) can have effects manifested in terms of behavior. There has been increasing recognition of patterns of behavior that accompany some genetic disorders, and the term behavioral phenotype has been applied to these. These can provide genetic leads to areas for further exploration of chromosome and gene areas that may be responsible for certain behaviors. Their external environment can modify many genetic disorders, so that behavioral effects may or may not be apparent (e.g., phenylketonuria when phenylalanine is restricted). In multifactorial disorders, a model for the interaction of genes and environment is already present. These environmental influences are important in conditions such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). In both PTSD and MDD, prolonged stress conditions influence epigenetic regulation of neuronal gene transcription and the methylation of genomic DNA near key stress-response genes, which may influence stress vulnerability and resilience.

As previously discussed, the initial establishment of the broad categories of classical schizophrenia and affective, bipolar, or manic depressive illness was largely based on descriptive symptoms. These categories have been further subdivided over time, but they still represent somewhat heterogeneous subtypes that may, as in diabetes mellitus, represent more than one disease and etiology with different inheritance mechanisms. Previously, varying differences in nomenclature and in what was included in “schizophrenia” over the years have made genetic study and interpretation difficult. The major evidence for the role of genetic factors in schizophrenia and the mood disorders (MDs) originally came from family studies, twin studies, adoption studies, and biochemical analyses. More recently, genetic modeling, linkage, whole-genome linkage and association studies, proteomic approaches, whole-network gene expression studies, and other molecular genetic techniques are being used to understand the genetic contribution. Most of these early studies and techniques suffered from methodological problems, but nearly all of them documented some type of genetic component. At this time, however, the exact nature of the genetic contribution to the major mental disorders remains incomplete; however, significant advancements 431in research are rapidly pointing to the genetic and biologic underpinnings. Another way in which genetic contribution has been studied is by examining drug action and effects on psychiatric disorders and using that information to examine gene variations that might be relevant.

Nurses practicing in the mental health area are integral to documenting and supporting families and individuals with behavioral-related genetic issues. Counseling and therapy skills related to issues surrounding the diagnosis of a family member with a genetic disorder, whether it is a birth defect in an infant or another type of disorder in the adult, include feelings of shock, denial, stigma, guilt, depression, and anger. Genetic testing and treatment decisions, coping with the results, and deciding who and how to tell about the results are some of the psychological and interpersonal issues in which services may be needed.

Early-Onset Alzheimer Disease (EOFAD)

Early-onset Alzheimer disease (EOFAD) tends to cluster in families, often over several generations, and can be considered a familial disease; thus, it is inherited in an autosomal dominant manner. Mutations in one of three genes have been linked to some cases of EOFAD. Online Mendelian Inheritance in Man (OMIM) lists these genes as the amyloid precursor protein (APP) gene and two presenilin genes (PSEN-1 and PSEN-2). Those carrying any of these rare mutations tend to develop EOFAD during their fourth and fifth decades. Currently, 5% of a total 5 million cases of Alzheimer disease is classified as EOFAD.

Late-Onset Alzheimer Disease

Late-onset Alzheimer disease is the predominant form of Alzheimer disease and its genetic inheritance is more complex. A number of genes have now been identified, which may contribute to the chances of developing late-onset Alzheimer disease. The symptoms of Alzheimer disease are dementia beginning with loss of memory and progressing in severity to incapacitation. Other symptoms include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Typically the clinical duration of the disease is 8 to 10 years.

The three forms of apolipoprotein E (APOE) gene, APOE e2, APOE e3, and APOE e4, have been found to have the greatest influence on the disease and are found on chromosome 19. Further genomic studies have found additional genes, which are linked to increased risk, called CLU, PICALM, CR1, BIN1, ABCA7, MS4A, CD33, EPHA1, and CD2AP. Variants in these genes are linked to different risks of Alzheimer disease; however, they have a much smaller effect on the disease than for APOE. Teams of researchers have joined together to form the International Genomics of Alzheimer’s Project to conduct the largest genetics study of Alzheimer disease to date, and to provide further insights into the inheritance of the condition.

SCHIZOPHRENIA

According to the American Psychiatric Association’s DSM, schizophrenia is a psychotic disorder that “lasts for at least 6 months, and includes 1 month of active 432phase symptoms (i.e., two [or more] of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms)” (Tandon et al., 2013). Subtypes include paranoid, disorganized, catatonic, undifferentiated, and residual. In addition, schizoaffective disorder is a disturbance in which symptoms of schizophrenia and an MD occur together. The worldwide prevalence is about 1%. Some estimate that schizophrenia has heritability at about 80%, but unequivocal single genes have not yet been identified.

The major issues in studies include whether pure schizophrenia has been analyzed or whether the clinical spectrum of schizophrenic disorders has been included. At least 40 family and twin studies have been conducted. The essence of these studies is the consistent finding that there is a higher prevalence of the respective illness among blood relatives. Those studies that have compared the concordance of monozygotic (MZ) twins for schizophrenia with that of dizygotic (DZ) twins have found in all cases that the concordance rate for MZ twins is higher than for DZ twins. Although the exact rates have varied from study to study, these findings provide support for a heritability component. Overall concordance rates have varied from 35% to 92% in MZ twins and from 7% to 26% for DZ twins, with an overall pooled rate of 45.6% for MZ and 13.7% for DZ. High concordance rates appear to be associated with severity of the illness. The age of the onset of illness shows greater association between twins than would be expected by chance. In both groups, twins who have lived apart generally show similar concordance rates to those who have been raised in the same environment.

General conclusions from adoption studies reveal that children born of schizophrenic parents developed schizophrenia at significantly higher rates than did adoptees born of normal parents. Biologic relatives of those adoptees who developed schizophrenia had higher rates of schizophrenia and suicide than did the adoptive relatives and the biologic and adoptive relatives of adoptees who did not become schizophrenic. Adoptees born of normal parents but raised by schizophrenic adoptive parents did not show an increase in schizophrenia. In order to rule out the intrauterine environment or early interaction with a schizophrenic mother, some researchers studied paternal half-siblings. These half-siblings had the same biologic schizophrenic father but a different biologic mother. The increased incidence of schizophrenia found was interpreted as ruling out early maternal influences.

More recent studies have looked at the candidate gene approach or linkage, often focusing on genes or markers having pharmacologic, immunological, and biochemical associations. Based on these, some of those explored have been the gene for catecholamine methyltransferase, which metabolizes the neurotransmitters dopamine, epinephrine, and norepinephrine, as well as both receptors and transmitters for these and for gamma aminobutyric acid (GABA), serotonin, and monoamine oxidase. Other promising candidate genes for susceptibility include neuregulin (NRG1), dysbindin (DTNBP1), G72/G30 gene complex, RGS4 (the regulator of G-protein signaling-4), proline dehydrogenase (PRODH) disrupted in schizophrenia 1 (DISCI), the gene encoding phosphodiesterase 48 (PDE48), and catechol-O-methyltransferase (COMT). Many of these are located in chromosomal areas that are linked to schizophrenia. Molecular and mapping techniques have been 433used. Newer strategies such as microarray technology to examine gene expression appear promising. At present, the most promising information appears to be an association or linkage for schizophrenia with the following chromosomal sites: 1q21-22, 6p22-24, 6q21-22, 8p21, 10p11-15, 13q32, and 22q11-13. A subtype of schizophrenia, periodic catatonia, was also found to be associated with chromosome 15q14. In the case of chromosome 22, chromosomal microdeletions in chromosome 22q11.21-q11.23 may increase susceptibility. A known genetic syndrome, velocardiofacial syndrome (an autosomal recessive disorder with cardiac anomalies, learning disabilities, and cleft palate, also known as DiGeorge syndrome, discussed in Chapter 9), which is associated with small deletions in chromosome 22q11, includes about 10% who develop psychiatric disorders such as chronic paranoid schizophrenia. A candidate for a susceptibility gene on 22q12-13 is the A2a adenosine receptor, one of the receptors mediating central nervous system effects of adenosine, which showed linkage to schizophrenia in some persons.

Another area of investigation for etiology is unstable tandem repeat expansion (Chapter 4). In at least some cases, anticipation (the appearance of more severe disease progressively earlier in successive generations) and a parent-of-origin effect has been noticed in schizophrenia, giving credence to the possible involvement of unstable tandem repeat nucleotide expansion in etiology. A theory that has had a resurgence of interest is that of events that disrupt neurodevelopment, and thus result in schizophrenia, such as Rh incompatibility and severe nutritional deficiencies. Advanced paternal age has also been associated with a higher risk for adult schizophrenia, perhaps due to de novo paternal mutations. Despite evidence for some yet unknown genetic basis for schizophrenia, environmental disturbances appear to be needed for ultimate expression.

Bipolar disorder (BD) and schizophrenia have been recognized as the most heritable common psychiatric disorders. Due to the wide heterogeneity of these diagnostic groups, identification of genes causal for susceptibility has not been straightforward. In recent years, there has been significant progress in the identification of common genetic risk factors for both BD and schizophrenia. Each gene by itself has a small effect on risk; certain chromosomal copy number variants (CNVs) are rarer, but have a larger effect on risk. Genome-wide association studies (GWAS) of schizophrenia and BD have recently found evidence for association to specific risk loci, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in BD. The commonality of the ZNF804A and CACNA1C loci to influence risk for both disorders supports the hypothesis that schizophrenia and BD are not etiologically distinct. This is one of the early studies that points to common mechanisms between psychiatric disorders.

Common genetic changes have also been demonstrated between autism, attention deficit hyperactivity disorder (ADHD), BD, major depression, and schizophrenia. These five diseases were previously believed to be distinct. Significant illness-associated genetic variation was found, including variation in two genes that code for the cellular machinery regulating the flow of calcium into neurons: CACNA1C and CACNB2. CACNA1C is known to impact brain circuitry involved in emotion, thinking, attention, and memory, which are disrupted in psychiatric illness. The 434identification of these common genes points to the possibility of a fundamental biologic mechanism in these disorders.

MOOD DISORDERS

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