Genetic studies in Alzheimer's disease

Alzheimer's disease (AD), the most common cause of dementia in aged populations, is believed to be caused by both environmental factors and genetic variations. Extensive linkage and association studies have established that a broad range of loci are associated with AD, including both causative and susceptibility (risk factor) genes. So far, at least three genes, APP, PS1, and PS2, have been identified as causative genes. Mutations in these genes have been found to cause mainly early-onset AD. On the other hand, APOE has been identified to be the most common high genetic risk factor for late-onset AD. Polymorphisms in the coding region, intron, and promoter region of certain genes constitute another kind of genetic variation associated with AD. A number of other genes or loci have been reported to have linkage with AD, but many show only a weak linkage or the results are not well reproduced. Currently, the measurable genetic associations account for about 50% of the population risk for AD. It is believed that more new loci will be found to associate with AD, either as causative genes or genetic risk factors, and that eventually the understanding of genetic factors in the pathogenesis of AD will be important for our efforts to cure this illness.     

New findings in the genetics of major psychoses

Schizophrenia and bipolar disorder have a largely unknown pathophysiology and etiology, but they are highly heritable. Although linkage and association studies have identified a series of chromosomal regions likely to contain susceptibility genes, progress in identifying causative genes has been largely disappointing. However, rapid technological advances are beginning to lead to new insights. Systematic genome-wide association and follow-up studies have reported genome-wide significant association findings of common variants for schizophrenia and bipolar disorder. The risk conferred by individual variants is small, and some variants confer a risk for both disorders. In addition, recent studies have identified rare, large structural variants (copy number variants) that confer a greater risk for schizophrenia. This review summarizes recent developments in genetic research into schizophrenia and bipolar disorder, and discusses possible future directions in this field.     

Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia

The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.     

Interpreting the association between cannabis use and increased risk for schizophrenia

Recent longitudinal studies from Sweden, the Netherlands, New Zealand, and Israel report that cannabis use during childhood and adolescence doubles the risk of later appearance of psychosis or schizophrenia. These data have been interpreted as indicating that cannabis has a causal effect along the pathway to psychosis. In this paper, we will offer an alternative explanation of these data. Recent investigations of patients with schizophrenia found increased density of cannabinoid receptors in the dorso-lateral prefrontal cortex and the anterior cingulate cortex. Others reported higher levels of endogenous cannabinoids in the blood and cerebrospinal fluid of patients; these findings were independent of possible cannabis use. Several genetic studies have reported an association between genes encoding the cannabinoid receptor and schizophrenia. Thus, an alternative explanation of the association between cannabis use and schizophrenia might be that pathology of the cannabinoid system in schizophrenia patients is associated with both increased rates of cannabis use and increased risk for schizophrenia, without cannabis being a causal factor for schizophrenia.     

The genetic epidemiology of personality disorders

Genetic epidemiologic studies indicate that all ten personality disorders (PDs) classified on the DSM-IV axis II are modestly to moderately heritable. Shared environmental and nonadditive genetic factors are of minor or no importance. No sex differences have been identified. Multivariate studies suggest that the extensive comorbidity between the PDs can be explained by three common genetic and environmental risk factors. The genetic factors do not reflect the DSM-IV cluster structure, but rather: i) broad vulnerability to PD pathology or negative emotionality; ii) high impulsivity/low agreeableness; and iii) introversion. Common genetic and environmental liability factors contribute to comorbidity between pairs or clusters of axis I and axis II disorders. Molecular genetic studies of PDs, mostly candidate gene association studies, indicate that genes linked to neurotransmitter pathways, especially in the serotonergic and dopaminergic systems, are involved. Future studies, using newer methods like genome-wide association, might take advantage of the use of endophenotypes.     

Genetics in schizophrenia: where are we and what next?

Understanding the genetic basis of schizophrenia continues to be major challenge. The research done during the last two decades has provided several candidate genes which unfortunately have not been consistently replicated across or within a population. The recent genome-wide association studies (GWAS) and copy number variation (CNV) studies have provided important evidence suggesting a role of both common and rare large CNVs in schizophrenia genesis. The burden of rare copy number variations appears to be increased in schizophrenia patients. A consistent observation among the GWAS studies is the association with schizophrenia of genetic markers in the major histocompatibility complex (6p22.1)-containing genes including NOTCH4 and histone protein loci. Molecular genetic studies are also demonstrating that there is more overlap between the susceptibility genes for schizophrenia and bipolar disorder than previously suspected. In this review we summarize the major findings of the past decade and suggest areas of future research.     

Toward a modern search for schizophrenia genes

Genetic epidemiology has provided consistent evidence that schizophrenia has a genetic component It is now clear that this genetic component is complex and polygenic, with several genes interacting in epistasis. Although molecular studies have failed to identify any DNA variant that clearly contributes to vulnerability to schizophrenia, several regions have been implicated by linkage studies. To overcome the difficulties in the search for schizophrenia genes, it is necessary (i) to use methods of analysis that are appropriate for complex multifactorial disorders; (ii) to gather large enough clinical samples; and (iii) in the absence of genetic validity of the diagnostic classification currently used, to apply new strategies in order to better define the affected phenotypes. For this purpose, we describe here two strategies: (i) the candidate symptom approach, which concerns affected subjects and uses proband characteristics as the affected phenotype, such as age at onset, severity, and negative/positive symptoms; and (ii) the endophenotypic approach, which concerns unaffected relatives and has already provided positive findings with phenotypes, such as P50 inhibitory gating or eye-movement dysfunctions.     

Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk

We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho-physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level.     

The genetics of obsessive-compulsive disorder: a review

Obsessive-compulsive disorder (OCD) is a serious psychiatric disorder that affects approximately 2% of the populations of children and adults. Family aggregation studies have demonstrated that OCD is familial, and results from twin studies demonstrate that the familiality is due in part to genetic factors. Only three genome-wide linkage studies have been completed to date, with suggestive but not definitive results. In addition, over 80 candidate gene studies have been published. Most of these studies have focused on genes in the serotonergic and dopaminergic pathways. Unfortunately, none have achieved genome-wide significance, and, with the exception of the glutamate transporter gene, none have been replicated. Future research will require the collaboration of multidisciplinary teams of investigators to (i) achieve sufficiently large samples of individuals with OCD; (ii) apply the state-of-the-art laboratory techniques; and ( iii) perform the bioinformatic analyses essential to the identification of risk loci.     

Incorporation of molecular data and redefinition of phenotype: new approaches to genetic epidemiology of bipolar manic depressive illness and schizophrenia

Considerable advances have been made in identifying specific genetic components of bipolar manic depressive illness (BP) and schizophrenia (SZ), despite their complex inheritance. Meta-analysis of all published whole-genome linkage scans reveals overall support for illness genes in several chromosomal regions. In two of these regions, on the lonq arm of chromosome 13 and on the long arm of chromosome 22, the combined studies of BP and SZ are consistent with a common susceptibility locus for the two disorders. This lends some plausibility to the hypothesis of some shared genetic predispositions for BP and SZ. Other linkages are supported by multiple studies of specific chromosomal regions, most notably two regions on chromosome 6 in SZ. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BP and SZ. Endophenotypes of SZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to the short arm of chromosome 6, and abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to illness, and other genes have been associated with susceptibility to side effects of pharmacological treatment. These genetic findings may eventually be part of an integrated genetic, environmental, and interactive-factor epidemiology of the major mental illnesses.     

Cognitive impairment as a risk factor for psychosis

Since the time of Kraepelin and Bleuler, it has been recognized that schizophrenia is associated with a profound and persistent cognitive impairment. This paper reviews the major clinical and epidemiological studies of cognitive functioning in schizophrenia and other psychotic disorders, and presents several possible models to explain the association between cognitive impairment and psychosis. Cognitive impairment is present in the majority of patients with schizophrenia, and, in some, it is already evident in the premorbid stages of the disorder. This cognitive impairment is not secondary to psychotic symptoms, negative symptoms, or socioeconomic status. Cognitive impairment can also be observed in nonpsychotic family members of psychotic patients. On the basis of this evidence, it has been proposed that abnormal cognitive functioning can be considered as a possible causal risk factor for psychosis. Recent studies assessing the relationship between genetic background, cognition, brain function, and schizophrenia are presented here as an outline for future research.     

Postmortem studies in schizophrenia

For over a century, postmortem studies have played a central part in the search for the structural and biochemical pathology of schizophrenia. However, for most of this time, little progress has been made. Recently, the situation has begun to change, helped by the emergence of more powerful methodologies and research designs, and by the availability of brain imaging to provide complementary information. As a result, it can now be clearly concluded that there are structural cerebral abnormalities in schizophrenia that are intrinsic to the disorder. The neuropathological process is not primarily degenerative, but involves a change in the normal cytoarchitecture of the brain, probably originating in development. Neurochemically, there is postmortem evidence for alterations in several transmitter systems including dopamine, glutamate, serotonin, and γ-aminobutyric acid (GABA). The cardinal findings are reviewed here, together with a consideration of the conceptual and methodological issues that face postmortem studies of schizophrenia.     

Genetics of bipolar disorder

Bipolar disorder especially the most severe type (type I), has a strong genetic component. Family studies suggest that a small number of genes of modest effect are involved in this disorder. Family-based studies have identified a number of chromosomal regions linked to bipolar disorder, and progress is currently being made in identifying positional candidate genes within those regions. A number of candidate genes have also shown evidence of association with bipolar disorder, and genome-wide association studies are now under way, using dense genetic maps. Replication studies in larger or combined datasets are needed to definitively assign a role for specific genes in this disorder. This review covers our current knowledge of the genetics of bipolar disorder, and provides a commentary on current approaches used to identify the genes involved in this complex behavioral disorder.     

Depressogenic effects of medications: a review

The literature is filled with reports that link medications with the onset or progression of depression. Because depression is so common in patients with medical illness, assessing whether a medication has in fact caused depression, or whether the relationship is coincidental, can be challenging. In this article, we review the literature on the association between medications and depression. For most agents, there are case reports or small studies linking the medication with the onset of depression, but more rigorous prospective studies are either lacking or found no association between the agent and depression. However, several medications, (eg, barbiturates, vigabatrin, topiramate, flunarizine, corticosteroids, mefloquine, efavirenz, and interferon-alpha) do appear to cause depression in some patients and should be used with caution in patients at risk for depression.     

The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia

Objective: Genetic linkage studies in schizophrenia (SZ) have primarily focused on the phenotype of disease susceptibility. A limited number of studies, however, have reported suggestive linkage to specific SZ symptom domains including regions on chromosomes 6, 8, and 20. We examined these chromosomal regions for association to positive, negative, and disorganized symptom clusters, using a dense set of single-nucleotide polymorphisms (SNPs). Methods: We ascertained 178 Caucasian patients with SZ for lifetime severity of clinical symptomatology using a structured diagnostic interview. The cohort was genotyped with the Affymetrix 500K microarray, from which we selected, a priori, 4833 intragenic SNPs located within chromosomal regions previously linked to specific SZ symptom clusters. Parametric tests, corrected for multiple testing, were used to compare the effects of allelic variation within these SNPs to the lifetime severity of the specific symptom domain that had been implicated by prior linkage studies. Results: We were able to extend previous reports of linkage between chromosome 6q and both positive and disorganized symptoms. Lifetime severity of positive symptoms was significantly (P = 2.50 × 10⁻⁵) associated with a SNP within the origin recognition complex subunit 3–like (ORC3L) gene, a gene implicated in synaptic plasticity. Level of disorganized symptoms was significantly (P < 6.00 × 10⁻⁵) associated 2 SNPs within the brain-specific angiogenesis inhibitor 3 (BAI3) gene, which is highly expressed in brain during development. Conclusions: These data point toward specific candidate genes located within previously implicated linkage peaks for clinical symptomatology. Identification of functional variants within these regions and a characterization of the effect of these risk genotypes on the treatment of specific clinical symptoms are needed.     

Nature and nurture in neuropsychiatric genetics: where do we stand?

Both genetic and nongenetic risk factors, as well as interactions and correlations between them, are thought to contribute to the etiology of psychiatric and behavioral phenotypes. Genetic epidemiology consistently supports the involvement of genes in liability. Molecular genetic studies have been less successful in identifying liability genes, but recent progress suggests that a number of specific genes contributing to risk have been identified. Collectively, the results are complex and inconsistent, with a single common DNA variant in any gene influencing risk across human populations. Few specific genetic variants influencing risk have been unambiguously identified. Contemporary approaches, however, hold great promise to further elucidate liability genes and variants, as well as their potential inter-relationships with each other and with the environment. We will review the fields of genetic epidemiology and molecular genetics, providing examples from the literature to illustrate the key concepts emerging from this work.     

The past,present, and future of direct-to-consumer genetic tests

Technological advances in the field of human genetics have resulted in a wave of discoveries of common DNA sequence variants that are associated with a risk of common complex diseases, such as heart attack, that account for a substantial proportion of morbidity, mortality, and health care costs in most contemporary populations. The overall predictive power of these sequence variants can be considerable, due to the high incidence of these diseases and the sheer number of associations that have been discovered. Health care providers have been slow to utilize this knowledge for preventative medicine. However, several companies have taken on a translational role by offering genetic tests based on these discoveries direct to consumers. In this paper, we review the current state and future prospects of such genetic tests, as scientists involved both in the discovery of disease associations and the development of genetic tests.     

Childhood trauma and psychosis - what is the evidence?

In the last decade, a substantial number of population-based studies have suggested that childhood trauma is a risk factor for psychosis. In several studies, the effects held after adjusting for a wide range of potentially confounding variables, including genetic liability for psychosis. Less is known about the mechanisms underlying the association between childhood trauma and psychosis. Possible pathways include relationships between negative perceptions of the self, negative affect, and psychotic symptoms, as well as biological mechanisms such as dysregulated cortisol and increased sensitivity to stress. Psychotic patients with a history of childhood trauma tend to present with a variety of additional problems, including post-traumatic stress disorder, greater substance abuse, higher levels of depression and anxiety, and more frequent suicide attempts. Initial studies suggest that trauma-specific treatments are as beneficial for these patients as for other diagnostic groups.     

Alcoholism: the dissection for endophenotypes

Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.