Why genetic investigation of psychiatric disorders is so difficult

doi:10.1016/j.gde.2004.04.005

Current Opinion in Genetics & Development

Volume 14, Issue 3, June 2004, Pages 280-286

https://doi.org/10.1016/j.gde.2004.04.005 Get rights and content

Abstract

Genetic investigations of psychiatric disease have historically relied on subjectively assessed disease diagnoses to define phenotypes. Recent developments in several areas have provided various new approaches to behavioral disorder phenotyping that promise to advance our understanding of the genetic and environmental etiologies of these traits. Such developments include re-evaluation of the boundaries between different psychiatric categories, implementation of quantitative neurobiological assessments that may serve as endophenotypes, generation of increasingly sophisticated animal behavioral models, and investigation of explicit environmental covariates. At the same time, movement toward large-scale, collaborative efforts is increasing the effectiveness of traditional genetic mapping approaches.

Introduction

There is a widespread perception that elucidating the genetic basis of psychiatric diseases may be more difficult than for other types of common disorders. This perception has two roots. First, during the 20^th Century, psychiatry went through a long estrangement from medical science, and there may be a residual suspicion that psychiatric phenotypes are not as ‘real’ as phenotypes investigated in other medical specialties. Second, and related to the first point, psychiatric phenotypes have rested on subjective clinical evaluation and criteria, with no biological markers. Psychiatric genetic investigations have focused mainly on obvious combinations of phenotypic features, in the form of disease diagnoses [1]. Whereas some investigators focus on narrowly defined disease phenotypes, to avoid confounds related to heterogeneity, others argue that we may miss important information and decrease statistical power by attenuating a broader spectrum.

In reviewing the state of psychiatric genetics, we here focus on new developments in behavioral trait phenotyping. We note recent progress in several areas: re-evaluations of the boundaries between different psychiatric categories, the explosion of interest in endophenotypes, the development of animal models for phenotypic features related to human diseases, and the investigation of phenotypes with explicit environmental covariates.

Section snippets

Genetic epidemiology

Genetic epidemiologic studies conducted over most of the 20^th Century helped establish the disease categories universally employed in psychiatry. The discovery that, as categorized, psychiatric disorders were highly heritable suggested the feasibility of mapping genes contributing to their susceptibility. Recent epidemiologic studies have deconstructed these diagnostic categories, but it is not yet known whether the variable symptoms and subtypes described represent biological variants of a

Endophenotypes

The identification of intermediate phenotypes (endophenotypes), which may have a simpler genetic architecture than disease diagnoses, could enhance the power of mapping studies of psychiatric disorders, and may also help resolve difficulties in defining the boundaries of spectrum disorders in relatives of affected probands. A major issue in applying endophenotypes to gene mapping is that heritability has not yet been established for many such features. Brain morphometric features are potential

Animal models

The pace of efforts to develop animal genetic models for psychiatric disorders is accelerating; in part this is due to technological developments that make it possible to generate more precise models (e.g. conditional knockouts, in which loss of expression of a gene is limited to a particular brain region). Human psychiatric phenotypes are assessed primarily via clinical interview or subjective report: as such, they are impossible to reproduce in mice. Therefore, these models are intrinsically

Genetic mapping of behavioral traits

The intriguing results of several recent association and linkage studies of psychiatric disorders have been interpreted by some observers as substantial milestones: for example, the news and editorial staff of Science voted the ‘decoding’ of mental illness as the second most important scientific breakthrough of 2003 [26]. Some caution, however, is warranted with respect to the interpretation of such findings, many of which have either failed to meet rigorous standards for statistical

Gene–environment interactions and association studies

Most observers assume that understanding human behavior requires consideration of nurture as well as nature; one benefit of association studies in population samples is that such samples are suitable for examining gene–environment interactions. Caspi et al. [28] conducted an association analysis between MDD and a single promoter polymorphism in the serotonin transporter. Numerous studies have tested for such an association, with equivocal results [29]. This study differs from the others in two

Linkage studies

Recent linkage studies of major psychiatric disorders have attempted various strategies to compensate for uncertainties regarding clinical phenotypes. There is a trend towards accruing larger samples, to ‘overpower’ complexity. For example, a recent report [31^•] identified significant evidence for a gender-specific locus for MDD, a notoriously heterogeneous trait, on chromosome 12q, using a sample of 1,890 individuals from 110 Utah pedigrees. Other studies have attempted to combine samples from

Candidate genes identified by mapping studies

Success in identifying prospective disease genes has been most apparent in mapping studies of SZ; efforts are underway to understand the expression and physiologic function of the identified candidates. The identification of G72 as a risk factor for SZ, for example, has led to investigation of an associated enzyme, D-amino-acid oxidase, and to speculation that these genes may both contribute to SZ risk via pathology in the NMDA receptor pathway [38]. This same locus (13q 33) has also been

Conclusions

The studies reviewed here reiterate the fact that decades of research have not established the biological validity of current psychiatric diagnostic categories. Nevertheless, there is cause for increased optimism that we may soon identify genetic variants associated with particular behavioral phenotypic features. These recent investigations indicate a variety of promising developments including the accumulation of large, and therefore powerful, study samples, the application of new phenotyping

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

•
of special interest
••
of outstanding interest

Acknowledgements

This project was supported by National Institutes of Health grants R01 MH49499, R01 NS37484, R01 NS40042 and 2K02 MH01375.

References (55)

T.D Cannon et al.
Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia
Proc Natl Acad Sci USA
(2002)
P Svenningsson et al.
Diverse psychotomimetics act through a common signaling pathway
Science
(2003)
J Fullerton et al.
Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism
Am J Hum Genet
(2003)
C.E Glatt et al.
Association analysis of candidate genes for neuropsychiatric disease: the perpetual campaign
Trends Genet
(2002)
J.B Potash et al.
Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder
Am J Psychiatry
(2003)
C Garner et al.
Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method
Am J Hum Genet
(2001)
E Hattori et al.
Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series
Am J Hum Genet
(2003)
W Hennah et al.
Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects
Hum Mol Genet
(2003)
Y Ozeki et al.
Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth
Proc Natl Acad Sci USA
(2003)
H Stefansson et al.
Neuregulin 1 and susceptibility to schizophrenia
Am J Hum Genet
(2002)

P.F Sullivan et al.

Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies

Arch Gen Psychiatry

(2003)

K.S Kendler et al.

The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women

Arch Gen Psychiatry

(2003)

Cited by (44)

Subcortical brain volumes, cortical thickness and cortical surface area in families genetically enriched for social anxiety disorder – A multiplex multigenerational neuroimaging study
2018, EBioMedicine
Social anxiety disorder (SAD) is a disabling psychiatric condition with a genetic background. Brain alterations in gray matter (GM) related to SAD have been previously reported, but it remains to be elucidated whether GM measures are candidate endophenotypes of SAD. Endophenotypes are measurable characteristics on the causal pathway from genotype to phenotype, providing insight in genetically-based disease mechanisms. Based on a review of existing evidence, we examined whether GM characteristics meet two endophenotype criteria, using data from a unique sample of SAD-patients and their family-members of two generations. First, we investigated whether GM characteristics co-segregate with social anxiety within families genetically enriched for SAD. Secondly, heritability of the GM characteristics was estimated.
Families with a genetic predisposition for SAD participated in the Leiden Family Lab study on SAD; T1-weighted MRI brain scans were acquired (n = 110, 8 families). Subcortical volumes, cortical thickness and cortical surface area were determined for a-priori determined regions of interest (ROIs). Next, associations with social anxiety and heritabilities were estimated.
Several subcortical and cortical GM characteristics, derived from frontal, parietal and temporal ROIs, co-segregated with social anxiety within families (uncorrected p-level) and showed moderate to high heritability.
These findings provide preliminary evidence that GM characteristics of multiple ROIs, which are distributed over the brain, are candidate endophenotypes of SAD. Thereby, they shed light on the genetic vulnerability for SAD. Future research is needed to confirm these results and to link them to functional brain alterations and to genetic variations underlying these GM changes.
Leiden University Research Profile ‘Health, Prevention and the Human Life Cycle’.
Neurobiological candidate endophenotypes of social anxiety disorder
2016, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Thereby, the genes underlying the vulnerability for SAD are until now largely unknown. The search for SAD genes is complicated by the heterogeneity of the disorder and the fact that the diagnosis is based on clinical assessments and not on biologically-based measurements (Bearden et al., 2004; Glahn et al., 2007; Gottesman and Gould, 2003). In addition, SAD is a polygenic disorder: multiple genetic variants, each with a relatively small effect, interact and lead to disease vulnerability (Binder, 2012; Domschke and Dannlowski, 2010; Fox and Kalin, 2014).
Social anxiety disorder (SAD) is a disabling psychiatric disorder with a complex pathogenesis. Studies indicate a genetic component in the development of SAD, but the search for genetic mechanisms underlying this vulnerability is complicated. A focus on endophenotypes instead of the disorder itself may provide a fruitful path forward. Endophenotypes are measurable characteristics related to complex psychiatric disorders and reflective of genetically-based disease mechanisms, and could shed light on the ways by which genes contribute to the development of SAD. We review evidence for candidate MRI endophenotypes of SAD and discuss the extent to which they meet the criteria for an endophenotype, focussing on the amygdala, the medial prefrontal cortex, whole-brain functional connectivity and structural-anatomical changes. Strongest evidence is present for the primary endophenotype criterion of association between the candidate endophenotypes and SAD, while the other criteria, involving trait-stability, heritability and co-segregation of the endophenotype with the disorder within families, warrant further investigation. We highlight the potential of neuroimaging endophenotypes and stress the need for family studies into SAD endophenotypes.
Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD
2016, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Attention-deficit/hyperactivity disorder (ADHD), a neurobehavioral disorder affecting 12% of children and 5% of adults (Biederman et al., 2010), is characterized by increased impulsivity, hyperactivity and inattention (Bearden et al., 2004; Castellanos et al., 2005; American Psychiatric Association., 2013).
Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5 mg/kg) or water vehicle provided Monday-Friday from postnatal days 28–55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituted an adverse consequence associated with increased risk for cocaine abuse liability.
Sexual Dimorphisms in Psychosis Risk: A Neurodevelopmental Perspective
2015, Sex Differences in the Central Nervous System
Schizophrenia is a psychiatric disorder with early neurodevelopmental origins. Recent converging evidence points to sex differences among neurodevelopmental factors that give rise to, or reflect, compromises in central nervous system integrity, and play a role in risk for developing schizophrenia and other psychotic disorders. In this chapter we provide a cursory overview of sexual dimorphisms in clinical phenomenology, social cognition, social/role functioning (and their neurobiological underpinnings), and select key neurodevelopmental factors implicated in psychosis, as well as corresponding theoretical conceptualizations. Recent evidence also highlights the need for accurate early identification of persons at high risk for psychosis, during incipient stages prior to illness onset (the “psychosis prodrome”), with focus on preventive intervention. For this reason, we focus on the high-risk literature, toward maximizing our understanding of pathophysiology, and identifying sexually dimorphic putative biomarkers that precede illness onset. We briefly discuss clinical implications of the findings and bolster the case for additional carefully designed studies that directly and comprehensively investigate (sex-dependent and sex-specific) sexual variation in psychosis risk.
Genetic influence on the working memory circuitry: Behavior, structure, function and extensions to illness
2011, Behavioural Brain Research
Citation Excerpt :
Histologically, this model shows evidence of impaired development of dendrites, dendritic spines, and excitatory synapses in the hippocampus [79], as well as abnormal transcription of proteins related to synapse formation in prefrontal and hippocampal tissue [80]. These mice also display deficits in spatial WMem performance [81], much like patients with 22qDS do [71]. Critically, Sigurdsson et al. [81] recently demonstrated that these behavioral WMem impairments are associated with abnormal, long-range synchronization in a fronto-temporal learning and memory circuit.
Working memory is a highly heritable complex cognitive trait that is critical for a number of higher-level functions. However, the neural substrates of this behavioral phenotype are intricate and it is unknown through what precise biological mechanism variation in working memory is transmitted. In this review we explore different functional and structural components of the working memory circuitry, and the degree to which each of them is contributed to by genetic factors. Specifically, we consider dopaminergic function, glutamatergic function, white matter integrity and gray matter structure all of which provide potential mechanisms for the inheritance of working memory deficits. In addition to discussing the overall heritability of these measures we also address specific genes that may play a role. Each of these heritable components has the potential to uniquely contribute to the working memory deficits observed in genetic disorders, including 22q deletion syndrome, fragile X syndrome, phenylketonuria (PKU), and schizophrenia. By observing the individual contributions of disruptions in different components of the working memory circuitry to behavioral performance, we highlight the concept that there may be many routes to a working memory deficit; even though the same cognitive measure may be a valid endophenotype across different disorders, the underlying cause of, and treatment for, the deficit may differ. This has implications for our understanding of the transmission of working memory deficits in both healthy and disordered populations.
Dietary methyl donor deficiency during pregnancy in rats shapes learning and anxiety in offspring
2011, Nutrition Research
Two important lines of research have enhanced our understanding of the molecular role of nutrition in influencing behavior. First, exposure to an adverse environment during early life can influence the long-term behavior of the offspring. Second, regulation of the nervous system development and functioning appears to involve epigenetic mechanisms that require a continuous supply of methyl group donors in food. We hypothesized that a maternal diet during pregnancy deficient in methyl donors (MDD) may lead to altered behavior in offspring through permanent changes in hippocampal DNA methylation. We used a rat model of prenatal dietary MDD to test this hypothesis in female offspring as they aged. Prenatal MDD reduced birth weight, litter size, and newborn viability. Aged female offspring of MDD mothers showed increased anxiety and increased learning ability in comparison with control diet group offspring. To explore the role of MDD on epigenetic mechanisms in the brain of adult offspring, we studied expression and methylation of 4 selected genes coding for glucocorticoid receptor, hydroxysteroid dehydrogenase 11 type 2, neuronatin, and reelin proteins in the hippocampus. No major group differences in methylation or expression of the studied genes were detected, except for a significant down-regulation of the reelin gene in the MDD female offspring. The prenatal MDD diet caused intrauterine growth restriction, associated with long-term effects on the behavior of the offspring. However, the observed behavioral differences between the MDD and control diet offspring cannot be explained by epigenetic regulation of the specific genes investigated in this study.

View all citing articles on Scopus

View full text

Why genetic investigation of psychiatric disorders is so difficult

Abstract

Introduction

Section snippets

Genetic epidemiology

Endophenotypes

Animal models

Genetic mapping of behavioral traits

Gene–environment interactions and association studies

Linkage studies

Candidate genes identified by mapping studies

Conclusions

References and recommended reading

Acknowledgements

Proc Natl Acad Sci USA

Science

Am J Hum Genet

Trends Genet

Am J Psychiatry

Am J Hum Genet

Am J Hum Genet

Hum Mol Genet

Proc Natl Acad Sci USA

Am J Hum Genet

Am J Hum Genet

Proc Natl Acad Sci USA

Synapse

Proc Natl Acad Sci USA

Proc Natl Acad Sci USA

Am J Med Genet

The human phenome project

Nat Genet

Gene expression profiling of depression and suicide in human prefrontal cortex

Neuropsychopharmacology

Differences in early childhood risk factors for juvenile-onset and adult-onset depression

Arch Gen Psychiatry

Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish Adoptive Family Study of Schizophrenia

Am J Psychiatry

Familial aggregation of delusional proneness in schizophrenia and bipolar pedigrees

Am J Psychiatry

A twin study of genetic relationships between psychotic symptoms

Am J Psychiatry

Hierarchy and heritability: the role of diagnosis and modeling in psychiatric genetics

Am J Psychiatry

The Roscommon Family Study. IV. Affective illness, anxiety disorders, and alcoholism in relatives

Arch Gen Psychiatry

The heritability of bipolar affective disorder and the genetic relationship to unipolar depression

Arch Gen Psychiatry

Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies

Arch Gen Psychiatry

The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women

Arch Gen Psychiatry