Trends in Genetics
Endophenotypes for psychiatric disorders: ready for primetime?
Section snippets
The need for a new approach to psychiatric genetics
The inherent imprecision of psychiatric phenotyping might be the most important factor contributing to the failure of genetic investigations to identify any genes that unequivocally contribute to susceptibility to psychiatric disorders 1, 2. Unlike other areas of medicine, psychiatry has no biochemical markers or anatomic variants on which to base its diagnoses. Instead, subjective assessments form the basis of both clinical and research psychiatric diagnoses, including those used to define the
Are there necessary and sufficient criteria for a viable endophenotype?
Recently, several publications in the psychiatric literature have catalogued criteria for evaluating the validity and utility of putative endophenotypic markers (Table 1). Some criteria are universally agreed, whereas others are more controversial. Although it is difficult to specify a priori which criteria are most important, we propose tentative guidelines to assist in such endeavors. The conditions that we believe to be both necessary and sufficient for a useful endophenotype, with
Reliability and reproducibility of candidate endophenotype findings
We concur that one of the primary requirements for an endophenotype to be widely adopted is that it be reliably assessed [9]. Although it is generally assumed that endophenotypic measures have better reliability – the accuracy of the scores of a measure – and are more ‘objective’ than psychiatric diagnoses, this has not been adequately evaluated for many candidate endophenotypes commonly cited in the literature. Assessment of reliability involves both multiple assessments of the same subject
Heritability of candidate endophenotypes
Endophenotypes must be sufficiently heritable to be mapped through genome-wide analysis, either by linkage or association. Currently, only sparse data exist regarding the heritability of many proposed candidate endophenotypes [4]. For example, dysfunctional temporal processing is implicated in core deficits in time estimation in individuals with attention-deficit hyperactivity disorder (ADHD). This trait has been linked to cerebellar dysfunction, and is thus considered to be an attractive
Developing coherent sets of candidate endophenotypes
The features of disease phenotypes can typically be conceptualized in terms of broad functional domains. For example, bipolar disorder (BP) involves disturbances of mood, attention, interpersonal function, and activity levels and patterns. Symptoms in these various functional domains can be associated with abnormal anatomic findings in brain regions implicated in these functions. Comprehensive endophenotype batteries for BP must therefore assay all of these relevant variables. Table 2
The specificity of endophenotypes and their association with categorical disease phenotypes
Some investigators 18, 19 have suggested that the utility of potential endophenotypes depends on how specific they are for a particular disorder. Although one interpretation of findings of common endophenotypes across disorders is, of course, that the trait in question represents a nonspecific indicator of brain dysfunction (e.g. attentional impairment), such a finding might also signal common underlying neurobiological substrates [20]. For example, there is increasing evidence that some genes
Analytic guidelines for genetic investigation of endophenotypes
As with categorical phenotypes, it is important to employ rigorous criteria for evaluating the statistical significance of linkage and association studies using endophenotypes. There has been considerable recent attention paid to the problem of false positive results for association studies of single candidate genes; in large part this problem reflects the low prior probability that any specific gene is associated with a given trait, whether a disease phenotype or an endophenotype.
Multivariate approaches
Some QTL signals might only be detectable when endophenotypic variables are combined. Although multivariate approaches are gaining more attention as genetic studies increasingly obtain multiple types of phenotypic data, there is no consensus about the most effective means to combine such information.
One strategy for dealing with numerous measured traits is to first focus on those that demonstrate the greatest heritability. The creation of a correlation matrix of all variables measured in a
The use of endophenotypes in the study of non-psychiatric complex traits
It is useful to compare candidate endophenotypes proposed thus far in the field of psychiatric genetics with those that have been used in the investigation of non-psychiatric complex disorders. Asthma is an example of a common, multiply determined disorder, the development of which is related to both genetic and environmental factors. Asthma is characterized by the production of high levels of immunoglobulin E (IgE) in response to common allergens. Atopy, which refers to the presence of
Future directions
Our comments thus far have focused on steps to improve the utility of currently identified endophenotypes in humans, using standard approaches. Two examples of recent developments that can further enhance the informativeness of endophenotype investigations are given below.
Concluding remarks
Because DSM-IV psychiatric diagnoses are based on clusters of symptoms that do not necessarily describe homogenous disorders, this classification system undoubtedly contributes to the difficulties in finding genes for psychiatric disorders 42, 47, 48. It is important to ensure that the ‘new wave’ of endophenotype investigations does not succumb to the same pitfalls, by virtue of poorly selected candidate endophenotypes.
Acknowledgements
This work was partly supported by NIMH K23MH074644-01 (to C.E.B.), K02MH001375 and R01MH049499 (to N.B.F)
Glossary
- Bipolar disorder:
- a psychiatric disorder formerly known as manic-depressive illness, usually involving extreme mood swings from periods of severe depression to periods of abnormally elevated mood (mania). Symptoms of mania can also include irritability, an overly-inflated sense of self-esteem and distractibility. Persons experiencing an episode of mania are generally talkative, have decreased need for sleep and might engage in reckless or risk-taking behaviors.
- Categorical phenotype:
- a definition
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2019, Drug and Alcohol DependenceCitation Excerpt :The findings appear to be the strongest in high risk children when visual tasks are employed (Porjesz and Begleiter, 1990, 1998). Over time several lines of evidence have suggested that reduced P3 amplitudes in adults also may be associated with other psychiatric disorders that have significant comorbidity with AUD (see, for example: (Bearden and Freimer, 2006; Hasler et al., 2004; Iacono, 1998; Pfefferbaum et al., 1995; Pogarell et al., 2007)). More recently, several studies have used the technique of extracting event-related oscillations (EROs) from ERP data to develop additional and potentially more informative electrophysiological measures of alcohol-related psychopathology.