The results of the present analyses have important implications both for understanding the nature of child and adolescent psychopathology and for the design of future studies of etiology and pathophysiology.
Structure of Genetic Influences
The present findings support hypotheses derived from studies of adult twins based on categorical diagnoses of mental disorders5, 8
that two sets of pleiotropic genetic factors nonspecifically influence risk for all internalizing or all externalizing psychopathology dimensions during childhood and adolescence. Furthermore, the present findings are consistent with the new hypothesis that a set of highly pleiotropic genetic influences are globally associated to varying degrees with risk for all
11 prevalent forms of child and adolescent psychopathology. Furthermore, all psychopathology dimensions also are influenced by unique genetic factors with varying, but usually small magnitudes of effect. It is informative that some psychopathology dimensions had slightly more unique than shared genetic variance, but the estimates of unique genetic variance never exceed 55% of the total genetic variance for any dimension of psychopathology.
These findings strongly suggest that most additive genetic factors associated with variation in the common psychopathology dimensions in children and adolescents are not specific to each individual dimension of psychopathology. Rather, the three patterns of pleiotropy identified in these analyses appear to be the principal modes of genetic risk transmission for most of the 11 dimensions of child and adolescent psychopathology.
The present findings based on sharing of etiologic influences were not consistent with the hypothesis based on studies of mental disorders in adults that anxiety disorders and depression can be parsed into two correlated higher-order “distress” (MDD, dysthymia, GAD, and post-traumatic stress disorder) and “fears” (specific phobia, agoraphobia, social phobia, and panic disorder) domains.17, 35, 36
It is possible that separate higher-order fears and distress factors would have been identified in the present study had symptoms of post-traumatic stress disorder been assessed, but it also is possible that the distinction between the distress and fears domains only emerges in adulthood. Still, it is important to note that internalizing factor in and might be considered to be a “fears” factors because MDD and GAD did not load on it in the best-fitting models.
Structure of Environmental Influences
As shown in and , nonshared environmental influences jointly influenced multiple correlated psychopathology dimensions to a modest extent, but the majority of the nonshared environmental variance was unique for most dimensions. Exceptions are ODD, which was found to share half of its nonshared environmental variance with higher-order factors, and MDD and GAD, which had the highest loadings on the global E factor and small unique E variances. This suggests that nonshared environmental influences on MDD and GAD are mostly not unique to them in this age range.
Shared environmental influences were mostly near or at zero, with the exception of modest C for SAD and OCD. Correlations in C across dimensions were sometimes large, but the absolute magnitude of C that these disorders shared was small.
Taken together, these findings indicate that phenotypic correlations among dimensions of child and adolescent psychopathology are primarily, but not entirely, due to correlated additive genetic influences. This does not rule out the possibility of gene-environment correlations and interactions as sources of shared etiologic influences. This is because gene-environment correlations and gene-environment interactions with C are folded into estimates of A in biometric models, whereas gene-environment interactions with E are included in estimates of E.37, 38
Nonetheless, the present findings on child and adolescent psychopathology are generally consistent with Plomin's “generalist genes, specialist environments” hypothesis for cognitive abilities.39, 40
That is, pleiotropic genetic factors tend to promote correlations among phenotypes, whereas environments tend to promote their differentiation.
Implications for Taxonomy and Neurobiology
If the emerging view that common forms of psychopathology are best treated as dimensional phenomena which are dichotomized using data-based but conventional thresholds to facilitate treatment decisions is supported, the present findings have important implications for taxonomy. They support an etiologic explanation for the observation that child and adolescent psychopathology is phenotypically organized within the higher-order internalizing and externalizing domains.3, 15
As with adult psychopathology,8
we hypothesize that dimensions of child and adolescent psychopathology within both the internalizing and externalizing domains are highly correlated largely because they share genetic influences. Furthermore, the present findings suggest an etiologic explanation for the well-documented, but largely ignored, robust correlation between the internalizing and externalizing domains of psychopathology.2, 3, 15
That is, the broad construct of “psychopathology” may have a physical reality in the sense that all 11 psychopathology dimensions were found to share some of the same genetic influences, albeit to varying extents.
Limitations and Future Directions
The present findings are based on a standard method of combining symptom reports from multiple informants, but additional psychometric research is needed to compare alternative methods of doing so. Although the present findings were replicated using the parent informant only, other methods of combining reports from multiple informants could have yielded different results. Therefore, the paucity of knowledge on the optimal way to combine data from multiple informants is a limitation of the present study that would similarly limit other studies of child and adolescent psychopathology at present.
It is important to attempt to disconfirm the present hypotheses regarding the higher-order genetic structure of child and adolescent psychopathology in future studies for at least three reasons. First, consistent with previous recommendations,6
this hypothesis implies that rather than searching for genetic polymorphisms associated with psychopathology one disorder at a time, it should be far more informative to simultaneously search for networks of pleiotropic genetic factors associated with multiple forms of psychopathology (and for the dimension-specific genetic and environmental factors uniquely associated with each dimension of psychopathology). This would require measuring multiple phenotypes in each study (across both internalizing and externalizing domains) and conducting genetic association analyses that squarely address the likelihood of widespread pleiotropy. Although the field will eventually discover which genetic variants are associated with multiple psychopathology dimensions even if we mostly study mental disorders one at a time, the present hypothesis imposes a testable model on the data that should make gene discovery more efficient and revealing about the biological nature of psychopathology.
Second, there is evidence from the study of somatic characteristics that pleiotropic genes generally have stronger effects than other genes.41
This also could be true of genes that are pleiotropically associated with multiple psychopathology dimensions. Because the hypothesized global psychopathology genetic factor is related to many psychopathology dimensions (regardless of which symptoms are exhibited at any point in time), the association between each pleiotropic gene variant with higher-order psychopathology dimensions may be stronger than the association of the same variant with lower-order psychopathology dimensions. Indeed, there is evidence that the heritability of the higher-order latent externalizing factor could be almost twice that of lower-order dimensions.9, 10
Therefore, the likelihood of detecting gene variants associated with higher-order psychopathology dimensions may be greater than for lower-order dimensions.
Third, because gene variants associated with the higher-order phenotypes simultaneously influence multiple
psychopathology dimensions, they increase risk for comorbid
mental health problems. Therefore, it is particularly important to discover pleiotropic psychopathology risk genes because comorbid mental disorders are associated with more distress, functional impairment, persistence, and mental health service use than single disorders.42
It will be important to test the present etiologic hypothesis at the molecular level. In the present analyses, the genetic influences on each psychopathology dimension were latent, inferred from the analyses of twin pairs. If such participants are genotyped, however, it should be possible to directly estimate A from the measured polymorphisms, although the genotyping and statistical methodologies for doing so are still under development.43
In principle, A for each psychopathology dimension could be estimated from the sums of the varying magnitudes of association of all polymorphisms with that phenotype. The variance-covariance matrix of the A components for all psychopathology dimensions could then be computed and subjected to CFA to determine if the same higher-order factor structure fits the genetic data based on measured polymorphisms.
If the present hypothesis is supported at the molecular level, it would likely force a foundational shift in how the neurobiology of common forms of psychopathology is conceptualized. Genetic polymorphisms influence risk for psychopathology by encoding protein components of neurons and other relevant biological systems through a chain of processes. If many genetic polymorphisms are pleiotropically associated with variation in all psychopathology dimensions (and within the internalizing and externalizing domains) that would almost certainly mean that those correlated forms of psychopathology share many aspects of their genetically influenced pathophysiology. That is, in contrast to the dominant paradigm in which forms of psychopathology are studied singly as if each were neurobiologically unique, the present genetic hypothesis implies that patterns of dysfunction in neurobiological systems may be related to risk for multiple psychopathology dimensions, likely through transactions with the environment. In turn, this implies that neurobiological studies should consider both multiple neurobiological systems and multiple forms of psychopathology at the same time to identify both the common and dimension-specific mechanisms underlying psychopathology.