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Irritability has been proposed to underlie the developmental link between oppositional problems and depression. However, little is known about the genetic and environmental influences on irritability and its overlap with depression. This paper tests the hypothesis that the association between irritability and depression is accounted for by genetic factors. As such, it draws on the notion of “generalist genes” i.e., genes of general effect that underlie phenotypic overlap between disorders.
The G1219 study, a UK-based twin sample (N=2651), was used in a cross-sectional and longitudinal design. Irritable and headstrong/hurtful dimensions of oppositional behavior were derived using factor analysis. Regression was used to estimate the association between depression and delinquency. Multivariate genetic analyses were used to estimate the genetic overlap between irritability versus headstrong/hurtful behaviors with depression and delinquency respectively.
Irritability showed a significantly stronger phenotypic relationship with depression than delinquency, whereas headstrong/hurtful behaviors were more strongly related to delinquency than depression. In multivariate genetic analyses, the genetic correlation between irritability and depression (0.70; CI: 0.59-0.82) was significantly higher than that between irritability and delinquency (0.57; CI: 0.45-0.69); conversely, the genetic correlation between headstrong/hurtful behaviors and delinquency (0.80; CI: 0.72-0.86) was significantly higher than that between headstrong/hurtful behaviors and depression (0.46; CI: 0.36-0.57). In longitudinal models, the phenotypic association between irritability at Time 1 and depression at Time 2 was accounted for by the genetic association between irritability and depression at Time1.
The findings are consistent with the theory that genes with general effects underlie the relationship between irritability and depression.
Irritable mood, a common and impairing symptom in psychopathology 1-3, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adults 4, 5. However, little is known about the genetic and environmental influences on irritability and its overlap with psychiatric disorders. This paper uses a twin sample to test the hypothesis that the association of irritability and depression is due to genetic factors.
An unexplained aspect of developmental psychopathology concerns the transition from disruptive behavior problems to mood and anxiety problems 6. A striking example is the recent finding that oppositionality in youth is a potent predictor of depression in young adult life, over and above depression in early life 7. It has recently been proposed that irritable mood may explain this transition from oppositionality to later depression 5, 7, 8. Data suggest that oppositionality in youth comprises at least two dimensions with differential predictions9-12: an irritable dimension, more strongly associated with depressive disorders than with antisocial behaviors; and a headstrong/hurtful dimension, (capturing argumentative, rule breaking alongside spiteful behaviors), more strongly associated with antisocial behaviors than depressive disorders 5, 11, 12. These differential associations have been demonstrated in a series of longitudinal studies spanning childhood into adulthood 5, 11.
It remains unknown whether such differential phenotypic links are accounted for by genetic or environmental factors. For example, is the overlap between irritability and depression accounted for by one set of shared genes, whilst a different set of genes explain the link between headstrong/hurtful behaviors and antisociality? Previous genetic studies have found that genetic factors may have broader influences than initially thought; indeed so called “generalist genes” are thought to explain the association between closely linked phenotypes 13, 14. An alternative explanation for such phenotypic overlap lies in the realm of overlapping environmental factors. Family- or person-specific environmental influences may be associated with both irritability and depression and thus underlie their relationship, while a different set of such overlapping environmental risks may underlie the relationship of headstrong/hurtful behaviors with antisociality. Answering these questions would help understand the mechanisms underlying these key developmental pathways.
This paper uses a genetically-informative design to address these questions. We begin by examining phenotypic links between the two components of oppositionality (irritability and headstrong/hurtful behaviors) and depressive problems and antisocial behaviors. Consistent with previous findings, we predict a double dissociation, such that adolescent irritability will show differential concurrent and longitudinal relationships to depressive problems, while headstrong/hurtful behaviors will be specifically related to antisocial outcomes. We use young people’s self-reports, thus complementing previous work based on parent- and teacher report 5, 11, 12 and re-examining previous negative findings5 about the relationship between self-reported irritability and psychopathology. Focusing on adolescence offers the additional advantage that the differential relationships of irritability can be tested at a time when adult mood problems are emerging 15 and antisocial behaviors reach a peak 16.
In the next step, we use multivariate twin modelling to test the paper’s main hypothesis that the genetic findings will show a double dissociation consistent with the phenotypic findings. We expect that genetic factors shared between irritability and depression underlie their phenotypic association and, similarly, that genetic factors shared between headstrong/hurtful and antisocial behaviors explain their phenotypic association. This prediction is based on the notion of “generalist genes”, which are hypothesized not to be disorder specific, but, rather, to exert wider effects giving rise to closely linked behavioral 17 or cognitive phenotypes 13, 14. Indeed, we have recently provided further empirical evidence in support of this theory by showing substantial genetic links between cognitive bias, depression, and anxiety problems18.
Data from the G1219 sample were used as previously described 18. This is a longitudinal study of 3640 adolescent twins and siblings (age range 12-19 at initial contact). Analyses here focus on the second and third waves of the data collection. Data collection for waves 2 and 3 (from hereon referred to as time 1 and time 2) respectively took place approximately 8 (range: 0–24 months) and 33 months (range 24–60 months) after initial contact. At time 1, data were available from 2651 individuals (73% of the original sample at wave 1) whilst corresponding figures for time 2 were 1597 adolescents (44% of the original sample at wave 1). Zygosity was established through a questionnaire measure completed by mothers. The sample consists of 118 monozygotic male, 199 monozygotic female, 138 dizygotic male twin pairs, 190 dizygotic female, 463 opposite-sex dizygotic twin pairs and 109 male sibling pairs, 132 female sibling pairs and 186 opposite-sex sibling pairs. At times 1 and 2, the proportions of boys were 43.9% and 41.3% respectively. The mean ages at times 1 and 2 were 15 years (range12–21) and 17 years (range 14–23). To handle the effects of initial response and attrition bias, a single weighting variable was included in all genetic analyses as previously described 18. Informed consent was obtained from parents/ guardians of all adolescents under 16 years, and from the adolescents themselves when over 16. Ethical approval was provided by the Research Ethics Committees of the Institute of Psychiatry, South London and Maudsley NHS Trust, and Goldsmiths, University of London.
Depressive symptoms were rated by self report using the Short Mood and Feelings Questionnaire (19-21). At time 1, a four-point response format (never to always) was used to allow for discrimination at the lower end of the spectrum. The standard three-point scale was used at time 2.
Using the ASEBA family of instruments22, 23, we formed a delinquency scale from 11 items as previously described24 that capture lacks guilt, deviant peers, lying, preferring older peers, running away from home, setting fires, stealing, swearing, truanting, and use of alcohol/drugs.
Items used to define dimensions of oppositionality were drawn from the Youth Self Report22 (YSR, Ages 11-18) and the Adult Self Report23 (ASR, Ages 18-59) of the ASEBA family of instruments. At time 1, we used the following items from the YSR: Argue a lot, mean to others, destroy others’ things, disobey parents, disobey at school, have a hot temper, tease others a lot, stubborn, mood/feelings change suddenly. The last item was included on the basis that mood lability is a commonly used term to describe chronic irritability 25. At time 2, we used comparable items with the exception that they did not include the item disobey parents, and the item stubborn was rephrased as stubborn, sullen, or irritable.
At each wave, we conducted exploratory factor analyses using the oppositionality items with weighted least squares estimation (due to the categorical nature of the items) on a random half of the dataset. These yielded two factors with eigenvalues ≥ 1, corresponding to previously described dimensions of oppositionality10-12, 26. Table 1 shows that (with the exception of the cross-loading argue a lot item), all items loaded clearly on either the irritable (have a hot temper, stubborn (time 1) or stubborn, sullen or irritable (time 2) mood/feelings change suddenly) or the headstrong/hurtful (disobey parents (only available at time 1),mean to others, destroy others’ things, disobey at school, tease others a lot) factors.
We note that although the ASR item ‘stubborn, sullen or irritable’ would be expected to load on the irritability dimension, the YSR version of that item (simply labelled ‘stubborn’) might be more ambiguous, and reflect headstrong as well as irritable tendencies. Although both versions of the item loaded clearly and consistently on the irritable dimension in the factor analyses, we re-ran all the main analyses excluding this item (as detailed below) to ensure any potential ambiguity did not bias the study’s results.
The results of the exploratory factor analyses were further tested in confirmatory factor analyses in the other half of the sample. A single factor model—in which all the items would load—was compared to the two factor—irritable and headstrong/hurtful—model derived by exploratory factor analysis. All fit indices from maximum likelihood estimation and the χ2 difference score in weighted least squares estimation indicated a better fit for the two-factor versus the single factor model, (Supplementary Table 1 of the appendix). The Cronbach alpha coefficients were 0.67 (time 1) and 0.55 (time 2) for the headstrong/hurtful and 0.61 (time 1) and 0.66 (time 2) for the irritable dimension.
Cross-sectional associations between variables were explored using correlation and robust regression with either depression or delinquency as the outcome and both dimensions of oppositionality entered simultaneously as predictors. Longitudinal associations between the dimensions of oppositionality at time 1 and psychopathology at time 2 were examined using regression models adjusting for the dimensional psychopathology score measured at baseline. For example, where depression scores at time 2 were the outcome, the predictors were the two dimensions—irritable and headstrong/hurtful behavior—at time 1 and the depression scores at time 1. Robust standard error (sandwich) estimators27 were used to account for dependence of twin observations.
The twin design compares the degree of similarity among monozygotic (sharing 100% of their genes), and dizygotic twins (sharing on average 50% of their genes). Relative differences in within-pair correlations are used to estimate additive genetic (A), shared environmental (C), and non-shared environmental (E) effects on measures.
Variables were regressed for age and sex as is standard practice for quantitative genetic model fitting. Variables were transformed to ensure all skew statistics were between the range of 1 and −1.
Models were fitted in the Mx program28 using raw data maximum likelihood, with weighting corrections to account for selective attrition. The fit statistic provided for raw data modelling (twice the log likelihood [−2LL]) of the observations was used to compare the fit of the genetic model to that of a saturated model. Following parsimony, the fit of sub-models was assessed by χ2 difference tests and the Akaike’s Information Criterion (χ2 – 2df), with lower χ2 values and more negative Akaike values indicating a better fit.
We used multivariate genetic models to test the paper’s hypotheses using both cross-sectional and longitudinal approaches.
In the first, cross-sectional step, we interpreted a Cholesky decomposition as a correlated factors solution to examine whether the genetic findings mirrored the phenotypic associations. We tested whether: a) genetic overlap between irritability and depression is stronger than that between headstrong/hurtful behaviors and depression; and b) genetic overlap between headstrong/hurtful behaviors and delinquency is stronger than that between irritability and delinquency.
In the second, longitudinal, step we used trivariate (3-variable) and then quadrivariate (4-variable) Cholesky decomposition models. The purpose of the trivariate model was to investigate whether any genetic or environmental relationships remained between irritability at Time 1 and delinquency at Time 2 on the one hand, and headstrong/hurtful behaviors at Time 1 and depression at Time 2 on the other, after accounting for headstrong/hurtful behaviors and irritability (both at Time 1) respectively. The quadrivariate Cholesky models additionally adjust for depression at Time 1 when examining depression at Time 2 as an outcome and for delinquency at Time 1 when examining delinquency at Time 2 as an outcome.
Irritability was significantly higher in girls than in boys (2.27+1.57 vs 1.86+1.54, t=6.6, p<0.001) and headstrong/hurtful behaviors were more common in boys than girls (1.84+1.85 vs 1.38+1.53, t=6.9, p<0.001).
The correlations between the study’s main variables are shown in Table 2. Inspecting the coefficients and confidence intervals, irritability showed a stronger association with depressive ratings than did headstrong/hurtful behaviors. Conversely, headstrong/hurtful behaviors showed a stronger association with delinquency than did irritability. Figure 1a shows the findings of cross-sectional robust regression models, with either depression or delinquency as the outcome and with the two dimensions of oppositionality entered simultaneously as predictors. It illustrates a double dissociation, in which irritability is significantly more strongly associated with depression than with delinquency, whereas, in contrast, headstrong/hurtful behaviors are significantly more strongly associated with delinquency than with depressive problems. Controlling for gender and age did not alter the pattern of the results.
Longitudinal robust regression models showed the same pattern. Irritability, but not headstrong/hurtful behaviors, at time 1 was a significant predictor of self-reported depression symptom scores at time 2, after controlling for self-reported depression symptom scores at time 1 (0.14 [0.08 to 0.20] and 0.01 [−0.05 to 0.07] respectively. Conversely, headstrong/hurtful behaviors, but not irritability, were significant predictors of self-reported delinquency scores at time 2, even after adjusting for self-reported delinquency scores at time 1 (0.19[0.12 to 0.27] and 0.05 [−0.00 to 0.10] respectively). The pattern of results was unchanged when the reduced irritability scale (omitting the ‘stubborn’ item) was used instead (Suppl. Table 2).
Genetic overlap between irritability and both depression and delinquency was first assessed cross-sectionally. A saturated model was fit which estimates variances, covariances and means for the raw data to get a baseline index of fit (χ2=22733.580, df=9337). Subsequent models were compared to the saturated model to determine the best fitting model. We found that a model without sex differences in A, C and E parameters but allowing for variance difference across the sexes, fit the data best (χ2=22848.251, df=9648, p=<0.01 Akaike information criterion=-155.481). However, shared environment was small and non-significant; we therefore present results from an AE model.
Heritability ranged from 0.31 for irritability to 0.56 for delinquency, shown in the diagonal of Table 3. Genetic correlations (shown in the off diagonals of Table 3 and in figure 1b) ranged from 0.46 (between headstrong/hurtful behaviors and depression) to 0.80 (between headstrong/hurtful behaviors and delinquency). Genetic correlations between headstrong/hurtful behaviors and depression (0.46) were significantly lower than between headstrong/hurtful behaviors and delinquency (0.80). Genetic correlations between irritability and delinquency were significantly lower (0.57) than between irritability and depression (0.70). These results didn’t change when using the time 2 data, with the exception that the genetic correlations between irritability and delinquency did not differ significantly from those between irritability and depression (Suppl Table 3).
Next, we explored the extent to which longitudinal genetic associations showed a similar pattern to the phenotypic associations. We first explored whether there was shared genetic variance between headstrong at Time 1 and depression at Time 2, over and above the genetic association already identified between each of these variables and irritability at Time 1. This is akin to testing whether there is a partial genetic correlation between headstrong/hurtful behaviors and depression that accounts for their longitudinal association, independent of associations with irritability. Similarly we tested whether there was any shared genetic variance between irritability at Time 1 and delinquency at Time 2 independent of headstrong/hurtful behaviors at Time 1. To test this we used two separate trivariate Cholesky models. The results are shown in Figures 2a and and2b.2b. Headstrong/hurtful behaviors at Time 1 and depression at Time 2 shared no genetic variance after accounting for irritability at Time 1 (Figure 2a). Similarly, irritability at Time 1 and delinquency at Time 2 shared no genetic variance after accounting for headstrong/hurtful behaviors at Time 1 (Figure 2b). Again these remain unchanged when the ‘stubborn’ item was omitted from the irritability scale (see Suppl. Figures 1a and b).
We then asked whether the genetic relationship between irritability at Time 1 and depression at Time 2 was explained through shared genetic effects between irritability and depression at Time 1. As shown in Figure 3a, the genetic association between irritability and depression at Time 1 fully accounted for the longitudinal association between irritability at Time 1 and depression at Time 2. Similarly, the relationship between headstrong/hurtful behaviors at Time 1 and delinquency at Time 2 was explained through the genetic association of headstrong/hurtful behaviors and delinquency at Time 1 (Figure 3b).
Several new findings emerge from this paper about the phenotypic and genetic correlates of irritability. Heritability of irritability by adolescent self report is relatively low, consistent with previous data in adults 29. Phenotypically, irritability was specifically related to subsequent depressive symptoms, whereas the headstrong/hurtful dimension was associated with delinquency. The paper’s main hypothesis was that the same pattern of double dissociation would be found in the multivariate genetic analyses, and this was found to be the case. The genetic relationship between headstrong/hurtful behaviors and depression was entirely due to the overlap with the irritable dimension. Conversely, the genetic relationship between irritability and delinquency was entirely due to the overlap with headstrong/hurtful behaviors. Also, the concurrent genetic relationship between irritability and depression at Time 1 accounted for the genetic relationships between irritability at Time 1 and depression at Time 2. The same pattern of results was found for the relationship between headstrong/hurtful behaviors at Time 1 and delinquency at Time 2. In previous longitudinal analyses10-12, 26, headstrong items have been shown to be differentially strongly related to ADHD and conduct problems, whereas hurtful items were preferential predictors of more aggressive conduct problems and callous and unemotional traits. However, in this paper, headstrong and hurtful emerged as a common factor, in keeping with another recent epidemiologic study10, possibly reflecting the limited number of items available.
Irritability has traditionally been studied in the context of antisocial behavior in both early life and adult studies 30, 31. However, it is debated whether disruptive behaviors form a unitary construct. Consistent with our previous findings 5, 11, 12, we show that the relationship between irritability and antisociality may be because of their correlation with headstrong/hurtful behaviors. Our findings support a model whereby irritability is linked with depression, forming part of a nexus of negative mood with common genetic underpinnings. The finding that strong phenotypic links between syndrome constellations or disorders may be explained by genetic, as opposed to environmental, overlap is consistent with prior theory 13, 14 and empirical data 18.
Our findings have numerous implications. First, they are relevant for understanding developmental transitions. Recent evidence suggests that oppositional behaviors are the most robust early predictors of depression in young adult life 4, even after adjusting for conduct disorder or early depression. Our findings go a step further by showing that the relationship between oppositional problems and depressive symptoms may be due to the irritability component of oppositionality, rather than to disruptive headstrong and hurtful behaviors. The findings of this study are based on adolescent self report and thus extend previous findings based on parent and teacher report5, 11, 12. In contrast to the present study, in past work we did not find that self reported irritability predicted psychiatric disorders5. These different findings might be due to the considerably smaller size of the previous study, differences in length of follow up, and the different instruments used.
Second, our findings may have implications about the aetiology of depression. We found that the relationship between irritability and depression is largely explained by common genes. By contrast, we found only a small overlap in non-shared environmental factors between irritability and depression. It will be important to characterize the shared genetic mechanisms between irritability and depression, which may include affective processing mechanisms.
Third, our findings support clinical notions that irritability is a presenting symptom of depression, and that patients presenting with irritability should be screened carefully for depression2, 32-34. This thinking is reflected in the youth, but not adult, criteria for depression in the DSM-IV. Whether treatments targeting irritability would treat and/or prevent depressive symptoms is a topic for future research.
This study has several limitations. First, there was considerable attrition at follow up. However, while attrition bias poses a problem for estimating prevalences, it is less likely to bias associations between variables 35. Second, the study relied on an existing measure out of which the irritability and headstrong/hurtful items were extracted. However, the modest internal consistencies of the scales would reduce the power of detecting differences. Given the double dissociations we found in this study, it seems unlikely that internal consistency has had differential effects on the study’s results. Third, our use of age-appropriate versions of the ASEBA scales (ref) at times 1 and 2 meant that one item in the irritability scale was differently worded at the two study sweeps (‘stubborn, sullen or irritable’ at time 2, ‘stubborn’ at time 1). Although both versions of this item loaded clearly and consistently on the irritability factor, we repeated all the main analyses excluding this item to ensure that any potential ambiguity in the simpler (time 1) wording had not biased the findings. All of the key findings remained unchanged.
In summary, our findings provide further evidence that irritable mood may underlie the relationship between oppositionality and depression and suggest that the association between irritability and depression is due to genetic overlap.
A typical presentation of a young person scoring high on irritability would be:
Jack is a 15 year-old boy who reports having difficulties controlling his feelings of anger. He describes often feeling annoyed “at everyone and everything” right from the start of the day and mostly for no apparent reason. He has frequent arguments with his girlfriend where he can go “into a right rage” and stay like that for hours after that. He tells you that “it feels weird” to be so angry, but is not sure what to do about it.
A typical presentation of a young person scoring high on headstrong/hurtful would be:
Alfie is a 16 year-old boy who openly tells you that he “couldn’t care less” about rules recently laid out for him at school. He describes how he gets antagonistic in his relationships to other young people at school and that he thinks some of them are “plainly stupid” and that he has no problem telling them so. He tells you how he recently splashed water on his sister’s iPod because she “deserved it”.
It should be noted that irritability and headstrong/hurtful should be seen as dimensions, rather than separate diagnostic categories. This has two implications. Firstly, such behaviours shouldn’t necessarily be seen as pathological. Secondly, young people may show behaviors from both dimensions (as indicated by the fact that irritability and headstrong/hurtful are correlated dimensions) and outcomes may depend on the relative mix of intensity of these two dimensions