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Behav Genet

DOI 10.1007/s10519-011-9506-x

ORIGINAL RESEARCH

Two Sources of Genetic Liability to Depression:
Interpreting the Relationship Between Stress Sensitivity
and Depression Under a Multifactorial Polygenic Model
Xinying Li • Matt McGue • Irving I. Gottesman

Received: 13 April 2011 / Accepted: 12 September 2011
Ó Springer Science+Business Media, LLC 2011

Abstract Psychopathology theories, clinical observations, and research all point to multiple sources of liability
to depression. This article uses a longitudinal twin-study
design to characterize the contribution of two geneticallyinfluenced sources of depression risk: the first corresponding to stress sensitivity and the second representing
risk that is independent of stress sensitivity. The sample
consisted of 606 pairs of same-sex adolescent twins
recruited from Beijing, China. Mean (SD) age at intake
(Wave1) and follow-up (Wave2) was 13.2 (2.6) and 15.1
(2.6) years, respectively. A Reaction Level index was
developed to reflect individual differences in stress sensitivity. Biometric models were fit to examine the genetic
influence on the variance of and covariance between stress
sensitivity and depressive symptoms. Results showed that
both Reaction Level and depressive symptoms were moderately heritable. The genetic correlation between depressive symptoms and Reaction Level was estimated to be
.884. Genetic contributions to Reaction Level accounted
for 37.5% of the total variance of depressive symptoms.
Another set of genetic factors, which did not contribute to

Edited by Deborah Finkel.
X. Li
Key Laboratory of Mental Health, Institute of Psychology,
Chinese Academy of Sciences, Beijing, China
M. McGue  I. I. Gottesman
Department of Psychology, University of Minnesota,
Minneapolis, MN, USA
I. I. Gottesman (&)
Department of Psychiatry, University of Minnesota Medical
School, 2450 Riverside Ave, Minneapolis, MN 55454-1495,
USA
e-mail: gotte003@umn.edu

Reaction Level, accounted for 10.5% of the total variance
of depressive symptoms. We interpret our results within the
context of a multifactorial polygenic model, whereby
depression risk is due to the combined contribution of
multiple genetic and environmental factors.
Keywords China  Twins  Stress sensitivity 
Endophenotype  Depressive symptoms  Adolescence

After Caspi et al. (2003) reported an interaction effect of
life stress and 5-HTTLPR genotype on risk of depression,
the importance of G 9 E interactions in the etiology of
depression has been widely accepted, albeit with a few
exceptions (Eaves 2006). The resulting prominence G 9 E
research has gained within the field raises a practical
question concerning future genetically-informed research
on depression: Must all future genetic research on
depression be based on a G 9 E model or is there more to
be learned about the genetic contributions to depression
risk? In the current article we make the case that there is
still much to be learned about the nature of the genetic
influence on depression using traditional twin-study
designs. Specifically, we seek to determine how depression
and stress sensitivity are genetically related.
The multifactorial polygenic model (Gottesman and
Shields 1967, 1982) provides a conceptual foundation for
our research. In this model, which was originally put forward
for schizophrenia, Gottesman and Shields (1967, 1982)
proposed three sources of liability: a general environmental
liability, a specific genetic one and a general genetic one.
The specific genetic liability conveys a specific risk for the
development of schizophrenia, whereas the general genetic
liability would be a common background contributor to
many psychiatric disorders. The two genetic sources of

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two limitations of previous research should be addressed. Despite the supportive evidence. or depressive reactivity (e. For example. (2) The genetic contributors to stress sensitivity. we have followed Fowles (1992) and assessed stress sensitivity as an individual’s depressive reaction to SLEs. As expected. hormonal reactivity (Bale 2006). a methodology that allows for the comparison of individuals who experience different amounts of SLEs is needed. Caspi et al. similar notions have been proposed by others (Kendler et al. In the present study. which corresponds to the general genetic liability to depression within the multifactorial polygenic framework. 1995. empirical evidence is inconsistent and does not lead to definitive conclusions. including depression. although the association between SLEs and the risk of onset of a depressive episode decreases as the number of recurrent episodes increases (Burcusa and Iacono 2007). it still lacks a clear operational definition.. In the present study. For example.e. a methodology that allows for the separate investigation of depression risk mediated through stress reactivity and independent of stress reactivity is needed. 2001). 2003). The first one. 331 pairs were female twins . Among them. Taken together. Consistent with this notion. 2001). co-twin affected) (Kendler et al.. although psychopathology theories and some research results suggest the existence of two sources of genetic liability to depression.g. McGuffin et al. (1988) investigated individuals from 83 families ascertained through clinically depressed probands. China. Thus. 2003). Second. serve as part of genetic component of depressive symptoms. This result was replicated in another study (Kendler et al. For example. would yield a systems-based appreciation of total risk. which together with epigenetic (Haque et al. The latter would be offset by genetic and environmental assets. 1988). Clues for the two sources of genetic liability have long been noticed in both clinical practice and scientific research.Behav Genet liability combine in some fashion to yield a combined genetic liability. monozygotic twin. corresponding to the general genetic liability in the multifactorial polygenic model. Regarding the etiology of depression. In extending this framework to depression. (3) There will also be a specific genetic liability to depression. this phenomenon was weak to absent among individuals with high genetic background (e. stress sensitivity) represents a general genetic liability for multiple psychiatric disorders. corresponding to the specific genetic liability in the multifactorial polygenic model. Methods Sample This study is based on data from an ongoing longitudinal study of adolescent behavioral and emotional disorders conducted in Beijing. 2009) and stochastic factors (Woolf 1997). 2009). 2007. the risk of onset of major depression for individuals with a high genetic background (monozygotic twin. we focused on 606 pairs of same-sex twins who joined the study in 2007 (Wave1). which is independent of stress sensitivity. The second line of evidence has shown that depression is genetically influenced even in the absence of SLEs. We propose to test the following hypotheses: (1) Individual differences in stress sensitivity are heritable. The first line of evidence. involves a genetically influenced sensitivity to stress. they did not observe familial aggregation for sensitivity to stress.g. stress sensitivity has been implicated in various disorders. such as affective disorders and drug addiction (Becker et al. Each study has usually focused on one aspect of reactivity to stressors. co-twin affected) was significantly higher than for individuals with a low genetic background 123 (monozygotic twin. However. some studies have not replicated the existence of two sources of genetic liability. Efforts were made in the present study to compensate for the two limitations by adopting modern statistical methods and introducing a novel variable. (1995) found that in the absence of SLEs. and explicitly proposed two major sources of genetic liability. McGuffin et al.. Kendler et al. Reaction Level. Fowles (1992) claimed that reactivity to stressful life events (SLEs) (i. Tellegen et al. First. For the present study. and consented to participate in the follow-up in 2009 (Wave2). in a population-based twin study. we applied the multifactorial polygenic model to depression. has suggested that stress sensitivity and the genetic loading of depression could function in somewhat independent ways. the relatives of probands whose onset of depression followed exposure to SLEs were no more sensitive to recent SLEs than the relatives of probands whose onset of depression had no obvious preceding SLE. suggesting familial/ genetic aggregation of depression. as an index of individual differences in stress sensitivity (see ‘‘Methods’’ for details). Although stress sensitivity has been frequently discussed in previous studies due to its important role in the etiology of psychopathology. has its effect regardless of stress sensitivity and the presence/absence of SLEs. such as negative affect reactivity (Wichers et al. implying the existence of a genetic liability that is independent of SLEs. Participants were recruited from elementary and high schools that were randomly selected from all 18 counties or districts in the Beijing municipality. co-twin unaffected). In our opinion. coming from research on recurrent depression. The second one. they found a higher prevalence of depression among the first-degree relatives than among a community sample.

According to the results of a DNA-based zygosity determination method (Chen et al. 216 male). after school hours. cases whose response seemed odd were excluded according to specific criteria.CDIwave1) into z-score based on his/her SLE group mean and SD. biased cognition. failing in competition) were included. Confidentiality and anonymity of the participants’ responses to the questionnaires were ensured. 26. we then divided participants according to the number of SLEs they had experienced between the two waves. Statistical analyses Before testing our main hypotheses.1 (2. we tested whether there was a linear association between SLEs and change in depressive symptoms between Wave1 and Wave2.9% vs. The inter-rater reliability was . Measures Participants’ depressive symptoms were measured using the Children’s Depression Inventory (CDI. severe family economic difficulty).6) and 15. 22 independent SLEs.. 17. which are largely independent of the children’s behavior (e. 2010) whose predictive accuracy is close to 100%.2 (2. as a measure of individual differences in sensitivity to SLEs that was independent of the level of SLEs experienced. there was no significant difference between the twin families and families from the population-based sample in terms of family income. Thus.g. There is no validity scale within this measure. We constructed this index in multiple steps. Thus.38. Arrangements were made for the twins to participate in their classrooms. in which the same measurement of family income and parental education level were used as in this twin sample. which is consistent with the finding that parents are relatively poor reporters of children’s depressive symptoms (Angold et al. Mean (SD) age at intake and follow-up were 13. suicidal ideation.). We assessed and analyzed both dependent and independent SLEs. we introduced an index. Research staff were there to answer any questions that the students might have about the questionnaire. which was developed for children and adolescents.2% vs. 16. Consents were obtained from the twins themselves and their parents. That is.7% for mothers). 59 male). trained research staff distributed the questionnaires to the participants and instructed them to complete the questionnaire independently. Questionnaires for parents were taken home by the twins and mailed back to our laboratory.6) years. Parents also rated their twin children’s depressive symptoms using the same questionnaire. Thus. 79. 2009).).5% for fathers. If there was a linear association (In fact.. the representativeness of this twin sample appears acceptable. Finally. twins were asked to provide their saliva samples using the OrageneÒ DNA selfcollection kit (Genotek Inc. First. so that higher scores indicate more depressive symptoms. The inter-rater reliability was . When cleaning the entire data set. the socioeconomic status of the twin families was compared to that of 10. we did not include the parent-reported data in the following data analysis.82.9% of the parents completed and returned the questionnaires. The answers of 13 items were arranged in the opposite direction to the other 14 items. Hence. namely ‘‘Reaction Level’’. The original items regarding positive life events were excluded because negative life events are more likely than positive life events to be related to psychological problems (Kessler 1997). This measure consists of 27 items dealing with negative feelings. Scores of these 13 items were reversed prior to data analysis. death of a family member. each individual’s CDIdiff score was transformed (CDIdiff = CDIwave2 . we 123 . 454 pairs were monozygotic (MZ) twins (238 female. respectively. Although more parents in the twin sample received college education than parents in the population-based sample (25. we did not include the parent-reported data in the following data analysis.Behav Genet and 275 pairs were male twins. Cronbach’s a of the self-reported CDI raw score was . trouble with teacher. 1986. Institutional Review Board approved the research protocols. 1987). we trained our research staff to pay attention to the participants’ behavior while they were filling out the questionnaires.g. 2004). Both parents and children completed this questionnaire. After completion. giving a follow-up participation rate of 99%. Each item in the checklist was scored 1 if the target adolescent indicated a specific event had occurred and 0 if the event had not occurred. There was no significant difference between the twin families whose parents returned questionnaires and those who did not in terms of family income. because they are both able to influence children’s depressive symptoms. Participants rated depressive symptoms that they had experienced over the past 2 weeks on a 3-point scale. Only seven pairs dropped out of the study at Wave2. and 152 pairs were dizygotic (DZ) twins (93 female. this was the case. and 17 dependent SLEs that may be dependent on the children’s behavior (e. SLEs that occurred during the interval between Wave1 and Wave2 were assessed with a modified version of the Life Events Checklist (Johnson and McCutcheon 1980). The reliability and validity of CDI have been well established (Smucker et al.509 Beijing families from a large population-based sample (Chen et al. Its Chinese version has been widely used in China. To assess the representativeness of this twin sample. Kovacs 1992). to quantify individual differences in stress sensitivity and facilitate direct comparison between individuals in different SLE groups. Finally. or somatic symptoms.35. After describing the purposes of the study and explaining the procedures. Timbremont et al.

e. A positive Reaction Level means that this child was more sensitive than average.. Wave2 CDI scores were regressed on Wave1 CDI scores and the resulting residuals used as the depression phenotype in the bivariate model. To further confirm that the specific genetic component (Ag) works regardless of the SLE level. Total variance was parsed into additive genetic (A). Total genetic variance of depressive symptoms is calculated as: a22 ? a32. then. the main effect of SLE on depressive symptoms was added to the model by estimating the mean of depression as l ? bmM. 1. Given that the Reaction Level is not correlated with SLE level. i. 1999). C and E components contributing to depressive symptoms specifically (i. univariate models were fit to estimate the relative contributions of genes and environment to the variance of the depressive symptoms (CDIwave1 and CDIwave2). C and E to total variance were estimated by using sex-limitation models (Neale and Maes 1996). Estimates of the A. less easily depressed when responding to same amounts of SLEs as others. Non-shared environmental influences (E) are estimated from the within-pair differences. 1995) that recognize that individuals differ in how they respond to the same environmental event. Alternatively. All variables were age-regressed prior to univariate analysis. Cs and Es in Fig. A significant change in model fit (v2) following constraining parameters for male and female to be equal indicates a significant sex difference. Sex differences in total variance or the relative contribution of A. Depressive symptoms in this model are Wave2 CDI scores with Wave1 CDI score being controlled Level and depressive symptoms were arranged in the Cholesky model is consistent with the hypothesized relationship between predictor and consequence. where ‘‘a’’ is the main genetic effects and the ‘‘ba’’ is the regression coefficient marking the extent to which the genetic effects vary as a function of the SLE level.e.e. The order for how Reaction 123 Fig. . C and E components were derived by comparing the correlation among MZ twins (who share 100% of their genes) to that among DZ twins (who share on average 50% of their genes). i. Reaction Level and SLE level. Ag. Next. respectively.e. 1 Bivariate Cholesky model of Reaction Level and depressive symptoms for one member of a twin pair. The two genetic paths were re-expressed as linear functions of the SLE level: a ? baM. C and E components contributing to the covariance between Reaction Level and depressive symptoms (i. with the former representing the general genetic liability and the latter representing the specific genetic liability. this model estimates the A. First. and non-shared environmental (E) components.. and the parameters e2 and e3 are two possible sources of nonshared environmental influences on depressive symptoms. Similarly. Within-pair correlation not due to genetic factors is attributed to C (rDZ [ 1/2rMZ). Greater MZ relative to DZ correlation is attributed to A (rMZ [ rDZ). The proportions by which the general and specific genetic components explain the total genetic variance of depressive symptoms are calculated as: a22/(a22 ? a32) and a32/ (a22 ? a32). which also include measurement error. Biometric modeling was utilized to test our main hypotheses (Neale et al. As. we incorporated gene-environment interaction terms (Purcell 2002) into the bivariate model to examine the moderation effect of SLE on the paths from As ? depressive symptoms. a significant bas (regression coefficient in the path from As ? depressive symptoms) should not be expected. paths from shared and non-shared environment factors to depressive symptoms were re-expressed as: c ? bcM and e ? beM. the parameters c2 and c3 are two possible sources of shared environmental influence on depressive symptoms. although the environmental influences were not our major interest in the present study.. 1) as well as the A. Cg and Eg in Fig. shared environmental (C). 1). and from Ag ? depressive symptoms (Fig. Our first hypothesis is supported if a significant contribution of A to Reaction Level was observed. A ‘‘0’’ Reaction Level means that the child had an average change in depression symptoms for those having the same number of SLEs as she or he had. As shown in Fig. The parameters a2 and a3 indicate the two sources of genetic influence on depressive symptoms. This idea is consistent with the concepts of reaction range (Gottesman 1974) and reaction surface (Turkheimer et al. In order to control for baseline level of depression.Behav Genet computed z-scores separately within each SLE group. more easily depressed when responding to the same number of SLEs as others. Similar to the genetic influence.. respectively. a negative Reaction Level means that this child was less sensitive than average. If As has its effect on depression regardless of SLE level. a bivariate Cholesky decomposition model (Neale and Maes 1996) was fit to examine our second hypothesis that the genetic contributors to stress sensitivity serve as part of the genetic component of depressive symptoms. 2). This z-score is consequently uncorrelated with number of SLEs and is what we called ‘‘Reaction Level’’. where M is the number of SLEs and bm is the regression coefficient.

Descriptive analyses Fig. and Wave2 (39.20 Reaction Level -. 3.95 CDI score in Wave2 39.70 2. t = .32 for males and 36. t = . and the Reaction Level MZ DZ Male Mean (N = 432) SD Female Mean (N = 476) SD Male Mean (N = 118) SD Female Mean (N = 186) SD CDI score in Wave1 37. p \ .13 6. 37. ps \ . a linear association between SLEs and change in CDI scores was observed (r = . respectively. Table 1 provides descriptive statistics for depressive symptoms (CDIwave1 and CDIwave2). This linear association between SLEs and depression has also been reported in previous studies (e.001).14. Based on these findings. 2 Bivariate Cholesky model incorporating interactions between SLE and latent genetic and environmental factors on depressive symptoms As shown in Fig.CDIwave1) Model-fitting analyses were performed with the Mx software (Neale 1997). p = .99 -.28 38.. Multiple linear regression further revealed that each of these variables contributed independently to the prediction of Wave2 depression (B = 1. the sample-size adjusted BIC.16 6. Ge et al.90 38.34 and 6. . They also experienced similar amounts of SLEs during the time interval between the two waves (2.01 .023 for Wave1 depression. t = -11.36 40. Lower values indicate better fit.73 2.48. All variables were age and sex-regressed prior to bivariate analysis to correct for potential biases. SLEs and Reaction Level.33 37.96 -. and the Deviance Information Criterion (DIC) between nested models.35 and . .Behav Genet Results Creation of Reaction Level Fig. p = .40 36.48 6.94 40. The mean increase in CDI scores did not differ between the two sexes (t = -.70).13 2. p \ . individual differences in depression were clearly observed within each SLE group: Change in CDI scores varied among children who had experienced similar amounts of SLEs. Model fit was evaluated by comparing -2 9 loglikelihood (-2LL). Meanwhile. The participants reported more depressive symptoms in Wave2 than in Wave1 (39.42. the more depressed this child would be (indicated by greater increase in his/her CDI score from Wave1 to Wave2).45 for males and 39.68 2.06 .91.80.g.97 for females. Bayesian Information Criterion (BIC). . The more SLEs one had experienced.01 .74 for males and 2. SLE level and Reaction Level (r = .95 . Y-axis represents the change in their CDI scores during the time interval between the two waves (CDIdiff = CDIwave2 . p = . Participants were divided into seven groups according to the number of SLEs they had experienced. Akaike’s Information Criterion (AIC). p = .28 for females. 3 The association between the number of SLEs and depressive symptoms.37 6.004.52 7.94).38 2. we divided the participants’ responses into 7 SLE groups and created a Reaction Level index for each participant.13 .s.89). stressful life events occurring between the two waves.30.13. p = .07.86 6. Skewed variables were log-transformed to better approximate normality. .00. SE = .68).008.14 6.001). 2009).35 v. SLE level and Reaction Level Table 1 Descriptive statistics of depressive symptoms in Wave1 and Wave2. Male and female adolescent twins reported similar levels of depressive symptoms in both Wave1 (37.36).10 Stressful life events 2. t = .27 7.99 123 .52.83 2.08.001).72 for females. There was also no sex difference in Reaction Level (t = -. Wave2 depression was significantly correlated with Wave1 depression.38.96 3.

00) – – Es ? depressive symptoms e3 1. C. .68. the Cg and Cs components were excluded from the bivariate models.09.90.06) Bag -.57) 1. .00.48 .48 (3. Depressive symptoms also exhibited substantial non-shared environmental effects.26) .17) Eg ? Reaction Level e1 .67.36.06 (.57 . SLEs also exhibited a moderate heritability (cf.36. however.71) 5. 1.42 . however. 2. Lower panel presents the results of fitting the bivariate Cholesky model with moderation effect of SLEs 123 .22 -2.94) – – As ? depressive symptoms a3 1.32. Interestingly.91) Beg .49 (.33) . . and E in males and females are however similar.001). both the Wave1 and Wave2 depressive symptoms were moderately heritable.11 (-. F(3) = 4.20 . was minimal and non-significant.15 (.04. all path coefficients in the bivariate model were significant. Because the relative contributions of A. . .22.15.06) Bas .001). The results of regression analysis reinforced the rationale used to set up the bivariate Cholesky model (Fig. 4.72 (. the a2 and a3 were significant. For the SLEs.42 (.30 . 1).00 (.37 . C and E estimates (95% confidence intervals) and model fit statistics rMZ rDZ A C E Fit statistics v2 df p AIC CDI score in Wave1 .42 (. McGuffin et al.06 (-. we report the common parameter estimates for male and female twins in Table 2.20) .52.84 (1.00.73 4 . p \ . p \ . ps \ .64.18 (. The contribution of shared environment to depressive symptoms. The non-shared environment effect also included error.81 (1. the heritability of depressive symptoms increased by 16% during the time interval from Wave1 to Wave2.31 .60) 3. .01) As ? depressive symptoms a3 1.58 (.44) . .78) Eg ? depressive symptoms e2 Es ? depressive symptoms e3 – – 3.96) – – Bivariate model Ag ? Reaction Level a1 .61 (. . As shown in the upper part of Table 3. for the full regression model.39. . 1988). indicating greater variance for males than for females.53. .01.45.63. Univariate models Fitting the sex-limitation model did not reveal any significant sex difference regarding either the total phenotypic variance or the relative contribution of A.78 -6.27) 1. . supporting our first hypothesis.27 respectively. . constraining the total variance to be equal between the two sexes led to a significant decrease in model fit (Dv2(1) = 18.77) – – Eg ? depressive symptoms e2 3.54.43.72 CDI score in Wave2 . . 2. C and E components to total variance for depressive symptoms (Wave1 and Wave2) and Reaction Level.61 (.33 (. .39 (. 1.69) – Without moderation effect of SLEs Ag ? depressive symptoms a2 3. . 4. As shown in Table 2.29 -2.23) Upper panel presents the results of fitting the bivariate Cholesky model without moderation effect of SLEs.60 (3.60) .48) .00. .31.68.56) .10.85 (1.12.76) Bes .05.61 (1. . implying that adolescence might be a critical period in the etiology of depression.00.001.48. Closely relevant to the purpose of this study.08.49 . Bivariate models Since the shared environmental effects to both depressive symptoms and Reaction Level were minimal and non-significant.28 4 .49) 5. a moderate and significant heritability of Reaction Level was observed.24 Reaction Level .61 (3. .98 Stressful life events .00 (. 3. 3. indicating substantial effects from the Table 3 Parameter estimates with 95% confidence intervals for the bivariate models Model Path Intercept Parameter Coefficient for moderator effect Estimates Parameter Estimates – Bivariate model Ag ? Reaction Level a1 . a minor shared environmental effect and a substantial non-shared environmental effect.61 (.05) – – Eg ? Reaction Level e1 . The remaining variance in Reaction Level could mainly be attributed to the non-shared environmental effect.51 -4. As expected.64) .02 4 .40. .68) – – With moderation effect of SLEs Ag ? depressive symptoms a2 3.18 (.73 (. .52 (.68 (3.76 4 . R2 = .Behav Genet Table 2 Twin correlation and univariate A.

According to previous literature. the best fitting model was a model that contained the two non-shared environmental moderators (beg and bes).28 -1872.82 -2389. Moreover. To the best of our knowledge. little is known about the extent to which stress sensitivity is attributable to genetic influences.18 No general non-shared environmental component (Eg) 8540. These findings are consistent with the multifactorial polygenic model whereby the genetic liability to psychopathology represents the combined contributions of both general and specific factors.78 1274. such as DSM-IV.57 1983 3784.96 1983 4574.15 1978 3680. and another part that worked independently of stress sensitivity.843–. evidence has shown that ‘‘depressive symptoms’’ as measured by CDI are predictive of clinical depressive disorder. that is. O’Connor and Dyce 2001). neither genetic component (Ag and As) could be excluded from the model.70 715.5% (95% CI: 8. To determine whether the absence of significant moderation effect of SLE on genetic pathways was a consequence of insufficient statistical power. excluding either environmental component (Eg and Es) led to poorer model fits. since many scholars have argued that normal and abnormal trait variation can be treated within a single.56 -624.82 1983 3807.1%) to the total variance of depressive symptoms.0%) to the total variance of depressive symptoms. both the general genetic source (Ag) and the specific genetic source (As) did not interact with the SLE level.50 -566.20 hypothesized general genetic source (Ag) and specific genetic source (As) to depression..03 -578. Albeit important.Behav Genet Table 4 Fit statistics for bivariate models Model -2LL df AIC BIC BICadj DIC Full bivariate model without moderation effect of SLEs 7636.36 No general genetic component (Ag) 7773.5% (95% CI: 29. In fact. It is noteworthy that ‘‘depressive symptoms’’. Fixing either a2 or a3 to 0 leads to poorer model fits (Table 4).72 -2446.. since most studies investigating the genetic basis of stress sensitivity have used animal models (e.23 -183.57 696. 2010) or studied specific gene loci in terms of G 9 E interaction (e.05 -608. statistically independent of stress sensitivity.15 1978 3680. Caspi et al. On the contrary. the general non-shared environmental component (Eg) and the specific non-shared environmental component (Es) interacted with SLE level. stress sensitivity acts as a trait that plays an important role in the etiology of depression. However.884 (95% CI: . Bartolomucci et al.72 1980 3679.45 1980 3717.916).36 Without genetic moderators (bag & bas) 7639. which were measured by the CDI in the present study. we successfully decomposed the genetic contribution to depressive symptoms into two parts: One part that had its effects on depression in terms of genetically-influenced individual differences in stress sensitivity. we successfully showed evidence for the two sources of genetic liability to depression: one corresponding to genetic contributors of stress sensitivity. the present study added to the literature by showing that stress sensitivity is moderately heritable.73 -50.76 No specific genetic component (As) 7750.18 -627.02 697. Discussion In the present study.02 697. Thus. For example.g. Thus. refers to a symptomatic spectrum detectable in the general population.96 -2005.28 1983 4840.07 Without non-shared environmental moderators (beg & bes) 7667.52 Full bivariate model with moderation effect of SLEs 7636. and another which is specific.g. As shown in the lower part of Table 3.49 747.57 -2400. this is the first adolescent twin study on the heritability of stress sensitivity.56 -624.1–13. 123 . Further analysis showed that the genetic correlation between depressive symptoms and Reaction Level is . we tested all competing models from the models with one moderator (any one out of the four) to multiple moderators.15 -2442. Results of fit statistics of this model and its nested models are shown in Table 4. the CDI total score differentiates depressive disorder from anxiety disorder and disruptive behavior disorder (Timbremont et al. heightened stress sensitivity could be a psychological scar which influences the recurrence of depression (Burcusa and Iacono 2007). unified structural framework. It is not conceptually identical to Major Depressive Disorders or other forms of mood disorders which are measured by clinical diagnostic criteria. but did not contain the two genetic moderators (bag and bas). Similarly. results of this study will contribute to our understanding of genetic and environmental liability to clinical depression.45 -2427. 2005. As shown in Table 4. 2003).4–45. while the hypothesized specific genetic source (As) contributed 10. 2004). and that abnormal traits can be modeled as extremes of normal trait variation (Markon et al.44 1142.08 No specific non-shared environmental component (Es) 8806.01 758. The hypothesized general genetic source (Ag) contributed 37. Hence.15 -2442.

Farmer 2004). the finding that the effects of non-shared environmental factors on depressive symptoms were moderated by SLE level reminds us of the importance of E 9 E interactions in the development of depression.001). the depressogenic effects of different SLEs appeared to cumulate. Thapar and McGuffin 1994).31.01. both ps \ . The main aim of an endophenotype strategy is to reduce the complexity of phenotypes and to fill the gap in the pathway between symptoms and putative genes by introducing variables that are measurable constructs in the pathway. dependent v. Kendler et al. whereas studies using self-reported questionnaires usually get relatively higher 123 estimates (Kendler et al. Furthermore. 1999). The term ‘‘endophenotype’’ was first described as an internal phenotype for psychopathology (Gottesman and Shields 1972. Lee et al. p = . Thapar and McGuffin 1994). Findings of this study highlight the importance of both biological factors and psychosocial factors in the development of depression.001). Thapar and McGuffin 1994). 1999) report lower heritability of depression than we reported in our study and that others have reported in some similar studies (Kendler et al. Future research is needed to answer why genetic factors exhibit more impact in adolescence than in any other period of one’s life. such that the number. a transitional period within which dramatic changes occur in biological domain as well as in psychosocial domain. chronic v. Thus. we also measured major SLEs that occurred before Wave1 (such as parental divorce) as well as chronic stressors. however. the heritability of depressive symptoms observed in our adolescent twin sample is much higher than the heritability observed in adult twins or twins younger than 10–11 years (McGue and Christensen 1997. However.. or cascading effects. More evidence is needed before one can . 1973). 2001). 1999) usually get relatively low estimates.18 for independent ones. The gender difference in depression. Since the independent SLEs were associated with depression symptoms. Consistent with previous studies (e.41 for dependent SLEs. In this study. Regression analysis showed that Wave2 depression was significantly predicted by recent SLEs (B = . The participants of the current study were in adolescence.33) when controlling for Wave1 depressive symptoms and Reaction Level. this finding is not consistently found in Chinese samples (e. robust genetic influence appears during adolescence. Thus.g. r = . 2003. we focused on more recent SLEs in the present study. Some studies (e.. In addition to the SLEs that occurred between Wave1 and Wave2 (and therefore may be transient). we found that the Reaction Level fulfilled at least two criteria out of six for being an endophenotype (Chan and Gottesman 2008. the observed genetic correlation between Reaction Level and depressive symptoms also supports that stress sensitivity could be an endophenotype for depression. such as ‘‘being blamed and spanked by parents quite often’’ were more potent than others in predicting depressive symptoms. the E 9 E interactions. it is heritable and associated with symptoms (depressive symptoms in this study). Thapar and McGuffin 1994).. Thus. Multiple environmental risk factors may have their adverse effects in an interactive as well as additive way. is a well established finding in western samples.g. Gottesman and Gould 2003). rather than just the occurrence.g... 2008. p \ . Adolescence is such a life stage during which one often faces a confluence of diverse life stressors.s. Sun et al. 2008. 2008. in contrast to G 9 E interactions and G 9 G interactions. 2010) even observe a higher prevalence of depression in boys than in girls. Studies using clinical interview techniques (Silberg et al. Silberg et al. the heritability of depressive symptoms increased by 16% from Wave1 to Wave2.Behav Genet Stress sensitivity could be a promising candidate as an endophenotype for clinical depression (cf. Furthermore. Consistent with several other studies (Kendler et al. that is. Different types of SLEs (e. Although stress sensitivity has been proposed as a candidate endophenotype for depression (Hasler et al. Difference in measurement methodology may account for this inconsistency. we did not differentiate the effects of different SLEs in this study. 2004). whereby females are more vulnerable than males. Some events.g. Both biological factors (such as puberty) and psychosocial factors (such as life stressors) could account for the significant rise in rates of depressive symptoms for adolescents (Ge et al. we found that dependent SLEs were more strongly associated with depressive symptoms than independent SLEs (r = . transient ones. Researchers have speculated that more life stressors and/or less coping strategy in boys might be able to account for the absence of strong evidence for gender difference in Chinese samples. 2009). In contrast. independent ones) may have different effects on adolescents. but not by SLEs prior to Wave1 (B = . we included them along with the dependent SLEs in our SLE scale. simultaneous exposure to multiple environmental risk factors would constitute an extraordinarily level of risk. little effort has been made to test its validity. It is worth mentioning that some adolescent twin studies (e. They warrant more attention in future research.. First. seem to be underemphasized in recent studies. Nevertheless.s. The identification and validation of endophenotypes is crucial for this strategy. Second. of SLEs was associated with depressive symptoms.g. All the evidence implies that dramatic changes may occur in the underlying mechanisms of depression during the transitional period from childhood to adulthood. Comparison was also made among different types of SLEs.

since the definition and nature of stress sensitivity are far from clear. Conger RD. Cabib S. Science 301(5631):386–389 Chan RC. the observed correlation between Reaction Level and depressive symptoms might be a consequence of other mechanisms. Sugden K. Monteggia LM. Washington. Zhang J. Acknowledgments This study was funded by the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2EW-J-8) and the National Natural Science Foundation of China (31170993). Taylor A. Taylor JR. Minneapolis. multiple sources of genetic and environmental factors combined to convey risk for indicators to depression. In summary. Zhang J et al (2009) Emotional and behavioral effects of romantic relationships in Chinese adolescents. Dev Psychopathol 21(2):621–635 Gottesman II (1974) Developmental genetics and ontogenetic psychology: overdue detente and propositions from a matchmaker. Shields J (1967) A polygenic theory of schizophrenia. and paying more attention to children who may have a genetic disposition toward high stress sensitivity. Lesch KP et al (2010) Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice. Merikangas KR. and who are exposed to multiple SLEs and other adverse environments. Clin Psychol Rev 27(8):959–985 Caspi A. instead of a causal relationship. Craig IW. such as the hormonal cortisol reaction to stressful stimuli in the laboratory. the longitudinal design of the present study and a further regression analysis. Yehuda R et al (2007) Stress and disease: is being female a predisposing factor? J Neurosci 27(44):11851–11855 Burcusa SL. and the emergence of gender differences in adolescent depressive symptoms. there could be potential confounding in the interpretation of the results. Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. John K. Fourth. Perrot-Sinal TS. stressful life events. Carola V. Dis Model Mech 3(7–8):459–470 Becker JB. University of Minnesota Press. American Psychological Association. The first author was a postdoctoral guest worker in the Department of Psychology and the Institute of Child Development at the University of Minnesota while working on this project. Iacono WG (2007) Risk for recurrence in depression. In: DiLalla LF (ed) Behavior genetics principles—perspectives in development. Romeo RD. Li X. Natsuaki MN. We thank all the personnel involved in the sample recruitment and data collection. pp 55–80 Gottesman II. Investigating the genes associated with stress sensitivity could be a useful strategy for identifying depression-related genes. vol 8. J Child Psychol Psychiatry 28(6):901–915 Bale TL (2006) Stress sensitivity and the development of affective disorders. J Youth Adolesc 38(10):1282–1293 Chen J. the Reaction Level is not a precise measure of stress sensitivity. Li X. Twin Res Hum Genet 13(2):194–200 Eaves LJ (2006) Genotype 9 environment interaction in psychopathology: fact or artifact? Twin Res Hum Genet 9(1):1–8 Farmer A (2004) Bad luck and bad genes in depression. the confounding may be minor. Proc Natl Acad Sci USA 58(1):199–205 123 . Xiaojia Ge for his great contribution in founding the Beijing Adolescent Twin Project. enhance the possibility that the Reaction Level leads to depression. Gottesman II (2008) Neurological soft signs as candidate endophenotypes for schizophrenia: a shooting star or a Northern star? Neurosci Biobehav Rev 32(5):957–971 Chen Z. Moffitt TE. it should be meaningful to introduce such an index to roughly reflect individual differences in stress sensitivity. Duan Q et al (2010) Optimization of zygosity determination by questionnaire and DNA genotyping in Chinese adolescent twins. the Reaction Level was derived from the difference between Wave1 and Wave2 depression (within level of SLEs). Weissman MM. Dev Psychol 37(3):404–417 Ge X. pp 107–121 Fowles DC (1992) Schizophrenia: diathesis-stress revisited. which revealed a significant correlation between Reaction Level and Wave2 depressive symptoms after controlling for family income and the quality of parents’ marriage life. On the contrary. it is possible that these genetic effects are shared by other disorders. Second. Neiderhiser JM. Wickramaratne P et al (1987) Parent and child reports of depressive symptoms in children at low and high risk of depression. We have full control of all primary data and we agree to allow the journal to review our data if requested. Third. Conflict of interest The authors do not have any financial relationship with the organization that sponsored the research. and results obtained in laboratory studies may not be generalized to real life. Prusoff BA. Alternative measures do exist. Horm Behav 50(4):529–533 Bartolomucci A. 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