A r tic le. A d o le sce n t Irritab ility : P h e n o ty p ic A sso cia tio n s an d G e n e tic Lin k s W ith D e p re sse d M o o d

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1 A r tic le A d o le sce n t Irritb ility : P h e n o ty p ic A sso ci tio n s n d G e n e tic Lin k s W ith D e p re sse d M o o d Argyris Stringris, M.D., Ph.D. Helen Zvos, M.Sc. Ellen Leibenluft, M.D. Brbr Mughn, Ph.D. Thli C. Eley, Ph.D. O b je c tiv e : Irritbility hs been proposed to underlie the developm entl link between oppositionl problem s nd depression. Little is known, however, bout the genetic nd environm entl influences on irritbility nd its overlp with depression. Drwing on the notion of generlist genes (genes of generl effect tht underlie phenotypic overlp between disorders), the uthors test the hypothesis tht the ssocition between irritbility nd depression is ccounted for by genetic fctors. M e th o d : Dt from the G1219 study, U.K. twin/sibling sm ple (N=2,651), were used in cross-sectionl nd longitudinl design. The irritble nd hedstrong/hurtful dim ensions of oppositionl behvior were derived using fctor nlysis. Regression ws used to estim te the ssocition between depression nd delinquency. Multivrite genetic nlyses were used to estim te the genetic overlps between the two com ponents of oppositionlity (irritbility nd hedstrong/hurtful behviors) nd depression nd delinquency. R e su lts: Irritbility showed significntly stronger phenotypic reltionship with depression thn with delinquency, wheres hedstrong/hurtful behviors were m ore strongly relted to delinquency thn to depression. In m ultivrite genetic nlyses, the genetic correltion between irritbility nd depression (r A =0.70, 95% CI= ) ws significntly higher thn tht between irritbility nd delinquency (r A =0.57, 95% CI= ); conversely, the genetic correltion between hedstrong/hurtful behviors nd delinquency (r A =0.80, 95% CI= ) ws significntly higher thn tht between hedstrong/hurtful behviors nd depression (r A =0.46, 95% CI= ). In longitudinl m odels, the phenotypic ssocition between irritbility t wve 2 nd depression t wve 3 ws ccounted for by the genetic ssocition between irritbility nd depression t wve 2. C o n c lu sio n s: These findings re consistent with the theory tht genes with generl effects underlie the reltionship between irritbility nd depression. (A m J P sychitry ; : ) Irritble mood, common nd impiring symptom in psychopthology (1 3), hs been proposed to underlie the developmentl link between oppositionl problems in youth nd depression in dulthood (4, 5). However, little is known bout the genetic nd environmentl influences on irritbility nd its overlp with psychitric disorders. An unexplined spect of developmentl psychopthology concerns the trnsition from disruptive behvior problems to mood nd nxiety problems (6). A striking exmple is the recent finding tht oppositionlity in youth is potent predictor of depression in young dult life, over nd bove depression in erly life (7). It hs recently been proposed tht irritble mood my explin this trnsition from oppositionlity to lter depression (5, 7, 8). Dt suggest tht oppositionlity in youth comprises t lest two dimensions with differentil predictions (9 12): n irritble dimension, more strongly ssocited with depressive disorders thn with ntisocil behviors; nd hedstrong/hurtful dimension (cpturing rgumenttiveness nd rule breking longside spiteful behviors), more strongly ssocited with ntisocil behviors thn with depressive disorders (5, 11, 12). These differentil ssocitions hve been demonstrted in series of longitudinl studies spnning childhood into dulthood (5, 11). It remins unknown whether such differentil phenotypic links re ccounted for by genetic or environmentl fctors. For exmple, is the overlp between irritbility nd depression ccounted for by one set of shred genes, while different set of genes explins the link between hedstrong/hurtful behviors nd ntisocility? Previous genetic studies hve found tht genetic fctors my hve broder influences thn initilly thought; indeed, the generlist genes (13) re thought to explin the ssocition between closely linked phenotypes (13, 14). An lterntive explntion for such phenotypic overlp lies in the relm of overlpping environmentl fctors. Fmily- or person-specific environmentl influences my be ssocited with both irritbility nd depression nd thus underlie their reltionship, while different set of such overlpping environmentl risks my underlie the reltionship of This rticle is fetured in this m onth s AJP A u d io, is discussed in n Ed ito ril by Dr. Wm boldt (p. 4), nd is n rticle tht provides C lin icl G u id n ce (p. 54) Am J Psychitry 169:1, Jnury 2012 jp.psychitryonline.org 4 7

2 A d o lesc en t Ir r it b ility n d D ep r essed M o o d hedstrong/hurtful behviors with ntisocility. Answering these questions would help us understnd the mechnisms underlying these key developmentl pthwys. In this study, we used twin smple nd geneticlly informtive design to ddress these questions. We begn by exmining phenotypic links between the two components of oppositionlity (irritbility nd hedstrong/hurtful behviors) nd depressive problems nd ntisocil behviors. Bsed on previous findings, we predicted double dissocition, such tht dolescent irritbility would show differentil concurrent nd longitudinl reltionships with depressive problems, while hedstrong/hurtful behviors would be specificlly relted to ntisocil outcomes. We used young people s self-reports, thus complementing previous work bsed on prent nd techer reports (5, 11, 12) nd reexmining previous negtive findings (5) on the reltionship between self-reported irritbility nd psychopthology. Focusing on dolescence offers the dditionl dvntge tht the differentil reltionships of irritbility cn be tested t time when dult mood problems re emerging (15) nd ntisocil behviors rech pek (16). Next, we used multivrite twin modeling to test our min hypothesis tht the genetic findings would show double dissocition consistent with the phenotypic findings. We expected tht genetic fctors shred between irritbility nd depression would underlie their phenotypic ssocition nd, similrly, tht genetic fctors shred between hedstrong/hurtful nd ntisocil behviors would explin their phenotypic ssocition. This prediction ws bsed on the notion of generlist genes, which re hypothesized not to be disorder specific but rther to exert wider effects, giving rise to closely linked behviorl (17) or cognitive phenotypes (13, 14). Indeed, we recently provided further empiricl evidence in support of this theory by showing substntil genetic links mong cognitive bis, depression, nd nxiety problems (18). M e th o d S m p le Dt from the G1219 smple were used s previously described (18 20). The G1219 study is longitudinl study of 3,640 dolescent twins nd siblings (ges yers t initil contct). The present nlyses focus on wves 2 nd 3 of the dt collection (time 1 nd time 2, respectively), which took plce, on verge, 8 months (rnge, 0 24 months) nd 33 months (rnge, months), respectively, fter initil contct. Dt were vilble for 2,651 individuls t time 1 (73% of the originl smple) nd for 1,597 t time 2 (44% of the originl smple). Zygosity ws estblished through questionnire mesure completed by mothers. The smple consists of 168 monozygotic mle, 199 monozygotic femle, 138 dizygotic mle, 190 dizygotic femle, nd 463 opposite-sex dizygotic twin pirs nd 109 mle sibling pirs, 132 femle sibling pirs, nd 186 opposite-sex sibling pirs. Zygosity ws not vilble for 235 pirs t initil contct. At times 1 nd 2, the proportions of boys were 43.9% nd 41.3%, respectively. The men ges t times 1 nd 2 were 15 yers (rnge, 12 21) nd 17 yers (rnge, 14 23), respectively. To hndle the effects of initil response nd ttrition bis, single weighting vrible ws included in ll genetic nlyses, s previously described (18). Informed consent ws obtined from ll dolescents ge 16 or older nd from prents or gurdins of those under ge 16. Ethicl pprovl ws provided by the Reserch Ethics Committees of the Institute of Psychitry, King s College London; the South London nd Mudsley NHS Trust; nd Goldsmiths, University of London. M e su re s D e p re ssio n r tin g s. Depressive symptoms were rted by selfreport using the Short Mood nd Feelings Questionnire (21 23). At time 1, 4-point response formt (rnging from never to lwys ) ws used to llow for discrimintion t the lower end of the spectrum. The stndrd 3-point scle ws used t time 2. D e lin q u e n t b e h v io r. Using the ASEBA fmily of instruments (24, 25), we formed delinquency scle with 11 items, s previously described (26), tht cptures the elements of lcking guilt, hving devint peers, lying, preferring older peers, running wy from home, setting fires, steling, swering, trunting, nd using lcohol or drugs. D im e n sio n s o f o p p o sitio n lity. Items used to define dimensions of oppositionlity were drwn from the Youth Self-Report (24) (for ges 11 18) nd the Adult Self-Report (25) (for ges 18 59) of the ASEBA fmily of instruments. At time 1, we used the following items from the Youth Self-Report: rgue lot, men to others, destroy others things, disobey prents, disobey t school, hve hot temper, tese others lot, stubborn, nd mood/feelings chnge suddenly. The lst item ws included becuse mood lbility is commonly used term to describe chronic irritbility (27). At time 2, we used comprble items except tht they did not include the item disobey prents nd the item stubborn ws rephrsed s stubborn, sullen, or irritble. St tisticl A n lysis D e riv tio n o f th e irrit b le n d h e d stro n g /h u r tfu l d im e n - sio n s. At ech wve, we conducted explortory fctor nlyses using the oppositionlity items with weighted lest squres estimtion (given the ctegoricl nture of the items) on rndom hlf of the dt set. These nlyses yielded two fctors with eigenvlues 1, corresponding to previously described dimensions of oppositionlity (10 12, 28). As shown in Tble 1, with the exception of the cross-loding rgue lot item, ll items loded clerly on either the irritble ( hve hot temper ; stubborn [time 1] or stubborn, sullen or irritble [time 2]; nd mood/ feelings chnge suddenly ) or the hedstrong/hurtful ( disobey prents [vilble only t time 1], men to others, destroy others things, disobey t school, nd tese others lot ) fctors. An irritbility scle ws generted from the stndrdized sum score of the items loding on the irritble fctor, nd hedstrong/hurtful behviors scle ws creted from the stndrdized sum score of the items loding on the hedstrong/hurtful fctor t ech of the study s time points. Although the Adult Self-Report item stubborn, sullen, or irritble would be expected to lod on the irritbility dimension, the Youth Self-Report version of tht item ( stubborn ) might be more mbiguous nd reflect hedstrong s well s irritble tendencies. Although both versions of the item loded clerly nd consistently on the irritble dimension in the fctor nlyses, we rern ll the min nlyses with this item excluded to ensure tht ny potentil mbiguity did not bis the study s results. The results of the explortory fctor nlyses were further tested in confirmtory fctor nlyses in the other hlf of the smple. A single-fctor model in which ll the items would lod ws compred with the two-fctor (irritble nd hedstrong/hurtful) model derived by explortory fctor nlysis. All indices of fit from mximum likelihood estimtion nd the chi-squre difference score in weighted lest squres estimtion indicted better 4 8 jp.psychitryonline.org Am J Psychitry 169:1, Jnury 2012

3 Str in g r is, Zv o s, Leib en lu ft, et l. TA B LE 1. Lo d in g s fo r th e Irritb ility n d H e d stro n g /H u rtfu l Fcto rs in n Exp lo r to ry Fcto r A n ly sis o f O p p o sitio n lity Ite m s t Tim e s 1 n d 2 in Lo n g itu d in l Stu d y o f Tw in s n d Sib lin g s Time 1 Time 2 Item Irritbility Hedstrong/Hurtful Irritbility Hedstrong/Hurtful Argue lot Men to others Destroy things belonging to others Tese others lot Hve hot temper Mood or feelings chnge suddenly Disobey t school Disobey prents b Stubborn, sullen, or irritble c Fctor lodings b This item ws vilble only t time 1. c This item included only stubborn t time 1 nd stubborn, sullen, or irritble t time 2. fit for the two-fctor thn the single-fctor model (see Tble S1 in the dt supplement tht ccompnies the online edition of this rticle). The Cronbch lph coefficients were 0.67 nd 0.55 for the hedstrong/hurtful dimension t times 1 nd 2, respectively, nd 0.61 nd 0.66 for the irritble dimension t times 1 nd 2, respectively. P h e n o ty p ic n ly se s. Cross-sectionl ssocitions between vribles were explored using correltion nd robust regression with either depression or delinquency s the outcome nd both dimensions of oppositionlity entered simultneously s predictors. Longitudinl ssocitions between the dimensions of oppositionlity t time 1 nd psychopthology t time 2 were exmined using regression models djusting for the dimensionl psychopthology score mesured t bseline. For exmple, where depression scores t time 2 were the outcome, the predictors were the two dimensions irritble nd hedstrong/hurtful behvior t time 1 nd the depression scores t time 1. Robust stndrd error (sndwich) estimtors were used in Stt (SttCorp, College Sttion, Tex.) to ccount for dependence of twin observtions. G e n e tic n ly se s. The twin design compres the degree of similrity mong monozygotic (shring 100% of their genes) nd dizygotic twins (shring on verge 50% of their genes). Reltive differences in within-pir correltions re used to estimte dditive genetic (A), shred environmentl (C), nd nonshred environmentl (E) effects on mesures. Vribles were regressed for ge nd sex, s is stndrd prctice for quntittive genetic model fitting. Vribles were trnsformed to ensure tht ll skew sttistics were between 1 nd 1. Models were fitted in the Mx progrm ( using rw dt mximum likelihood, with weighting corrections to ccount for selective ttrition. The fit sttistic provided for rw dt modeling ( 2 log-likelihood) of the observtions to compre the fit of the genetic model to tht of sturted model. Following the principle of prsimony, the fit of submodels ws ssessed by chi-squre difference tests nd Akike s informtion criterion (c 2 2df), with lower chi-squre vlues nd more negtive Akike vlues indicting better fit. M u ltiv ri te g e n e tic m o d e ls. We used multivrite genetic models to test our hypotheses, using both cross-sectionl nd longitudinl pproches. In the first (cross-sectionl) step, we interpreted Cholesky decomposition s correlted-fctors solution to exmine whether the genetic findings mirrored the phenotypic ssocitions. We tested whether genetic overlp between irritbility nd depression is stronger thn tht between hedstrong/hurtful behviors nd depression, nd whether genetic overlp between hedstrong/hurtful behviors nd delinquency is stronger thn tht between irritbility nd delinquency. In the second (longitudinl) step, we used trivrite nd then qudrivrite Cholesky decomposition models. The purpose of the trivrite model ws to investigte whether ny genetic or environmentl reltionships remined between irritbility t time 1 nd delinquency t time 2 on the one hnd, nd hedstrong/ hurtful behviors t time 1 nd depression t time 2 on the other, fter ccounting for hedstrong/hurtful behviors nd irritbility (both t time 1), respectively. The qudrivrite Cholesky models dditionlly djust for depression t time 1 when exmining depression t time 2 s n outcome nd for delinquency t time 1 when exmining delinquency t time 2 s n outcome. R e su lts P h e n o typ ic Fin d in gs Scores on the irritbility scle were significntly higher in girls thn in boys (men=2.27 [SD=1.57] nd men=1.86 [SD=1.54], respectively; t=6.6, p<0.001), nd scores on the hedstrong/hurtful behvior scle were significntly higher in boys thn in girls (men=1.84 [SD=1.85] nd men=1.38 [SD=1.53], respectively; t=6.9, p<0.001). The correltions between the study s min vribles re listed in Tble 2. Irritbility showed stronger ssocition with depression rtings thn did hedstrong/hurtful behviors, nd hedstrong/hurtful behviors showed stronger ssocition with delinquency thn did irritbility. Figure 1 (top pnel) shows the findings of cross-sectionl robust regression models, with either depression or delinquency s the outcome nd with the two dimensions of oppositionlity entered simultneously s predictors. The figure illustrtes double dissocition, in which irritbility is significntly more strongly ssocited with depression thn with delinquency, wheres, in contrst, hedstrong/ hurtful behviors re significntly more strongly ssocited with delinquency thn with depression. Controlling for gender nd ge did not lter the pttern of the results. Longitudinl robust regression models showed the sme pttern. Irritbility, but not hedstrong/hurtful behviors, t time 1 ws significnt predictor of self-report depressive symptom scores t time 2, fter controlling for self-report depressive symptom scores t time 1 (b=0.14 Am J Psychitry 169:1, Jnury 2012 jp.psychitryonline.org 4 9

4 A d o lesc en t Ir r it b ility n d D ep r essed M o o d TA B LE 2. C ro ss-se ctio n l P h e n o ty p ic C o rre l tio n s in Lo n g itu d in l Stu d y o f Tw in s n d Sib lin g s Hedstrong/ Hurtful Rtings t Time 1 t Time 1 Rtings t Time 2 t Time 2 Vrible N r Ph 95% CI r Ph 95% CI r Ph 95% CI r Ph 95% CI r Ph 95% CI Irritbility 2, Hedstrong/hurtful behvior 2, rtings t time 1 2, t time 1 2, rtings t time r Ph denotes phenotypic correltion coefficients. TA B LE 3. Cro ss-se ctio n l M u ltiv ri te G e n e tic M o d e l Resu lts t Tim e 1, In d ic tin g G e n e tic n d Enviro n m e n tl In fl u e n ce s o n Ech Vrib le in Lo n g itu d in l Stu d y o f Tw in s n d Sib lin g s Cholesky Model Irritbility Hedstrong/Hurtful Rtings Genetic influences A or r A 95% CI A or r A 95% CI A or r A 95% CI A or r A 95% CI Irritbility Hedstrong/hurtful rtings Nonshred environmentl influences E or r E 95% CI E or r E 95% CI E or r E 95% CI E or r E 95% CI Irritbility Hedstrong/hurtful rtings In this model, genetic nd nonshred environmentl influences dd up to 1 on ech vrible. The numbers in boldfce long the digonls re heritbility coefficients (A) or nonshred environmentl influence coefficients (E); the off-digonl numbers re genetic correltions (r A ) or environmentl correltions (r E ). [95% CI=0.08 to 0.20] nd b=0.01 [95% CI= 0.05 to 0.07], respectively). Conversely, hedstrong/hurtful behviors, but not irritbility, were significnt predictors of self-reported delinquency scores t time 2, even fter djusting for self-reported delinquency scores t time 1 (b=0.19 [95% CI=0.12 to 0.27] nd b=0.05 [95% CI=0.00 to 0.10], respectively). The pttern of results ws unchnged when the reduced irritbility scle (omitting the stubborn item) ws used insted (see Tble S2 in the online dt supplement). G e n e tic A n lyse s Genetic overlp between irritbility nd both depression nd delinquency ws first ssessed cross-sectionlly. A sturted model ws fitted to estimte vrinces, covrinces, nd mens for the rw dt to get bseline index of fit (c 2 = , df=9337). Subsequent models were compred with the sturted model to determine the bestfitting model. We found tht model without sex differences in A, C, nd E prmeters but llowing for vrince difference cross the sexes fit the dt best (c 2 = , df=9648, p=<0.01; Akike informtion criterion= ). The shred environment effect ws smll nd nonsignificnt, however, so we present results from n AE model. Heritbility (A) rnged from 0.31 for irritbility to 0.56 for delinquency, s shown long the digonl of Tble 3. Genetic correltions (shown in the off digonls of Tble 3 nd in Figure 1, lower pnel) rnged from 0.46 (between hedstrong/hurtful behviors nd depression) to 0.80 (between hedstrong/hurtful behviors nd delinquency). Genetic correltions between hedstrong/hurtful behviors nd depression (r A =0.46) were significntly lower thn between hedstrong/hurtful behviors nd delinquency (r A =0.80). Genetic correltions between irritbility nd delinquency were significntly lower (r A =0.57) thn between irritbility nd depression (r A =0.70). These results did not chnge when using the time 2 dt, except tht the genetic correltions between irritbility nd delinquency did not differ significntly from those between irritbility nd depression (see Tble S3 in the online dt supplement). Next, we explored the extent to which longitudinl genetic ssocitions showed pttern similr to the phenotypic ssocitions. We first ssessed whether there ws shred genetic vrince between hedstrong/hurtful behviors t time 1 nd depression t time 2, over nd bove the genetic ssocition lredy identified between ech of these vribles nd irritbility t time 1. This is kin to testing whether there is prtil genetic correltion between hedstrong/hurtful behviors nd depression tht ccounts for their longitudinl ssocition independent of ssocitions with irritbility. Similrly, we tested whether there ws ny shred genetic vrince between irritbility t time 1 nd delinquency t time 2 independent of hedstrong/hurtful behviors t time 1. To do so, we used two seprte trivrite Cholesky models. The results re shown in Figure 2. Hedstrong/hurtful behviors t time 1 nd depression t time 2 shred no genetic vrince fter ccounting for irritbility t time 1. Similrly, irritbility t time 1 nd delinquency t time 2 shred no genetic vri- 5 0 jp.psychitryonline.org Am J Psychitry 169:1, Jnury 2012

5 Str in g r is, Zv o s, Leib en lu ft, et l. FIG U R E 1. C ro ss-se ctio n l P h e n o ty p ic n d G e n e tic A sso - ci tio n s fo r Irritb ility n d H e d stro n g /H u rtfu l B e h vio rs W ith D e p re ssio n n d D e lin q u e n c y in Lo n g itu d in l Stu d y o f Tw in s n d Sib lin g s Differentil phenotypic reltionships for irritbility nd hedstrong/hurtful with depression nd delinquency FIG U R E 2. Lo n g itu d in l C h o le sk y D e co m p o sitio n W ith D e - p re ssio n n d W ith D e lin q u e n c y s P rt o f th e M o d e l in Lo n g itu d in l Stu d y o f Tw in s n d Sib lin g s Longitudinl Cholesky decomposition with depression s prt of the model Regression Coefficients (With 95% CI) Hedstrong/Hurtful Irritble Differentil genetic reltionships for irritbility nd hedstrong/hurtful with depression nd delinquency A 1 A 2 A ( ) Irritbility 0.20 ( ) 0.32 ( ) 0.68 ( ) 0.20 ( ) 0.06 ( ) 0.50 ( ) 0.01 ( ) 0.24 ( ) Hedstrong 0.00 ( ) 0.00 ( ) 0.53 ( ) (Time 2) E 1 E 2 E 3 Genetic Correltions Coefficients (With 95% CI) Longitudinl Cholesky decomposition with delinquency s prt of the model A 1 A 2 A ( ) 0.22 ( ) 0.14 ( ) 0.18 ( ) 0.03 ( ) 0.23 ( ) nce fter ccounting for hedstrong/hurtful behviors t time 1. Agin these results remined unchnged when the stubborn item ws omitted from the irritbility scle (see Figure S1 in the online dt supplement). We then sked whether the genetic reltionship between irritbility t time 1 nd depression t time 2 ws explined through shred genetic effects between irritbility nd depression t time 1. As shown in Figure 3, the genetic ssocition between irritbility nd depression t time 1 fully ccounted for the longitudinl ssocition between irritbility t time 1 nd depression t time 2. Similrly, the reltionship between hedstrong/hurtful behviors t time 1 nd delinquency t time 2 ws explined through the genetic ssocition of hedstrong/hurtful behviors nd delinquency t time 1. D iscu ssio n Severl new findings emerge from this study of the phenotypic nd genetic correltes of irritbility. The heritbility Hedstrong 0.55 ( ) 0.08 ( ) 0.02 ( ) 0.60 ( ) Irritbility 0.00 ( ) 0.50 ( ) (Time 2) E 1 E 2 E 3 Pth coefficients nd confidence intervls re shown. A denotes genetic effects, nd E denotes nonshred environmentl effects. of irritbility by dolescent self-report is reltively low, consistent with previous dt from dults (29). Phenotypiclly, irritbility ws specificlly relted to subsequent depressive symptoms, wheres the hedstrong/hurtful dimension ws ssocited with delinquency. Our min hypothesis ws tht the sme pttern of double dissocition would be observed Am J Psychitry 169:1, Jnury 2012 jp.psychitryonline.org 5 1

6 A d o lesc en t Ir r it b ility n d D ep r essed M o o d FIG U R E 3. Lo n g itu d in l C h o le sk y D e co m p o sitio n W ith D e p re ssio n n d W ith D e lin q u e n c y s P rt o f th e M o d e l, A d ju ste d fo r D e p re ssio n /D e lin q u e n c y t Tim e 1 in Lo n g itu d in l Stu d y o f Tw in s n d Sib lin g s Longitudinl Cholesky decomposition with depression s prt of the model 0.52 ( ) A 1 A ( ) 0.01 ( ) 0.09 ( ) 0.24 ( ) A 3 A ( ) 0.17 ( ) 0.15 ( ) 0.10 ( ) 0.16 ( ) Irritbility Hedstrong (Time 2) 0.48 ( ) 0.06 ( ) 0.03 ( ) 0.03 ( ) 0.63 ( ) 0.04 ( ) 0.00 ( ) 0.48 ( ) 0.00 ( ) 0.49 ( ) E 1 E 2 E 3 E 4 Longitudinl Cholesky decomposition with delinquency s prt of the model 0.57 ( ) A 1 A ( ) 0.00 ( ) 0.03 ( ) 0.18 ( ) A 3 A ( ) 0.10 ( ) 0.28 ( ) 0.11 ( ) 0.16 ( ) Hedstrong Irritbility (Time 2) 0.43 ( ) 0.10 ( ) 0.06 ( ) 0.00 ( ) ( ) 0.04 ( ) ( ) 0.58 ( ) ( ) 0.47 ( ) E 1 E 2 E 3 E 4 Pth coefficients nd confidence intervls re shown. A denotes genetic effects, nd E denotes nonshred environmentl effects. 5 2 jp.psychitryonline.org Am J Psychitry 169:1, Jnury 2012

7 Str in g r is, Zv o s, Leib en lu ft, et l. in the multivrite genetic nlyses, nd this ws found to be the cse. The genetic reltionship between hedstrong/ hurtful behviors nd depression ws due entirely to the overlp with the irritble dimension. Conversely, the genetic reltionship between irritbility nd delinquency ws due entirely to the overlp with hedstrong/hurtful behviors. Also, the concurrent genetic reltionship between irritbility nd depression t time 1 ccounted for the genetic reltionships between irritbility t time 1 nd depression t time 2. The sme pttern of results ws observed for the reltionship between hedstrong/hurtful behviors t time 1 nd delinquency t time 2. In previous longitudinl nlyses (10 12, 28), hedstrong items hve been shown to be differentilly strongly relted to ADHD nd conduct problems, wheres hurtful items were preferentil predictors of more ggressive conduct problems nd cllous nd unemotionl trits. However, in this study, hedstrong/ hurtful behviors emerged s common fctor, in keeping with nother recent epidemiologic study (10), possibly reflecting the limited number of items vilble. Irritbility hs trditionlly been studied in the context of ntisocil behvior in both erly life nd dulthood (30, 31). However, it is debted whether disruptive behviors form unitry construct. Consistent with our previous findings (5, 11, 12), we show here tht the reltionship between irritbility nd ntisocility my result from their correltion with hedstrong/hurtful behviors. Our findings support model whereby irritbility is linked with depression, forming prt of nexus of negtive mood with common genetic underpinnings. The finding tht strong phenotypic links between syndrome constelltions or disorders my be explined by genetic, s opposed to environmentl, overlp is consistent with prior theory (13, 14) nd empiricl dt (18). Our findings hve severl implictions. First, they re relevnt for understnding developmentl trnsitions. Recent evidence suggests tht oppositionl behviors re the most robust erly predictor of depression in young dult life (4), even fter djusting for conduct disorder or erly depression. Our findings go step further by showing tht the reltionship between oppositionl problems nd depressive symptoms my be due to the irritbility component of oppositionlity, rther thn to disruptive hedstrong nd hurtful behviors. The findings of this study re bsed on dolescent self-report nd thus extend previous findings bsed on prent nd techer report (5, 11, 12). In contrst to the present study, in pst work we did not find tht self-reported irritbility predicted psychitric disorders (5). These different findings my be due to the considerbly smller size of the previous study, differences in durtion of follow-up, nd the different instruments used. Second, our findings my hve implictions bout the etiology of depression. We found tht the reltionship between irritbility nd depression is lrgely explined by common genes. By contrst, we found only smll overlp in nonshred environmentl fctors between ir- ritbility nd depression. It will be importnt to chrcterize the shred genetic mechnisms between irritbility nd depression, which my include ffective processing mechnisms. Third, our findings support the clinicl notion tht irritbility is presenting symptom of depression nd tht ptients presenting with irritbility should be screened crefully for depression (2, 32 34). This thinking is reflected in the youth criteri but not the dult criteri for depression in DSM-IV. Whether interventions trgeting irritbility would tret nd/or prevent depressive symptoms is topic for future reserch. This study hs severl limittions. First, there ws considerble ttrition t follow-up. However, while ttrition bis poses problem for estimting prevlences, it is less likely to bis ssocitions between vribles (35). Second, the study relied on n existing mesure out of which the irritbility nd hedstrong/hurtful items were extrcted. However, the modest internl consistencies of the scles would reduce the power of detecting differences. Given the double dissocitions we observed in this study, it seems unlikely tht internl consistency hd differentil effects on the study s results. Third, our use of ge-pproprite versions of the ASEBA scles t times 1 nd 2 ment tht one item in the irritbility scle ws worded differently in the two study wves ( stubborn t time 1 nd stubborn, sullen, or irritble t time 2). Although both versions of this item loded clerly nd consistently on the irritbility fctor, we repeted ll the min nlyses with this item excluded to ensure tht ny potentil mbiguity in the simpler (time 1) wording hd not bised the findings. All of the key findings remined unchnged. Received O ct. 2 6, ; revisio ns received M rch 8 nd June 2 1, ; ccepted June 2 7, (doi: /p pi.jp ). From the Deprtm ent of Child nd Adolescent Psychitry nd the So - cil, Genetic, nd Developm entl Psychitry Centre, Institute of Psy - chitry, King s Co lle ge Lo ndon; nd the Sectio n o n Bipolr Spectrum D iso rders, M o o d nd A nxiety D iso rders Pro grm, N IM H, Bethesd, M d. Address correspondence to Dr. Stringris (rgyris.stringris@kcl. c.uk). All uthors report no finncil reltionships w ith com m ercil in - terests. The first tw o uthors co ntrib uted eqully to this w o rk. D r. Stringris grtefully cknow ledges the support o f the W ellco m e Trust. R e fe re n ce s 1. Brotm n MA, Schm juk M, Rich BA, Dickstein DP, Guyer AE, Costello EJ, Egger HL, Angold A, Pine DS, Leibenluft E: Prevlence, clinicl correltes, nd longitudinl course of severe mood dysregultion in children. Biol Psychitry 2006; 60: Fv M, Hwng I, Rush AJ, Sm pson N, Wlters EE, Kessler RC: The im portnce of irritbility s sym ptom of m jor depressive disorder: results from the Ntionl Com orbidity Survey Repliction. 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