Investigating environmental links between parent depression and child depressive/anxiety symptoms using an assisted conception design

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1 Ivestigatig evirometal liks betwee paret depressio ad child depressive/axiety symptoms usig a assisted coceptio desig Article (Published Versio) Lewis, Gemma, Rice, Fraces, Harold, Gordo T, Collishaw, Stepha ad Thapar, Aita (2011) Ivestigatig evirometal liks betwee paret depressio ad child depressive/axiety symptoms usig a assisted coceptio desig. Joural of the America Academy of Child ad Adolescet Psychiatry, 50 (5). pp ISSN This versio is available from Sussex Research Olie: This documet is made available i accordace with publisher policies ad may differ from the published versio or from the versio of record. If you wish to cite this item you are advised to cosult the publisher s versio. Please see the URL above for details o accessig the published versio. Copyright ad reuse: Sussex Research Olie is a digital repository of the research output of the Uiversity. Copyright ad all moral rights to the versio of the paper preseted here belog to the idividual author(s) ad/or other copyright owers. To the extet reasoable ad practicable, the material made available i SRO has bee checked for eligibility before beig made available. Copies of full text items geerally ca be reproduced, displayed or performed ad give to third parties i ay format or medium for persoal research or study, educatioal, or ot-for-profit purposes without prior permissio or charge, provided that the authors, title ad full bibliographic details are credited, a hyperlik ad/or URL is give for the origial metadata page ad the cotet is ot chaged i ay way.

2 NEW RESEARCH Ivestigatig Evirometal Liks Betwee Paret Depressio ad Child Depressive/Axiety Symptoms Usig a Assisted Coceptio Desig Gemma Lewis, B.Sc., Fraces Rice, Ph.D., Gordo T. Harold, Ph.D., Stepha Collishaw, Ph.D., Aita Thapar, Ph.D. Objective: Liks betwee materal ad offsprig depressio symptoms could arise from iherited factors, direct evirometal exposure, or shared adversity. A ovel geetically sesitive desig was used to test the extet of evirometal liks betwee materal depressio symptoms ad child depressio/axiety symptoms, accoutig for iherited effects, shared adversity, ad child age ad geder. Method: Eight hudred fifty-two families with a child bor by assisted coceptio provided questioaire data. Mothers ad fathers were geetically related or urelated to the child depedig o coceptio method. Paretal depressio symptoms were assessed usig the Hospital Axiety ad Depressio Scale. Child depressio/axiety symptoms were assessed usig the Short Mood ad Feeligs questioaire ad six items tappig geeralized axiety disorder symptoms. Associatios betwee materal ad child symptoms were examied separately for geetically urelated ad related mother child pairs, adjustig for three measuremets of shared adversity: egative life evets, family icome, ad socioecoomic status. Aalyses were the ru separately for boys ad girls ad for childre ad adolescets, ad the role of pateral depressio symptoms was also examied. Results: Sigificat associatios betwee paret ad child symptoms were foud for geetically urelated mother child (r 0.32, p.001) ad father child (r 0.17, p.05) pairs ad geetically related mother child (r 0.31, p.001) ad father child (r 0.23, p.001) pairs ad were ot explaied by the shared adversity measuremets. Evirometal liks were preset for childre ad adolescets ad were stroger for girls. Coclusios: The trasmissio of depressio symptoms is due i part to evirometal processes idepedet of iherited effects ad is ot accouted for by shared adversity measuremets. Girls may be more sesitive to the egative effects of materal depressio symptoms tha boys through evirometal processes. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(5): Key Words: depressio, axiety, trasmissio, evirometal, geetic Childre of depressed parets are two to three times more likely tha the offsprig of odepressed cotrols to exhibit elevated levels of depressio ad axiety symptoms ad depressive disorder. 1 Despite cosistet evidece that depressio is familial, few studies This article is discussed i a editorial by Dr. David Reiss o page 431. Supplemetal material cited i this article is available olie. have tested the processes uderlyig itergeeratioal trasmissio of symptoms by teasig apart competig explaatios. First, exposure to paret depressio symptoms may have a direct evirometal effect o childre. Secod, liks betwee paret ad child symptoms could arise through iherited factors. Third, shared exposure to adversities such as bereavemet, divorce, or poverty may icrease risk for depressio i parets ad childre, accoutig for observed trasmissio effects. A greater uderstadig of the pathways ivolved i itergeeratioal tras- VOLUME 50 NUMBER 5 MAY

3 LEWIS et al. missio ca help i the idetificatio of modifiable risk factors for child/adolescet depressio symptoms that could be targeted i prevetive ad therapeutic itervetios. Few studies have used geetically sesitive desigs to estimate the ifluece of iherited factors ad separate evirometal from geetic effects. 2-5 Oe study did ot assess materal depressio directly 5 ad aother reported icosistet fidigs depedig o the iformat used. 4 Two studies have directly tested evirometal trasmissio of materal depressio. 2,3 Tully et al. 2 reported sigificat associatios betwee materal major depressio ad child major depressio i adopted ad oadopted families, with greater associatios i oadopted mother child pairs, suggestig evirometal ad geetic effects. Usig a childre-of-twis desig, Silberg et al. 3 foud that the itergeeratioal trasmissio of materal depressio symptoms was due to family evirometal factors but reported o geetic ifluece. Fidigs have suggested that paret depressio symptoms may exert evirometal risk effects o child depressio symptoms. However, previous studies have ot ruled out the possibility that specific measuremets of shared evirometal adversity (affectig parets ad offsprig) cotribute to this evirometal lik or accout for the associatio betwee materal depressio ad child symptoms. Further research o the mechaisms uderlyig itergeeratioal trasmissio of depressio is required. I additio to the role of shared adversity, such research should cosider the effects of child geder ad age, which have ot bee examied usig geetically sesitive desigs. There is evidece that differet factors may be ivolved i the etiology ad itergeeratioal trasmissio of depressio for boys ad girls. 6 Some studies have foud that the associatio betwee materal ad offsprig depressio is stroger i daughters tha i sos. 7,8 However, other studies have ot reported sigificat geder differeces. 9 The etiology of child ad adolescet depressio may also vary accordig to the developmetal stage of childre. A cosistet fidig from twi research has bee that geetic iflueces o depressio symptoms are greater i adolescets, whereas shared eviromet is more ifluetial i childre. 10 This suggests that oiherited factors could play a more promiet role i the itergeeratioal trasmissio of depressio symptoms for youger childre. There is also cosistet evidece that axiety ad depressio symptoms have shared geetic liability ad that, i prepubertal childre, this liability more commoly maifests as axiety. 11 This suggests the eed to examie axiety ad depressio i the offsprig of depressed parets. The preset study, based o a sample of childre coceived by assisted reproductio, aimed to test whether there are evirometally mediated liks betwee paretal depressio ad child depressio/axiety, ad whether they are accouted for by exposure to three measuremets of shared adversity-egative life evets, family icome, ad socioecoomic status. I additio, the effects of child age ad geder were ivestigated. The sample allows tests of evirometal ad geetic trasmissio usig priciples aki to the classic behavioral geetic adoptio desig: comparisos of associatios betwee geetically urelated ad related paret child pairs. Associatios of paret ad child symptoms i geetically urelated dyads idicates the presece of evirometal trasmissio, implicatig the role of the shared eviromet (C), whereas evidece for geetic effects would be show if associatios are greater i related versus urelated pairs (G). A recet study usig this sample examied depressio ad coduct symptoms i childre ad foud prelimiary evidece of evirometal liks. 12 However, this study focused o mediatio of the associatio by paret child warmth ad hostility ad did ot rule out the possibility that alterative iflueces such as shared adversity may accout for effects or that associatios may differ accordig to child age ad geder. It was hypothesized i the preset study that materal depressio symptoms, i additio to showig iherited trasmissio, would have direct evirometal liks ot accouted for by shared adversity, with symptoms of depressio ad axiety i childre, ad that the evirometal associatio would be stroger i girls ad preadolescet childre youger tha 11 years. METHOD Sample The sample cosisted of families recruited from 19 fertility cliics across the Uited Kigdom ad oe i the Uited States who had udergoe i vitro fertilizatio (IVF), with childre bor from 1994 through Twety-two cliics were approached ad 19 agreed to participate, represetig a cliic respose VOLUME 50 NUMBER 5 MAY 2011

4 ENVIRONMENTAL TRANSMISSION OF DEPRESSION SYMPTOMS rate of 86%. Childre icluded i this report were coceived by oe of four IVF methods: homologous (geetically related to both parets), sperm doatio (geetically related to mother oly), egg doatio (geetically related to father oly), or embryo doatio (geetically related to either paret). All gamete doors were urelated to parets. Oe child from each family participated. For multiple births, parets were asked to report o the firstbor child. Data were collected by postal questioaire from mothers ad fathers o two occasios (Time 1 [T1], 2006; Time 2 [T2], 2009). Questioaires icluded a rage of measuremets assessig details of the pregacy, child psychopathology, family eviromet, ad paretal psychopathology. Oe thousad oe hudred fifty-eight families were set questioaires at T1. Resposes were received from 852 families (74% respose rate). Seve hudred eighty-oe families agreed to be cotacted about further studies ad these families were mailed follow-up questioaires at T2. At T2, resposes were received from 482 families (62% respose rate). Participats who dropped out at T2 did ot differ from those who remaied i the study i materal depressio symptoms at T1 (mea retaied i study 4.24, stadard deviatio [SD] 3.04; mea dropped out of study 4.46, SD 3.10, t , p.30) or child depressio/axiety as rated by the mother (mea retaied i study 4.68, SD 3.96; mea dropped out of study 4.50, SD 4.57, t , p.55) ad by the father (mea retaied i study 4.34, SD 4.29; mea dropped out of study 3.93, SD 4.29, t , p.25). Attritio was ot associated with geetic relatedess to the child ( , p.33). The effects of potetial biases caused by sample attritio were ivestigated by ruig T1 aalyses o the subgroup retaied across waves; the same patter of results was foud (available o request). Comparisos with U.K. atioal orms have show that this sample does ot differ from the geeral populatio i psychological adjustmet, with miimal differeces foud betwee the coceptio groups. 13 The preset study used data from families i which the mother had respoded ( 852, 431 boys, 421 girls at T1; 459, 231 boys, 228 girls at T2). At T1 the umbers i each coceptio group were 436 homologous, 208 sperm doatio, 173 egg doatio, ad 35 embryo doatio, ad at T2 the umbers were 254 homologous, 99 sperm doatio, 91 egg doatio, ad 15 embryo doatio. The geetically urelated group cosisted of 208 mother child pairs (egg, embryo doatio) ad the geetically related group cosisted of 644 mother child pairs (homologous, sperm doatio). Childre were 4 to 10 years old (mea 6.3 years) at T1 ad 7 to 13 years old (mea 9.9 years) at T2. Mothers were 27 to 61 years old (mea years) ad fathers were 28 to 76 years old (mea 44.3 years) at T1. Most childre (91%) resided with both parets. Measuremets Materal Depressio Symptoms. Materal depressio symptoms were assessed usig the seve-item selfreport depressio subscale of the Hospital Axiety ad Depressio Scale. 14 This subscale showed good iteral cosistecy i this sample ( 0.75 at T1 ad 0.70 at T2) ad is well validated. 15 Scores o the subscale rage from 0 through 21, with higher scores represetig greater depressio symptoms. A recommeded cliical cutpoit higher tha 8 has bee validated i cliical ad commuity samples. 15 Child Axiety ad Depressio Symptoms. Child depressio symptoms were assessed usig paret ratigs (mothers ad fathers separately) o the Short Mood ad Feeligs Questioaire (SMFQ). Child self-reports were ot obtaied because of the childre s youg age ad for ethical reasos (childre might ot be aware of paretal IVF treatmet). The SMFQ is a 13-item selfreport measuremet of the presece ad severity of DSM-IV depressio symptoms, which showed good iteral cosistecy i this sample ( 0.73 for mothers ad 0.79 for fathers at T1 ad 0.75 for mothers at T2), ad is a well-validated measuremet i cliical ad commuity samples. 16 Total scores rage from 0 through 26, with higher scores represetig greater depressio symptoms ad the recommeded cliical cutpoit is higher tha Child axiety symptoms were assessed usig paret reports o six DSM-IV items for geeralized axiety disorder over the previous 3 moths (worries, restless, easily tired, irritable, difficulty cocetratig, problems sleepig). The axiety scale showed good iteral cosistecy i this sample ( 0.73 for mothers ad 0.67 for fathers at T1 ad 0.76 for mothers at T2). Axiety scores raged from 0 through 12, with higher scores represetig greater axiety symptoms. A combied depressio/axiety scale was created by summig SMFQ ad DSM-IV axiety items ad showed good iteral cosistecy ( 0.83 for mothers ad 0.85 for fathers at T1 ad 0.87 for mothers at T2). Scores o the composite measuremet raged from 0 through 38, with higher scores represetig more depressio/ axiety symptoms. Negative Life Evets. A 35-item Life Evets Checklist 17 completed by mothers measured the occurrece of a rage of sigificat evets i the child s life durig the previous year such as death of a paret, gradparet or siblig. Fourtee idepedet egative life evets likely to affect mother ad child were used. Family Icome. Mothers ad fathers were each asked to rate the approximate gross family icome o a six-poit Likert scale ragig from 10,000 to 60,000 a year. Family Socio-occupatioal Class. Families were classified accordig to the occupatio of the mai earer (Office for Natioal Statistics, 2000). VOLUME 50 NUMBER 5 MAY

5 LEWIS et al. Statistical Aalyses The sample was divided ito two groups: geetically urelated mother child pairs (egg ad embryo doatio) ad geetically related mother child pairs (homologous IVF ad sperm doatio). Associatio betwee materal depressio symptoms ad child depressio/axiety symptoms was calculated separately i each group. The priciple of the IVF desig is cosistet with the classic behavioral geetic adoptio desig: The presece of a associatio i urelated mother child pairs would provide evidece of evirometal trasmissio because iherited liks are removed, therefore idicatig the role of a shared eviromet (C). If a associatio is see oly i related mother child pairs, the this idicates iherited trasmissio suggestig that paret child liks are due to geetic factors (G). Whe a associatio is see i both groups but is stroger i the related group, this idicates geetic ad evirometal liks (G C). Associatios were calculated usig the Pearso product-momet correlatio coefficiet (r) sice variables were cotiuous ad ormally distributed after trasformatio. The differece i the magitude of correlatio coefficiets across groups was tested usig the Fisher R to Z trasformatio. This test coverts Pearso r to the ormally distributed variable Z, eablig a compariso of the stregth of associatios. Associatios were the retested i each group cotrollig for differeces i materal age, child age, ad family structure (two-paret or sigle-paret family). To test whether associatios differed accordig to child age, aalyses were coducted separately at T1 (mea child age 6.3 years) ad T2 (mea child age 9.9 years). The sample was the split at T2 ito childre ( 11 years old) ad adolescets ( 11 years old). All aalyses were coducted usig mother ad father ratigs of child symptoms to cotrol for shared rater effects; however, father ratigs were available oly at T1 because of low pateral respose at T2. Associatios betwee materal depressio symptoms ad child depressio/axiety symptoms (mother ad father rated) were the tested adjustig for three measuremets of shared adversity: idepedet stressful life evets, family icome, ad family social occupatioal class. The role of shared adversity was examied at T1 because of the larger available sample. The role of child geder was tested ext. Mother child associatios were examied separately for boys ad girls at both time poits (usig mother ad father ratigs at T1 ad mother ratigs oly at T2) to test whether the effects of geder varied by child age. The role of pateral depressio symptoms was ext examied. First, associatios betwee materal depressio symptoms ad child depressio/axiety were tested cotrollig for pateral depressio symptoms to rule out the possibility that father psychopathology could have bee drivig mother child associatios. Secod, the associatio betwee pateral depressio symptoms ad child depressio/ axiety was tested separately i geetically related (homologous IVF, egg doatio) ad urelated (sperm ad embryo doatio) father child pairs cotrollig for shared adversity. RESULTS Demographic Characteristics ad Paret ad Child Symptoms Childre were sigificatly youger i the mother urelated group (egg ad embryo doatio; mea age T1 urelated group 6.00 years; mea age T1 related group 6.35 years, t , p.001). A larger percetage of childre lived with their mothers oly i the urelated (10%) versus related (5%) group ad this differece was statistically sigificat ( , p.05). Mothers i the urelated group were sigificatly older; mea materal age i the urelated group was years ad i the related group, years (t , p.001). There were more multiple births i the urelated versus the related group (24% versus 21%) but this differece was ot statistically sigificat ( , p.05). Mea materal depressio symptoms did ot differ accordig to relatedess at T1 (mea urelated 4.63, SD 3.06, rage 0 15, 208; mea related 4.24, SD 3.06, rage 0 18, 642; t , p.11) or T2 (mea urelated 4.58, SD 3.49, rage 0 18, 106; mea related 4.04, SD 3.19, rage 0 21, 353; t , p.14). Mea pateral depressio symptoms did ot differ at T1 (mea urelated 3.86, SD 2.70, rage 0 14, 167; mea related 3.87, SD 3.12, rage 0 21, 410; t , p.97). Mothers reported sigificatly higher mea depressio symptoms tha fathers (t , p.01). Paret depressio symptoms were positively skewed so were square root trasformed. Child depressio/axiety symptoms also showed o sigificat differeces across groups accordig to mother ratigs (mea urelated 4.04, SD 3.54, rage 0 19, 208; mea related 4.78, SD rage 0 19, 641; t , p.06, at T1; mea urelated 5.18, SD 4.21, rage 0 21, 105; mea related 4.91, SD 4.82, rage 0 30, 352; t , p.60, at T2) ad father ratigs (mea urelated 3.66, SD 3.79, rage 0 20, 133; mea related 4.32, SD 4.37, rage 0 32, 437; t , p.12). Fiftee percet of mothers VOLUME 50 NUMBER 5 MAY 2011

6 ENVIRONMENTAL TRANSMISSION OF DEPRESSION SYMPTOMS TABLE 1 Testig Evirometal Trasmissio Cotrollig for Shared Adversity Geetically Related Geetically Urelated Partial Correlatio Partial Correlatio Idepedet egative life evets Mother-rated child symptoms 0.30*** *** 206 Father-rated child symptoms 0.23*** ** 131 Family icome Mother-rated child symptoms 0.29*** *** 202 Father-rated child symptoms 0.21*** ** 131 Family socio-occupatioal class Mother-rated child symptoms 0.31*** *** 197 Father-rated child symptoms 0.23*** ** 131 Multiple partial correlatio Mother-rated child symptoms 0.30*** *** 191 Father-rated child symptoms 0.22*** ** 129 Note: **p.01, ***p.001. ad 9% of fathers scored above the cliical cutpoit o the Hospital Axiety ad Depressio Scale at T1 ad 14% of mothers at T2. Five percet of childre scored above the cliical cutpoit o the SMFQ at T1 accordig to mother ad father ratigs ad 7% at T2 accordig to mother ratigs. Testig for Iherited ad Evirometal Liks Betwee Materal Depressio Symptoms ad Child Depressio/Axiety. The associatio betwee materal depressio symptoms ad child depressio/ axiety was sigificat i both groups for motherrated (urelated: 207, r 0.32, p.001; related: 639, r 0.31, p.001) ad father-rated (urelated: 132, r 0.26, p.01; related: 436, r 0.22, p.001) child symptoms at T1. Correlatio coefficiets did ot differ across related ad urelated groups accordig to Fisher R to Z for mother ratigs (Z 0.28, p.39) or father ratigs (Z 0.31, p.38) of child symptoms. Correlatio coefficiets did ot differ across raters i urelated (Z 0.66, p.25) ad related (Z 1.56, p.06) groups. To cotrol for kow group differeces, materal age, child age, ad family structure were the etered as covariates at T1. Associatios remaied sigificat for mother (urelated: 207, r 0.33, p.001; related: 638, r 0.31, p.001) ad father (urelated: 132, r 0.26, p.01; related: 436, r 0.22, p.001) ratigs of child symptoms. The patter of results was the same whe child depressio ad axiety symptoms were examied separately (Table S1, available olie). Testig Cotributio of Shared Adversity. The associatio at T1 was examied cotrollig for egative life evets likely to affect mother ad child, family icome, ad family social occupatioal class (Table 1). Associatios remaied sigificat ad uatteuated after cotrollig for each adversity separately across groups for mother- ad father-rated child symptoms. Whe all three variables were etered ito a multiple partial correlatio aalysis with materal depressio symptoms, associatios for mother- ad fatherrated child symptoms remaied sigificat i the two groups. Age Effects. The aalyses at T2 whe childre were 7 to 13 years old showed the same patter of effects as T1 (Table 2). Correlatio coefficiets did ot differ accordig to Fisher R to Z (Z 1.04, p.15). Materal depressio symptoms also predicted child depressio/axiety i the urelated ad related groups i childre youger ad older tha 11 years. Child Geder. Associatios tested separately for child geder are preseted i Table 3. A sigificat associatio betwee materal depressio symptoms ad mother-rated child depressio/ axiety was foud for girls i urelated ad related groups at T1. Correlatios did ot differ accordig to Fisher R to Z (Z 0.31, p.38). Whe father-rated data were used, the same patter was evideced for girls i urelated ad related groups ad correlatios did ot differ accordig to Fisher R to Z (Z , p.11). For girls at T2 the associatio remaied sigifi- VOLUME 50 NUMBER 5 MAY

7 LEWIS et al. TABLE 2 Associatios Betwee Materal Depressio Symptoms ad Child Depressio/Axiety Symptoms Tested Separately by Child Age Geetically Related Correlatio Relatedess Group Geetically Urelated cat i urelated ad related groups for motherrated child symptoms ad correlatios were ot sigificatly differet (Z 0.83, p.20). For boys at T1 the associatio was sigificat i the related but ot i the urelated group ad this patter was replicated with father-reported child symptoms (related: 210, r 0.21, p.001; urelated: 59, r 0.10, p.46). However, the magitude of associatios did ot differ sigificatly betwee geetically related ad urelated groups for mother (Z 0.82, p.38) or father (Z 0.75, p.23) ratigs. At T2 the associatio for boys was sigificat i related ad urelated groups. Comparisos of correlatios for boys ad Correlatio T1 (age 4 10 y) 0.31*** *** 207 T2 (age 7 13 y) 0.32*** *** 105 Sample split by age at T2 11 y old at T2 0.34*** * y old at T2 0.32*** *** 72 Note: T1 data collectio i 2006; T2 data collectio i *p.05, ***p.001. girls i the urelated group at T1 were sigificat for mother (Z 1.71, p.05) ad father (Z 1.73, p.05) ratigs, with a larger effect observed for girls. The differece betwee boys ad girls i the urelated group at T2 approached sigificace (Z 1.54, p.06). Geder ad age results remaied the same whe aalyses were reru icludig the previously used covariates ad shared adversities (results available from first author). Role of Pateral Depressio Symptoms. The associatio betwee materal depressio symptoms ad child depressio/axiety was tested cotrollig for the role of pateral depressio symptoms. Associatios remaied sigificat for mother ratigs of child symptoms (urelated: 133, r 0.31, p.001; related: 441, r 0.28, p.001) ad father ratigs (urelated: 131, r 0.17, p.05; related: 434, r 0.16, p.001). The associatio betwee pateral depressio symptoms ad child depressio/axiety was sigificat i the urelated ( 166, r 0.17, p.05) ad related ( 408, r 0.23, p.001) groups usig mother-rated child symptoms at T1. Correlatio coefficiets did ot differ accordig to Fisher R to Z (Z 0.67, p.25) ad remaied sigificat after cotrollig for the same covariates ad shared adversities. DISCUSSION The importace of geetically sesitive desigs i idetifyig evirometal risk factors is well recogized. The aim of this study was to test the TABLE 3 Associatios Betwee Materal Depressio Symptoms ad Child Depressio/Axiety Symptoms Tested Separately by Child Geder Relatedess Group Geetically Related Geetically Urelated Geder Effects Correlatio Correlatio Boys T1 Mother-rated child symptoms 0.28*** Father-rated child symptoms 0.21*** Girls T1 Mother-rated child symptoms 0.37*** *** 107 Father-rated child symptoms 0.24*** *** 107 Boys T2 0.26*** ** 43 Girls T2 0.41*** *** 60 Note: T1 data collectio i 2006; T2 data collectio i **p.01, ***p VOLUME 50 NUMBER 5 MAY 2011

8 ENVIRONMENTAL TRANSMISSION OF DEPRESSION SYMPTOMS extet to which evirometal liks betwee materal depressio symptoms ad child symptoms demostrated i previous reports were explaied by measuremets of shared adversity ad by child age ad geder. Results are cosistet with a evirometal lik betwee materal depressio symptoms ad child depressio/axiety. Associatios were observed regardless of whether mothers ad childre were geetically related. There are ow covergig fidigs across differet geetically sesitive desigs of evirometal liks betwee materal ad offsprig depressio. 2,3,12 The preset fidigs therefore cosolidate evidece that itergeeratioal trasmissio of depressio symptoms is due at least i part to evirometal mechaisms ad does ot arise etirely from shared geetic liability. The presece of a associatio i the urelated group also rules out passive gee-eviromet correlatio, which is abset i geetically urelated mother child pairs. The preset study accouted for three measuremets of shared adversity: egative life evets, family icome ad family socioecoomic status, ad depressio i fathers. Adjusted associatios remaied sigificat i geetically urelated ad related paret child pairs. This favors the suggestio that oiherited liks betwee mother ad child depressio may arise from direct evirometal effects ad are ot attributable to the extraeous variables measured i this study. This is cosistet with fidigs that shared stressful life evets ad social support etworks do ot cotribute to liks betwee materal ad child depressio. 4 Although the covariates, family icome, family social occupatioal class, ad life evets, may be geetically iflueced ad meaigful geetic variace may therefore be usystematically removed, the patter of geetic ad evirometal trasmissio was the same whether the covariates were icluded. Child age is a importat factor to cosider because depressio etiology has bee foud to differ developmetally, with greater geetic iflueces i adolescece. 18 Sigificat evirometal liks were foud whe childre were 4 to 10 ad 7 to 13 years old. At T2 sigificat evirometal trasmissio effects were foud i youger childre (7 to 11 years) ad those i early adolescece (11 to 13 years). Sigificat evirometal trasmissio effects were foud i both age groups, suggestig that associatios were ot due to the youg age of the sample ad that evirometal liks also operate i childre eterig early adolescece. This cocurs with previous geetically sesitive studies o trasmissio effects that looked at older samples. 2,3 Tully et al. 2 foud some idicatio for the role of geetic factors. Although geetic iflueces caot be ruled out i the preset study, o clear support was foud for a geetic cotributio to trasmissio apart from i boys (see later); materal child associatios were ot stroger i the geetically related group. Iterestigly, the study by Silberg et al. 3 also reported o sigificat geetic ifluece. However, i cotrast to the study by Tully et al., 2 our fidigs ad those of Silberg et al. 3 relied o symptoms rather tha diagoses of depressio so it is possible that iherited trasmissio is more proouced for more severe materal depressio symptoms. Ideed, a study of adolescet female twis foud that the cotributio of shared evirometal factors differed accordig to the pheotype examied, with shared evirometal effects observed for a broad depressive pheotype but ot for major depressive disorder. 19 Alteratively, it may be that the heritable pheotype maifests i a differet way, for example, as overall levels of psychopathology i childre rather tha as depressio symptoms per se. I cotrast to these previous studies, the preset study examied a composite of depressio/axiety scores. However, the patter of materal child associatios was foud to be the same for child depressio scores aloe. Aother cosideratio is that oe of the desigs (adoptio, childre of twis, IVF) are able to accout for geetic heterogeeity betwee depressio i childhood ad depressio i adulthood. If differet gees are resposible for depressio i childhood versus adulthood, 11 the this may have the effect of decreasig the geetic trasmissio estimate. This is a importat directio for future research. Based o a rage of studies suggestig that materal depressio may have stroger adverse effects for girls, the preset study examied whether patters of itergeeratioal trasmissio differed by geder. The sigificat associatio i geetically urelated mother daughter pairs idicated a evirometal effect. For mother so pairs, the associatio was sigificat oly i the geetically related group, suggestig that evirometal trasmissio was less strog for boys. These fidigs are i agreemet with VOLUME 50 NUMBER 5 MAY

9 LEWIS et al. umerous ogeetic studies that have reported stroger associatios betwee materal depressio ad child depressio i girls 7,8 ad suggest that for girls this effect may occur through evirometal pathways because the associatio was of a similar magitude i the geetically urelated ad related groups. This cocurs with research suggestig that girls are more sesitive to stressful life evets i geeral, especially those of a iterpersoal ature. The sigificat associatio betwee materal depressio symptoms ad child depressio/axiety i related but ot i urelated groups for boys does ot coclusively rule out evirometal trasmissio for boys because the differece i the magitude of correlatios was ot large. Ideed, evirometal trasmissio was see for boys i aalyses coducted at T2. Prior ogeetic studies of the associatio betwee materal ad child depressio have reported stroger associatios for girls oly at puberty, which coicides with the emergece of the geder differece i depressio prevalece. 8 However the preset study suggests that from a youger age, girls may already possess a icreased vulerability to materal depressio exposure. A recet study attests to this view. 20 The results of this study must be iterpreted i light of certai limitatios. Other umeasured shared adversities may have cotributed to the itergeeratioal lik. The associatio betwee materal depressio symptoms ad child mood caot be assumed to be uidirectioal. A lack of power i the logitudial aalyses whe the sample is split by coceptio group ad geder precluded a ivestigatio of reverse causatio. Despite evidece that the associatio is likely to be bidirectioal, research suggests that it is ulikely to be accouted for by child effects o paret symptoms aloe. A recet prospective logitudial study of paretal depressive symptoms ad child temperamet foud sigificat paret-to-child effects but little support for childto-paret effects. 21 Like other logitudial studies, attritio affected sample retetio especially for father participatio. There was o evidece that this biased the results (those who dropped out of the study did ot differ from those who were retaied i materal ad child depressio symptom scores), but it did limit the scope ad power available for some T2 aalyses. Sigificat evirometal trasmissio but a lack of differeces betwee the related ad urelated groups suggestig o geetic trasmissio could also be accouted for by the use of self-report questioaire measuremets, which are subject to greater error tha iterview measuremets. The preset study focused o symptom ratigs ad further studies focusig o cliical diagoses of paret depressio ad o cliical outcomes i childre would be of value. However, focus o symptoms is still useful to a uderstadig of cliical diagoses because symptoms ad disorder show similar correlates (e.g., icreased rates i postpubertal girls) ad similar patters of associatio with risk factors (e.g., life evets, family adversity). Aother issue is the use of a age-based cutoff to approximate the effects of pre- ad postpuberty because this is ot a exact measuremet of pubertal developmet. However, pubertal data were ot collected so this was the best available approximatio. IVF may result i epigeetic modificatios that lead to offsprig bor with impritig disorders. 22 I practice, however, this sample has bee show to be comparable to the ormal populatio i terms of emotioal ad behavioral adjustmet. This does ot rule out the possibility that epigeetic modificatios have occurred, although this would presumably have the effect of itroducig greater pheotypic differeces betwee parets ad childre i this sample compared with aturally coceived offsprig ad parets. The fidigs have cliical implicatios for the desig of prevetive itervetios: cocludig that a putative causal risk factor such as paretal depressio symptom exposure cofers its effect through a evirometal mechaism suggests that this factor ca be targeted to prevet ad treat child ad adolescet depressio. I support of this, evidece suggests that chages i curret materal depressio status have correspodig effects o child outcome. 23 The evirometal effect of materal depressio appears to be stroger i girls tha i boys, suggestig that depressio i mothers carries a particular risk effect for daughters, implyig that itervetios targeted at treatig paretal depressio may have a larger impact o girls as supported by a recet metaaalysis of prevetive itervetios. 24 I additio, paret depressio was foud to have a evirometal lik with axiety/depressio symptoms from childhood through to early adolescece. Little support was foud for the role of geetic factors o the trasmissio of depressio symptoms apart from for boys, ad this cocurs VOLUME 50 NUMBER 5 MAY 2011

10 ENVIRONMENTAL TRANSMISSION OF DEPRESSION SYMPTOMS with a prior geetically sesitive study usig a childre-of-twis model. 3 This does ot egate the role of child- ad adult-specific geetic factors i the etiology of depressio symptoms, which is a well-established ad cosistet fidig. It is likely that the etiology ad trasmissio of depressio are caused by a complex iterplay betwee geetic ad evirometal factors. Accepted Jauary 19, Ms. Lewis ad Drs. Collishaw ad Thapar are with the Child ad Adolescet Psychiatry Sectio ad the Medical Research Coucil Cetre for Neuropsychiatric Geetics ad Geomics, Cardiff Uiversity. Dr. Rice is with the Divisio of Psychology ad Laguage Scieces, Uiversity College Lodo. Dr. Harold is with the College of Biological Scieces, Uiversity of Leicester. This study was supported by a Wellcome Trust showcase award ad a Wellcome Trust Project grat. We thak the families who participated i this study ad our fertility ceter collaborators. We thak Professors Dale Hay ad Jacky Boivi of Cardiff Uiversity for assistace i the study desig ad Allyso Lewis ad Val Russell, also of Cardiff Uiversity, for ateatal data collectio ad admiistrative support. Disclosure: Ms. Lewis has received fudig from the Ecoomic ad Social Research Coucil ad the Nuffield Foudatio. Drs. Rice, Harold, Collishaw, ad Thapar report o biomedical fiacial iterests or potetial coflicts of iterest. Correspodece to Gemma Lewis, B.Sc., MRC Cetre for Neuropsychiatric Geetics ad Geomics, Departmet of Psychological Medicie ad Neurology, Cardiff Uiversity, Heath Park, Cardiff, CF14 4 XN, UK; LewisG16@Cardiff.ac.uk /$36.00/ 2011 America Academy of Child ad Adolescet Psychiatry DOI: /j.jaac REFERENCES 1. Weissma M, Wickramarate P, Nomura Y, Warer V, Pilowsky D, Verdeli H. Offsprig of depressed parets: 20 years later. Am J Psychiatry. 2006;163(6): Tully EC, Iacoo WG, McGue M. A adoptio study of paretal depressio as a evirometal liability for adolescet depressio ad childhood disruptive disorders. Am J Psychiatry. 2008; 165(9): Silberg J, Maes H, Eaves L. Geetic ad evirometal iflueces o the trasmissio of paretal depressio to childre s depressio ad coduct disturbace: a exteded Childre of Twis study. J Child Psychol Psychiatry. 2010;51: Rice F, Harold GT, Thapar A. The lik betwee depressio i mothers ad offsprig: A exteded twi aalysis. Behav Geet. 2005;35(5): Eley T, Deater-Deckard K, Fomboe E, Fulker DW, Plomi R. A adoptio study of depressive symptoms i middle childhood. J Child Psychol Psychiatry. 1998;39(3): Silberg J, Pickles A, Rutter M, et al. The ifluece of geetic factors ad life stress o depressio amog adolescet girls. Arch Ge Psychiatry. 1999;56: Fergusso DM, Horwood LJ, Lyskey MT. Materal depressive symptoms ad depressive symptoms i adolescets. J Child Psychol Psychiatry. 1995;36(7): Cortes RC, Flemig CB, Catalao RF, Brow EC. Geder differeces i the associatio betwee materal depressed mood ad child depressive pheomea from grade 3 through grade 10. J Youth Adolesc. 2006;35: Bureau JF, Easterbrooks MA, Lyos-Ruth K. Materal depressive symptoms i ifacy: Uique cotributios to childre s depressive symptoms i childhood ad adolescece. Dev Psychopathol. 2009;21: Thapar A, McGuffi P. A twi study of depressive symptoms i childhood. Br J Psychiatry. 1994;165: Kedler KS, Garder CO, Lichtestei P. A developmetal twi study of symptoms of axiety ad depressio: evidece for geetic iovatio ad atteuatio. Psychol Med. 2008;38: Harold GT, Rice F, Hay DF, Boivi J, Va de Bree M, Thapar A. Familial trasmissio of depressio ad atisocial behaviour symptoms: disetaglig the cotributio of iherited ad evirometal factors ad testig the mediatig role of paretig [published olie ahead of prit September 22, 2010]. Psychol Med. doi: /S Shelto KH, Boivi J, Hay D, et al. Examiig differeces i psychological adjustmet problems amog childre coceived by assisted reproductive techologies. It J Behav Dev. 2009;33(5): Zigmod AS, Saith RP. The hospital axiety ad depressio scale. Acta Psychiatr Scad. 1983;67(6): Bjellad I, Dahl AA, Haug TT, Neckelma D. The validity of the Hospital Axiety ad Depressio Scale. A updated literature review. J Psychosom Res. 2002;52(2): Thapar A, McGuffi P. Validity of the shorteed Mood ad Feeligs Questioaire i a commuity sample of childre ad adolescets: a prelimiary research ote. Psychiatry Res. 1998; 81(2): Johso JH, McCutcheo S. Assessig life stress i older childre ad adolescets: prelimiary fidigs with the life evets checklist. I: Saraso IE, Spielberger CD, eds. Stress ad Axiety. New York: Hemisphere; 1980: Rice F, Harold G, Thapar A. Assessig the effects of age, sex ad shared eviromet o the geetic aetiology of depressio i childhood ad adolescece. J Child Psychol Psychiatry. 2002; 43(8): Glowiski AL, Madde PA, Bucholz KK, Lyskey MT, Heath AC. Geetic epidemiology of self-reported lifetime DSM-IV major depressive disorder i a populatio-based twi sample of female adolescets J Child Psychol Psychiatry. 2003;44: Silk JS, Shaw DS, Skuba EM, Olad AA, Kovacs M. Emotio regulatio strategies i offsprig of childhood-oset depressed mothers. J Child Psychol Psychiatry. 2006;47(1): Haigto L, Ramchadai P, Stei A. Paretal depressio ad child temperamet: assessig child to paret effects i a logitudial populatio study. Ifat Behav Dev. 2010;33: DeBau MR, Niemitz EL, Feiberg AP. Associatio of i vitro fertilizatio with Beckwith-Wiedema sydrome ad epigeetic alteratios of LIT1 ad H19. Am J Hum Geet. 2003;72(1): Weissma M, Pilowsky D, Wickramarate P, et al. Remissios i materal depressio ad child psychopathology. JAMA. 2006; 295(12): Stice E, Shaw H, Boho C, Marti CN, Rohde P. A meta-aalytic review of depressio prevetio programs for childre ad adolescets: factors that predict magitude of itervetio effects. J Cosult Cli Psychol. 2009;77(3): VOLUME 50 NUMBER 5 MAY

11 LEWIS et al. TABLE S1 Correlatios Preseted Separately for Child Depressio ad Axiety Symptoms Geetically Related Geetically Urelated Correlatio Correlatio Child depressio symptoms T1 Mother-rated child symptoms Father-rated child symptoms Child axiety symptoms T1 Mother-rated child symptoms Father-rated child symptoms Child depressio symptoms T2 Child axiety symptoms T Note: T1 data collectio i 2006; T2 data collectio i e1 VOLUME 50 NUMBER 5 MAY 2011