Genetic and Environmental Risk Factors Associated with Obsessive-Compulsive Disorder and Its Symptom Dimensions: a Twin Study

Genetic and Environmental Risk factors associated with Obsessive-Compulsive Disorder and its symptom dimensions: A twin study

Clara López Solà

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School of Medicine University of Barcelona Department of Clinical Sciences Y TED WITH SOCIA OM DIMENSIONS: A TWIN STUD ORS AS ACT AL RISK F GENETIC AND ENVIRONMENT SIVE-COMPULSIVE DISORDER AND ITS SYMPT OBSES

Doctorate in Medicine Research Line: Clinical and Experimental Neuroscience Research Group: Psychiatry and Mental Health

2015

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GENETIC AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH OBSESSIVE-COMPULSIVE DISORDER AND ITS SYMPTOM DIMENSIONS: A TWIN STUDY

DOCTORAL THESIS CLARA LÓPEZ SOLÀ

SUPERVISORS Ben J. Harrison

José M. Menchón

JULY 2015

L'ignorance affirme ou nie; Sciences doute (“La ignorancia afirma o niega rotundamente; La ciencia duda” François Marie Arouet (Voltaire)

It would be possible to describe everything scientifically, but it would make no sense; it would be without meaning, as if you described a Beethoven symphony as a variation of wave pressure. (“Sería posible describir todo científicamente, pero no tendría ningún sentido; Carecería de significado describir la sinfonía de Beethoven como una variación de la presión de la onda auditiva”) Albert Einstein

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TABLE OF CONTENT

ACKNOWLEDGMENT...... ϵ

LIST OF TABLES...... 1ϭ

LIST OF FIGURES...... 1ϯ

LIST OF ABBREVIATIONS...... 1ϱ

LIST OF PUBLICATIONS...... ϭϳ

CHAPTER 1: INTRODUCTION...... ϭϵ 1.1. Obsessive-Compulsive Disorder (OCD). An Introduction to the

Multidimensional Approach...... 2ϭ 1.2. Obsessive-Compulsive and Related Disorders (OCRDs)...... …...... 2ϰ 1.3. Obsessive-Compulsive Disorder as an Anxiety Disorder (AD)………………..…….Ϯϴ 1.4. Twin Studies……………………………………………………………………………………………….ϯϬ 1.4.1. The Value of Twin Studies in Psychiatry…………………………………………..3Ϭ 1.4.2. Twin Studies in OCD with other Anxiety Disorders…………………………..3ϭ 1.4.3. Twin Studies in Obsessive-Compulsive and Related Disorders...... 3Ϯ 1.5. Summary...... 3ϯ

CHAPTER 2: GENERAL AIMS & HYPOTHESIS...... 3ϱ

CHAPTER 3: METHODS……………...... 4ϭ 3.1. Participants…………………………………………………………………………………………………….4ϯ 3.2. Psychometric Measures………………………………………………………………………………….4ϰ 3.ϯ. Statistical Analysis…………………………………………………………………………………………..ϰϲ

CHAPTER 4: RESULTS…………………………………………………………………………………………….ϰϵ

STUDY 1...... ϱϯ

STUDY 2...... 7ϭ

STUDY 3...... 1Ϭϵ

CHAPTER 5: DISCUSSION & CONCLUSIONS...... 14ϱ 5.1. Summary of Key Findings...... 1ϰϳ 5.2. General Discussion and Implications for Future Research...... 1ϰϵ 5.2.1. Implications for Genetic Research in OCD, ADs and OCRDs……………1ϰϵ 5.2.2. Implications for Research on Environmental Risk Factors……………...15ϱ 5.2.3. Gene-by-Environmental Interaction Factors…………………………………..1ϱϲ 5.2.4. Nosological Implications…………………………………………………………………16ϭ 5.2.5. Clinical Implications………………………………………………………………………..16Ϯ 5.3. Limitations...... 16ϰ 5.4. Conclusions...... 16ϱ

CHAPTER 6: SUMMARY IN SPANISH…………………………………………………………………….1ϲϳ

CHAPTER 7: REFERENCES……………………………………………………………………………………..18ϭ

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Y aquí, debajo de un árbol grande y frondoso de un pueblecito de l’Alt Empordà, Calabuig, y envuelta por el calor agradable del mes de mayo, me dedico a escribir los agradecimientos de esta tesis. Echo la vista atrás y me remonto a aquel enero de 2010 en Melbourne. Nunca pensé que aquella aventura de 4 meses daría lugar a lo que hoy defiendo como mi tesis doctoral, creo que nunca llegué a ser 100% consciente de lo que se iniciaba en aquel momento de cambio personal.

I can’t start the acknowledgments without saying a big thank you to my supervisor, Professor Ben Harrison. Professor Harrison has shown me how to write and organise a paper, to communicate clearly and succinctly, to discriminate between what is relevant and what is not, and to be creative and much more. You’ve always been there, although separated by thousands of miles. Thank you for helping during this long process, for trusting me in critical moments and, for motivating me to keep on with this project when everything seemed impossible. It was worth it! I’ve learnt a lot in this experience with you. You have shown me how to set up a successful research project and what it takes to do research in psychiatry. Words cannot describe the overwhelming gratitude I have for you. It’s been a pleasure for me to work under your supervision. Without you, none of this would have been possible. I would also like to thank to the ATR (especially Jenny and Shaie), John Hopper, Minh Bui, and Leo for all your interest and dedication from the beginning of the process and to all the 2,495 Australian twins that dedicated time and effort to answer our survey. Thank you so much! Lastly, thanks to Mike and Brad for all your help during my stay in Richmond, Virginia.

He d’estendre la meva gratitud al Professor Menchón per haver-me donat l’oportunitat, sense conèixer-me, de permetre’m formar part del gran equip de Bellvitge. Gràcies per oferir-me la possibilitat de demanar una beca pre-doctoral amb tu, que m’ha permès dedicar-me 100% al desenvolupament i aprenentatge de la metodologia d’aquesta tesis sense tenir carga assistencial i amb total flexibilitat. Gràcies sinceres, sense aquest temps i dedicació res hagués estat possible.

No puc deixar de dedicar unes paraules a la Dra. Alonso. Gràcies Pino per la teva saviesa emocional i professional, pel teu savoir-faire, per la teva senzillesa i profunditat alhora. Sempre amb bona cara, sempre facilitant el terreny, sempre ajudant, sense complicar les coses. He après de tu com a persona i com a professional, gràcies per aquests anys d’aprenentatge sostingut.

Al grup de TOC, gràcies Eva i Cinto, heu estat tremendament generosos amb mi i disponibles en tot moment per a preguntes i discussions científiques “tocquianes”, i per d’altres trobades menys formals. No puc deixar de mencionar al grup de neuroimatge, tres dels ara quatre anys que porto a Bellvitge han estat allà. Tot i que no dedicant-me directament a la vostra àrea específica, ocupava un lloc i sempre m’heu fet sentir que formava part del vostre grup de treball. Gràcies Carles per amenitzar molts dels moments i confiar en mi durant el projecte de “symptom provocation” i ara amb els hoarders, al Nacho per les teves ajudes informàtiques constants i la teva paciència, i a les noves, o ja no tant noves incorporacions, a la Ximena, Marta C, Maria, Andrés i recentment Oren i Mònica. Un agraïment molt especial a l’Esther Via, encara recordo el primer dia que vaig arribar a Bellvitge i em vas acollir fent-me sentir a casa, en cap moment vaig notar que era una estranya. Des de llavors fins ara has estat en tots els moments importants. I a la Marta Subirà, gràcies pel teu “temple”, per la

9 teva sinceritat i humilitat, per saber escoltar i calmar amb poques paraules. A totes dues gràcies sentides, mai a la feina meu deixa’t de banda i m’heu fet sentir que el que jo feia tenia cabuda.

Dels despatxos “ala nord” no puc deixar de mencionar a la Rosa, gran amiga i companya. Gràcies per tots els moments d’escolta activa, de riures, de pors hipocondríaques compartides, gràcies per deixar-me mostrar obertament qui era. I al Narcís, gràcies per confiar en mi en moments on jo no hi confiava i seguir volent apostar.

A tu Fullana, per haver-me guiat en el últim any de residència, haver-me posat en contacte amb l’equip de Bellvitge, i haver estat, tot i en la distància, seguint el meu camí.

A todas las personas que más cerca o más lejos han estado soportando mis altos y bajos, mis arrebatos, mis desorientaciones vocacionales, mis alegrías y mis miedos... A totes i tots vosaltres gràcies pel suport emocional en tot tipus d’històries de mil colors més enllà de lo professional: Nohemi, África, Judith, Nuri, Romi, Patri, Susa, Roger, Albert, Pedro, Sandra S, Itziar... Em sento orgullosa de formar part de les vostres vides i de poder seguir escrivint més històries junts. Al meu grup de la Uni Sarita, Xavi, Sandra, Andrea, Romina, Gerard, Darina... i d’altres més...gràcies per seguir, uns de més lluny i d’altres més a prop, aquest periple de la tesi i fer l’esforç de continuar en contacte! A ti Lorena, porque nuestros caminos se bifurcaron aquel enero de 2010 y ello nos ha permitido seguir a cada una nuestra leyenda personal. Gracias por seguir compartiendo momentos e instantes únicos.

A toda mi familia. A vosotros, mamá y papá que directa o indirectamente me pusisteis al frente de esta travesía académica, gracias por vuestro soporte incondicional. A ti Jesús por mantener el equilibrio familiar en muchos momentos, todo ello desde la sombra. Gracias a vosotras Sandra y Nuria por el acercamiento cálido de los últimos años. Y han seguido los cambios, cambios dinámicos que trasforman los marcos familiares rígidos en flexibles, unos se van y otros vienen. A ti mare, gracias por grandes consejos vitales, siempre vivirás en mi memoria, y a las nuevas incorporaciones, a ti Justina, la gran sorpresa. Muy especialmente a ti Marina, porque desde aquel 2012 que volaste a tierras lejanas haciendo camino, me he sentido igualmente acompañada en todo este trayecto, gracias por seguir tan de cerca mis cambios y por quererme incondicionalmente.

Y finalmente a ti Clemens, decirte que has estado de pleno involucrado durante los años en que este proyecto se ha ido gestando. En ese mismo periodo hemos ido construyendo nuestra historia. Me has enseñado sin quererlo… me has mostrado sin exhibirte… me has sorprendido gratamente… he subido y bajado… pero sin duda he crecido a tu lado… Gracias por estar presente y por aprender a sostenerme a momentos. Gracias por enseñarme a confiar en mí y en lo que la vida te ofrece... Sigamos caminando con los ojos, los brazos y el corazón abiertos.

Gracias a todos por vuestra ayuda durante esta etapa. Deseando ahora, abrir otra nueva…

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16 /LVWRI3XEOLFDWLRQV 1. López-Solà C, Fontenelle LF, Bui M, Hopper JL, Pantelis C, Yücel M, Menchón JM, Alonso P, Harrison BJ. Etiological Overlap between Obsessive-Compulsive Related and Anxiety Disorder Symptoms: A Multivariate Twin Study. British J Psychiatry. 2015; accepted, in-press. IF: 7.34

2. López-Solà C, Fontenelle LF, Alonso P, Cuadras D, Foley DL, Pantelis C, et al. Prevalence and heritability of obsessive-compulsive spectrum and anxiety disorder symptoms: A survey of the Australian Twin Registry. Am J Med Genet B Neuropsychiatr Genet. 2014; 165B (4): 314-25. IF: 3.27

3. López-Solà C, Gutiérrez F, Alonso P, Rosado S, Taberner J, Segalàs C, et al. Spanish version of the Dimensional Obsessive-Compulsive Scale (DOCS): Psychometric properties and relation to obsessive beliefs. Compr Psychiatry. 2014; 55(1): 206-14. IF: 2.26

4. Alonso P, López-Solà C, Gratacós M, Fullana MA, Segalàs C, Real E, Cardoner N, Soriano-Mas C, Harrison BJ, Estivill X, Menchón JM. The interaction between Comt and Bdnf variants influences obsessive-compulsive-related dysfunctional beliefs. J Anxiety Disord. 2013; 27(3): 321-7. IF: 2.97

5. Alonso P, Orbegozo A, Pujol J, López-Solà C, Fullana MA, Segalàs C, et al. Neural correlates of obsessive-compulsive related dysfunctional beliefs. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 47C: 25-32. IF: 4.025

6. Subirà M, Alonso P, Segalàs C, Real E, López-Solà C, Pujol J, et al. Brain Structural Alterations in Obsessive-Compulsive Disorder Patients with Autogenous and Reactive Obsessions. PLoS One. 2013; 8(9):e75273. IF: 3.5

7. Fullana MA, Cardoner N, Alonso P, Subirà M, López-Solà C, Pujol J, et al. Brain regions related to fear extinction in obsessive-compulsive disorder and its relation to exposure therapy outcome: a morphometric study. Psychol Med. 2013; 18:1-12. IF: 6.16

17 8. Segalàs C, Alonso P, Orbegozo A, Real E, Subirà M, López-Solà C, et al. Brain structural imaging correlates of olfactory dysfunction in obsessive-compulsive disorder. Eur Arch Psychiatry Clin Neurosci. 2014; 264(3):225-233. IF: 3.36

9. Real E, Gratacòs M, Labad J, Alonso P, Escaramís G, Segalàs C, Subirà M, López-Solà C, et al. Interaction of SLC1A1 gene variants and life stress on pharmacological resistance in obsessive-compulsive disorder. Pharmacogenomics J. 2013; 13(5): 470- 5. IF: 5.513

10. Alonso P, Gratacós M, Segalàs C, Escaramís G, Real E, Bayés M, Labad J, López-Solà C, et al. Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder. J Psychiatry Neurosci. 2012; 37(4):273-81. IF: 7.49

11. Binelli C, Muñiz A, Sanches S, Ortiz A, Navines R, Egmond E, Udina M, Batalla A, López-Solà C, Crippa JA, Subirà S, Martín-Santos R. New evidence of heterogeneity in social anxiety disorder: Defining two qualitatively different personality profiles taking into account clinical, environmental and genetic factors. Eur Psychiatry. 2015; 30(1):160-5. IF: 3.21

Articles Submitted in International Journals: 1. López-Solà C, Fontenelle LF, Verhulst B, Neale M, Menchón JM, Alonso P, Harrison BJ. Distinct etiological influences on obsessive-compulsive symptoms dimensions: a multivariate twin study.

2. Davey C, López-Solà C, Bui M, Hopper JL, Pantelis C, Fontenelle LF, Harrison, JB. The structure of negative mood states: Twin-study evidence for a causal influence of stress-tension on depression and anxiety.

3. Fusté G, Gil MA, López-Solà C, Rosado S, Bonillo A, Pailhez G, Bulbena A, Pérez V, Fullana MA. Psychometric properties of the Spanish version of the Panic Disorder Severity Scale (PDSS).

4. Goldberg X, Soriano-Mas C, Alonso P, Segalàs C, Real E, López-Solà C, Subirà M, Via E, Menchón JM, Cardoner N. Predictive value of familial risk, stressful life events and gender on the course of obsessive- compulsive disorder.

CHAPTER 1

INTRODUCTION

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34 Introduction Clara López-Solà

CHAPTER 2

GENERAL AIMS AND HYPOTHESES

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Clara López-Solà General Aims and Hypotheses 39

CHAPTER 3

METHODS

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44 Methods Clara López-Solà 7KHVXUYH\LVFRPSRVHGE\WKHIROORZLQJTXHVWLRQQDLUHV OCRDs self-reported questionnaires:

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46 Methods Clara López-Solà LQGHSHQGHQWSDWKZD\PRGHOVZHUHFRQGXFWHGLQRUGHUWRVLPSOLI\WKHGDWD6HH Study 2IRUPRUHLQIRUPDWLRQ ,&( )$/&21 DQDO\VLV ,QIHUHQFHRQFDXVDWLRQIURPH[DPLQDWLRQRIIDPLOLDO FRQIRXQGLQJ 7KRVH QRYHO DQDO\VHV ZHUH XVHG WR DVVHVV WKH SRWHQWLDO FDXVDO UHODWLRQVKLS EHWZHHQ 2&' DQG WKH $'V DQG 2&5'6 6HH Study 2 DQG LWV VXSSOHPHQWDU\PDWHULDOIRUPRUHLQIRUPDWLRQ 0XOWLYDULDWHWZLQDQDO\VLVXVLQJFRQWLQXRXVDQGFDWHJRULFDOYDULDEOHVLQWKH VDPHPRGHODQGFRQWUROOLQJE\DJHDQGJHQGHU3OHDVHVHHStudy 3IRUPRUH LQIRUPDWLRQ

Clara López-Solà Methods 47

CHAPTER 4

RESULTS

7KHSUHVHQWWKHVLVFRQWDLQVWKHIROORZLQJUHVXOWV 3DSHU /ySH]6ROj&)RQWHQHOOH/)$ORQVR3&XDGUDV')ROH\'3DQWHOLV&3XMRO-<F HO 0&DUGRQHU16RULDQR0DV&0HQFKyQ-0+DUULVRQ%- Prevalence and Heritability of Obsessive-Compulsive Spectrum and Anxiety Disorder Symptoms: A Survey of the Australian Twin Registry. 3DSHU /ySH]6ROj&)RQWHQHOOH/)%XL0+RSSHU-/3DQWHOLV&<FHO00HQFKyQ-0 $ORQVR3+DUULVRQ%- Etiological Overlap between Obsessive-Compulsive Related and Anxiety Disorder Symptoms: A Multivariate Twin Study. 3DSHU /ySH]6ROj&9HUKXOVW%1HDOH0)RQWHQHOOH/)3DQWHOLV&0HQFKyQ-0$ORQVR3 +DUULVRQ%- Distinct etiological influences on obsessive-compulsive symptom dimensions: a multivariate twin study.

Clara López-Solà 51

Study 1

American Journal of Medical Genetics: Part B

RESEARCH ARTICLE

Neuropsychiatric Genetics Prevalence and Heritability of Obsessive-Compulsive Spectrum and Anxiety Disorder Symptoms: A Survey of the Australian Twin Registry Clara Lo´pez-Sola`,1,2,3 Leonardo F. Fontenelle,4,5,6 Pino Alonso,1,2,3 Daniel Cuadras,7 Debra L. Foley,8 Christos Pantelis,9 Jesus Pujol,10 Murat Yu¨cel,11 Narcı´s Cardoner,1,2,3 Carles Soriano-Mas,1,3 Jose´ M. Menchoń,1,2,3 and Ben J. Harrison9* 1Bellvitge Biomedical Research Institute-IDIBELL, Department of Psychiatry, Hospital de Bellvitge, Barcelona, Spain 2Department of Clinical Sciences, Bellvitge Campus, University of Barcelona, Barcelona, Spain 3CIBERSAM (Centro de Investigacioń en Red de Salud Mental), Carlos III Health Institute, Madrid, Spain 4Programa de Ansiedade e Depressaõ, Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil 5Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil 6Instituto de Sau´de da Comunidade, Universidade Federal Fluminense (UFF), Rio de Janeiro, Brazil 7Statistics Unit, Sant Joan de Deu Fundation, Esplugues de Llobregat, Barcelona, Spain 8Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia 9Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Melbourne, Australia 10CRC-Hospital del Mar, CIBERSAM G21, Barcelona, Spain 11Monash Clinical and Imaging Neuroscience Laboratory, School of Psychology and Psychiatry, Monash University, Clayton, Australia

Manuscript Received: 29 October 2013; Manuscript Accepted: 26 March 2014

While past twin studies indicate moderate levels of heritability of incorporating sex-specific effects, using OpenMx. Prevalence “obsessive-compulsive related” and anxiety disorder symptoms, estimates ranged from 1.6% in the symptoms of generalized no single study has reported such estimates in the same twin anxiety to 16.9% for social phobia. Female twins demonstrated population nor examined potential genetic sex differences. significantly higher prevalence rates across all domains with the We assessed symptoms of obsessive-compulsive disorder, exception of obsessive-compulsive symptoms. Additive genetic body dysmorphic disorder, hoarding disorder, hypochondriasis, factors accounted for a moderate proportion of the total liability panic disorder, social phobia and generalized anxiety disorder in to each symptom domain. Evidence suggesting qualitative 2,495 adult twins (1,468 female). Prevalence estimates for the corresponding symptom measures were determined using em- Conflict of interest: None. pirically derived cut-off scores. Twin resemblance was assessed Grant sponsor: Early Career Researcher Grant from The University of by Pearson correlations and biometrical model-fitting analyses, Melbourne; Grant sponsor: National Health and Medical Research Council of Australia (NHMRC) Clinical Career Development Fellow- ship; Grant number: 628509; Grant sponsor: Spanish Ministry of Education, Culture and Sport; Grant number: FPU12/01636; How to Cite this Article: Grant sponsor: ‘Miguel Servet’ contract from the Carlos III Health Lo´pez-Sola` C, Fontenelle LF, Alonso P, Institute; Grant number: CP10/00604; Grant sponsor: NHMRC Senior Cuadras D, Foley D, Pantelis C, Pujol J, Principal Research Fellowship; Grant number: 628386; Grant sponsor: Yu¨cel M, Cardoner N, Soriano-Mas C, NARSAD Distinguished Investigator Award; Grant sponsor: NHMRC Menchoń JM, Harrison BJ. 2014. Senior Research Fellowship; Grant number: 1021973. Prevalence and Heritability of Obsessive- Correspondence to: Compulsive Spectrum and Anxiety A/Prof. Ben J. Harrison, Melbourne Neuropsychiatry Centre, The Disorder Symptoms: A Survey of the University of Melbourne Level 3, 161 Barry Street, Carlton, 3053 Australian Twin Registry. Melbourne, Australia. E-mail: [email protected] Article first published online in Wiley Online Library Am J Med Genet Part B 165B:314–325. (wileyonlinelibrary.com): 23 April 2014 DOI 10.1002/ajmg.b.32233

exto Clara López-Solà 55 Ó 2014 Wiley Periodicals, Inc. 314 LO´ PEZ-SOLA` ET AL. 315 genetic sex differences (i.e., distinct genetic influences between “OC-related disorders,” heritability rates have also been estimated genders) was observed for body dysmorphic concern and panic for compulsive hoarding symptoms (50%), body dysmorphic symptoms, while quantitative differences were observed for concern (44%), and skin picking (40%). This latter evidence has hoarding and social phobia symptoms, indicating stronger been marshalled from a single study of adult female twins from heritability in females. Novel findings in this study include the “TwinsUK” registry [Iervolino et al., 2009; Monzani et al., the observation of probable genetic sex differences in liability 2012a,b]. towards hoarding symptoms and dysmorphic concern, as well as To extend such recent findings, we performed the current study the lack of such differences in hypochondriasis. The trend to compare prevalence and heritability rates for OC-related and towards qualitative sex differences in panic symptoms has anxiety disorder symptoms in an adult twin population, including some intuitive appeal with regard to biological-experimental male and female twin pair combinations, and with the intention of models of panic. Ó 2014 Wiley Periodicals, Inc. testing the influence of gender on estimated heritability. While the “TwinsUK” sample included females twins aged up to 86 years, we Key words: obsessive-compulsive related disorders; anxiety restricted the recruitment of twins to between 18 and 45 years; that disorders; twins; genetic sex differences; heritability is, approximating the age range at which the onset of these disorders is most prevalent in the general population [Kessler et al., 2012]. We also extended the current survey to examine hypochondriasis INTRODUCTION symptoms given parallel debate regarding its optimal classification in relation to anxiety and OC-related disorders [Phillips Introduction of the Diagnostic and Statistical Manual of Mental et al., 2010]. Thus, the primary objective of the current study Disorders (DSM-5) has seen obsessive-compulsive disorder (OCD) was to examine the prevalence and heritability of OC-related reclassified from the anxiety disorders category into a new grouping and anxiety disorder symptoms together in a twin population, of “OC-related” disorders, including body dysmorphic disorder, as well as the potential influence of genetic sex differences in trichotillomania (hair-pulling disorder); as well as excoriation explaining these heritability rates. (skin picking) disorder and hoarding disorder as a new diagnosis. Separately, each of these disorders appears to have a clear familial aggregation [Bienvenu et al., 2000; Hettema et al., 2001; Chacon MATERIALS AND METHODS et al., 2007; Pertusa et al., 2008] as well as a higher prevalence rates in Participants females—at least in relation to the anxiety disorders category. Much Twins were recruited from the Australian Twin Registry (ATR)—a less is known about the influence of gender on the prevalence and large national voluntary twin registry [overviewed in Hopper heritability of OC-related disorders and whether there may exist et al., 2013]. A total of 6,950 participants (3,475 twin pairs) were potential genetic sex differences in terms of current estimated emailed by the ATR on our behalf to participate in an online survey heritability rates. Because of the historical link between OCD of their experience of OC-related and anxiety symptoms. Twins and other anxiety disorders, there are actually very few studies to were selected nation-wide according to age (18–45 years), zygosity, have assessed both categories of disorders in the same population at and gender combination, and a minimum duration of 6 months the same period of time. Epidemiological twin studies represent since having participated in an ATR-affiliated research study. Twin one such example, whereby the majority of published studies pairs were randomly selected to receive the study approach email— correspond to either the former (DSM-IV) conceptualization of averaging 112 twin pairs/per week. After 2 weeks, non-responding anxiety disorders or the recently adopted conceptualization of twins were followed up with a reminder email, followed by a further “OC-related disorders” [Monzani et al., 2014]. Given the ongoing telephone reminder 2 weeks later. A second phone follow up was debate that surrounds the DSM-5 revisions, there appears to be performed for all remaining non-responders. This data collection merit in the completion of studies that assess both groups of phase ran for approximately 1 year between June 2011 and disorders in the same population. May 2012 with an overall response rate of 35.9%. We obtained a Twin studies represent an important research platform in psy- final sample of 2,495 twins (1,468 females and 1,027 males; Fig. 1). chiatry that allows estimation of the relative importance of genetic (i.e., heritable) and environmental influences on complex traits [Neale and Cardon, 1992]. Previous twin studies of anxiety symp- Psychometric Measures toms and disorders have confirmed that additive genetic risk factors After providing informed consent and responding to a small are important to their etiology with the estimated heritability of number of sociodemographic factors twins completed the follow- anxiety disorders ranging between 23% and 40% [Hettema ing self-report measures in this order: (1) Obsessive Compulsive et al., 2001; Mosing et al., 2009; Tambs et al., 2009]. With regard Inventory-Revised (OCI-R) [Foa et al., 2002]; (2) Hoarding Rating to OCD, the heritability of diagnosable cases has been estimated at Scale-Self Report (HRS-SR) [Tolin et al., 2010]; (3) Social Phobia 29% [Tambs et al., 2009], with higher rates (48%) estimated in Inventory (SPIN) [Connor et al., 2000]; (4) Anxiety Sensitivity relation to the experience of obsessive-compulsive symptoms Index (ASI) for panic symptoms [Reiss et al., 1986]; (5) Dys- [Clifford et al., 1984; Iervolino et al., 2011]. In the latter instance, morphic Concern Questionnaire (DCQ) [Oosthuizen et al., the heritability of obsessive-compulsive symptoms has been 1998]; (6) Skin-Picking Scale (SPS) [Keuthen et al., 2001]; (7) reported as stable over time and mostly equivalent across genders Whiteley Index (WI) to assess hypochondriasis symptoms in non-clinical samples [van Grootheest et al., 2009]. Regarding [Pilowsky, 1967]; (8) Depression, Anxiety, and Stress Scale-21

Clara López-Solà 316 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

improve the normality of our data Box–Cox transformations were applied [Box and Cox, 1964]. Box–Cox represents a family of power transformations that extend traditional methods in order to identify the optimal normalizing transformation regardless of whether the variable is negatively or positively skewed. In Box–Cox l l transformation [y t ¼ (y 1)/l] lambda (l) can adopt an almost infinite number of values to calibrate a transformation to be maximally effective in moving a variable toward normality. We therefore estimated the best l for each variable, separately. Only with regard to the DCQ was the estimated l statistic equal to 0. In this case, a log transformation was applied to normalize the data. Maximum likelihood model fitting analyses were then conducted on transformed continuous variables. Estimation of cross-twin–within-trait correlations. The Box– Cox transformed data was used to estimate cross twin—within-trait correlations. Comparing cross-twin (MZ vs. DZ) within-trait correlations provides a first impression of the contribution of genetic and environmental influences on a trait [Neale and Cardon, 1992]. To investigate sex differences, twin correlations were calculated separately for the five zygosity groups: MZ males, FIG. 1. Flow of the eligible twins through the study. The DZ males, MZ females, DZ females, and DZ opposite-sex. following zygosity and gender combinations were approached: Estimation of heritability. All twin analyses were carried out in 795 male monozygotic (MZ) pairs; 666 male dizygotic (DZ) both genders using the OpenMx package for RStudio (“http:// pairs; 755 female MZ pairs; 666 female DZ pairs, and 583 male/ openmx.psyc.virginia.edu/getOpenMx.R”). Structural equation female pairs. modeling is an analysis tool where putative genetic and environmental influences are modelled to quantify their contribution to the estimated phenotypic variance for each trait measured in a population [Neale and Cardon, 1992]. An individual’s phenotype is (DASS-21) [Antony et al., 1998]; (9) Massachusetts General Hos- decomposed into A (additive genetic factors), C (shared environ- pital-Hair Pulling Scale (MGH-HPS) [O’Sullivan et al., 1995]. The ment, shared by twins), and E (non-shared environment plus mea- DASS-21 “Stress” subscale was chosen as a proxy measure of surement error). In addition, four models were performed to test for generalized anxiety symptoms. This subscale measures persistent potential sex differences: “qualitative,” “quantitative,” “scalar,” and arousal, tension, irritability, and tendency to overreact to stressful “null” models. Qualitative sex differences refer to the estimation of events. Previous studies endorse its utility differentiating general- distinct genetic and/or environmental influences for males and ized anxiety disorder (GAD) from other anxiety disorders [Brown females, which is implied if the correlation for DZ opposite-sex is et al., 1992] as well as being strongly correlated with other measures significantly less than the correlation for the same-sex DZ twins of worry [Brown et al., 1995]. Cut-off scores were used to classify [Haworth et al., 2008]. In other words, is there evidence of distinct “clinical levels” of symptom ratings on each scale (see “supplemen- genetic and/or environmental influences on a given trait in males tary online material”). The SPS was completed if participants first versus females? Quantitative sex differences, by comparison, refer answered “yes” to one screening question: “Do you often feel the to differences in the magnitude of common genetic and environ- urge to pick your skin?” Similarly, four screening questions were mental influences when comparing MZ male and DZ male with that completed for the MGH-HPS derived from the Structured Clinical of MZ female and DZ female. In other words, is there evidence of Interview for DSM-Research Version (SCID-I/P). These screening stronger heritability of a given trait in males versus females?” In questions were included in recognition of the likely low prevalence addition, we tested the fit of a “scalar model” whereby the genetic of symptoms and to reduce the general time burden of the survey as and environmental parameters are constrained to be equal in both a whole. sexes but allowing for a different variance in each trait for males and females. Finally, we refer to the “null model” as one that equates the genetic and environmental parameters and phenotypic variance to Statistical Analysis be equal in both sexes, allowing males and females to differ in their Estimation of prevalence. Prevalence estimates for each ques- mean scores on each scale. Reduced qualitative and quantitative tionnaire were performed to quantify how many twins scored above submodels, where the shared environmental parameter is removed, the proposed cut-offs on each measure putatively distinguishing were tested to explain the observed data most parsimoniously, thus between “non-clinical” and “probable clinical” cases. A comparison optimizing model fit. The qualitative ACE models were compared of the prevalence rates between genders for each measure was with a saturated model imposing equal means and variance restric- evaluated using the Chi-square (x2) statistic. tion across twins and zygosity to maximize information. The Akaike Data normality. All questionnaire responses demonstrated information criterion (AIC) statistic [Akaike, 1987] [x2 2(df)] varying degrees of skewness in their distributions. In order to and the difference in the x2 value relative to the chance in degrees of

Clara López-Solà 57 LO´ PEZ-SOLA` ET AL. 317 freedom provided an indication of the models’ goodness of fit levels. With regard to the DCQ, 8.8% of the entire sample (6.6% [Neale and Cardon, 1992]. female and 2.2% male) scored above the lower proposed cut-off (11) while almost 2% of the sample demonstrated probably case- RESULTS level symptoms when using the higher cut-off ( 17). With regard to the Stress subscale 5.2% (3.8% female and 1.4% male) reported Sociodemographic Measures severe symptoms of persistent arousal, tension and irritability Table I provides a comparison of the demographic composition (cut-off range 13–16), whereas only 1.6% of the sample reported of the MZ and DZ twin pair combinations. A total of 503 MZ and extremely severe symptoms ( 17) (Fig. 2). 445 DZ twin pairs as well as 275 MZ and 324 DZ singleton twins Prevalence estimates for the SPS and MGH-HPS were not as well completed the survey (1,468 females and 1,027 males). The mean estimated compared to other measures, primarily due to the use of (SD) age was 34.5 (7.8) and 33.9 (8) years for MZ and DZ, initial screening questions for these scales. With regard to SPS, only respectively. With regard to demographic indices, no significant 52 twin pairs (33 MZ and 19 DZ) and 8 MZ and 4 DZ singleton twins differences were observed between MZ and DZ twins (Table I). screened positive and completed all items, whereas no complete pairs answered the full MGH-HPS. For the SPS, 24% of these participants scored above the proposed cut-off (17.8% females; Estimation of Prevalence 6.3% males). Due to the low response rate for skin picking and Table II reports the mean scores for each scale in the total sample trichotillomania it was not possible to estimate their heritability and the number of twins scoring above the proposed cut-offs on in further analyses. each scale indicating probable “case level” symptoms. Across the entire sample, these prevalence estimates ranged from 1.6% in Estimation of Cross-Twin—Within-Trait relation to GAD symptoms (DASS-Stress subscale) to 16.9% in social phobia symptoms. Female twins had a significantly higher Correlations prevalence than males across all scales, except for the OCI-R. For all measures, cross-twin—within-trait Pearson’s correlations Because two cut-off scores have been proposed for the DCQ for male and female twins were double in magnitude in the MZ (11 and 17) and DASS-21 (between 13 and 16, and 17) scales, compared to DZ pairs (Table III), consistent with a genetic influ- we only report prevalence estimates for the highest proposed cut- ence across symptom domains. Correlations for opposite-sex offs in Table II in order to classify more clinically symptomatic DZ twins were similar for same-sex DZ twins in SPIN and

TABLE I. Demographic Characteristics of the Female and Male Twin Sample

Sociodemographic (N ¼ 2,495 twins) Monozygotic (N ¼ 1,281) Dizygotic (N ¼ 1,214) t-Student/x2 (P-value bilateral) Gender Male/male 204 pairs/125 singleton 111 pairs/132 singleton Female/female 299 pairs/150 singleton 194 pairs/192 singleton — Male/female — 140 pairs Age Mean (SD) 34.5 (7.8) 33.9 (8) 1.98 (0.05) Marital status Married/partner (%) 44% 47% 3.15 (0.53) Girlfriend/boyfriend (%) 12.1% 10.6% Divorced/separate (%) 33.7% 33.6% Single (%) 10.2% 8.6% Widowed (%) 0% 0.1% Education Primary/secondary school 59.1% 56.2% 3.97 (0.27) TAFE qualification 28.1% 28.3% Undergraduate 7.8% 9.4% Post-graduate 4.9% 6.2% Employment Student (%) 43.6% 39.9% 7.12 (0.21) Unemployed (%) 8.4% 7% Self-employed (%) 18% 19.1% Part/time employed (%) 12.5% 14.3% Full/time employed (%) 17.6% 19.7%

OCD, obsessive-compulsive disorder; TAFE, technical and further education.

58 Clara López-Solà 318 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

TABLE II. Means and Standard Deviation (SD) of the Total Scores in Each Scale By Sex and By Zygosity

Mean (SD) total score Prevalence

Total Sample Female Twins Male Twins Compare Sex Zygosity (N ¼ 2,495) (N ¼ 1,468) (N ¼ 1,027) between gender Variables (cut-off) Male Female MZ DZ N % N % N % x2 (P-value) OCI-R (21) 8.3 (7.8) 8.8 (8.6) 8.6 (8.6) 8.6 (8) 218 8.7 139 9.5 79 7.7 2.4 (0.12) HRS-RS (17) 2.7 (4) 2.8 (4.8) 2.7 (4.5) 2.9 (4.6) 64 2.6 48 3.3 16 1.6 7.1 (0.008) DCQ (17) 3.6 (3.3) 4.9 (4.4) 4.2 (3.9) 4.5 (4.1) 47 1.9 41 2.8 6 0.6 15.95 (<0.001) WI (8) 2.3 (2.4) 2.8 (2.7) 2.6 (2.7) 2.6 (2.6) 170 6.8 116 7.9 54 5.3 6.65 (0.01) ASI (30) 7.3 (7.3) 9.1 (9.4) 8.3 (8.7) 8.5 (8.7) 87 3.5 69 4.7 18 1.8 15.6 (<0.001) SPIN (21) 9.9 (9.7) 12.6 (12.1) 11.5 (11.5) 11.5 (10.9) 421 16.9 298 20.3 123 12 29.8 (<0.001) DASS.Stress 3.3 (3.6) 4.5 (4.3) 4.1 (4.2) 3.9 (3.9) 40 1.6 30 2 10 1 4.39 (0.04) (17)

MZ, monozygotic; DZ, dizygotic; OCI-R, obsessive-compulsive inventory–revised; HRS-SR, hoarding rating scale-self report; DCQ, dysmorphic concern questionnaire; WI, Whiteley index; ASI, anxiety sensitivity index; SPIN, social phobia inventory; DASS.Stress, stress subscale of the depression, anxiety, and stress scale. Prevalence for total sample and separated by gender of problematic symptoms based on empirically deﬁned cut-off scores on each scale.

hypochondriasis. However, opposite-sex DZ twins correlations toms, suggesting that qualitative sex differences might be expected were lower compare to same-sex correlations for panic (ASI), in the latter domains. obsessive-compulsive (OCI-R), generalized anxiety (Stress subscale), dysmorphic concern (DCQ), and hoarding (HRS-SR) symp- Estimation of Heritability The results of our model-fitting analyses are summarized in Tables IV and V. Consistent with the pattern of observed cross- twin—within-trait correlations, additive genetic factors (A) accounted for a moderate proportion of the total variation in liability to each symptom domain. However, we observed no genetic sex differences in OCI-R, hypochondriasis (WI) and generalized anxiety (DASS-Stress) symptoms. In relation to hypochondriasis and generalized anxiety symptoms, the scalar model demonstrated best fit, indicating a significant difference in phenotypic sex variance. For OC-related symptoms, we found a tendency for hoarding symptoms (HRS-SR) and DCQ to demonstrate genetic sex differences (Table IV). The quantitative model demonstrated best fit with regard to hoarding after removing the influence of shared environment (C), which significantly improved fit (P ¼ 0.90) compared to the quantitative ACE model (P ¼ 0.63). Specifically, we identified a tendency towards greater heritability of hoarding symptoms in females (38%) versus males (25%). For DCQ, the qualitative AE model demonstrated best-fit compared to the saturated model, after removing the influence of C (P ¼ 0.12). Although this result can only be described as a trend level effect, it was more parsimonious than the full ACE qualitative model (P ¼ 0.06). Other reduced FIG. 2. Percentage of problematic symptoms for male and models testing quantitative sex differences and non-genetic sex female based on empirically defined cut-off scores on each differences did not improve the fit of the data. Therefore, in relation scale. OCI-R, Obsessive-Compulsive Inventory–Revised; HRS-SR, to DCQ, potentially distinct genetic influences occur in this Hoarding Rating Scale-Self Report; DCQ, Dysmorphic Concern domain between males and females (genetic correlation between Questionnaire; WI, Whiteley Index; ASI, Anxiety Sensitivity Index; both sexes; rG ¼ 3.58 13). SPIN, Social Phobia Inventory; DASS.Stress, Depression, Anxiety In relation to the anxiety traits (Table V), evidence for genetic sex and Stress Scale-Stress Subscale. ns, Non-significant differences differences was identified in relation to panic (ASI) and social between gender. phobia (SPIN) symptoms. For panic symptoms, the qualitative AE model demonstrated best fit when compared with the saturated

Clara López-Solà 59 LO´ PEZ-SOLA` ET AL. 319

model (P ¼ 1). The full ACE quantitative model did not significantly improve fit (P ¼ 0.13), while other submodels showed a significant loss of fit: quantitative AE (P ¼ 0.09), scalar (P ¼ 0.08), 0.07, 0.27) 0.12, 0.23) 0.14, 0.20) 0.16, 0.16) 0.01, 0.32) 0.06, 0.26) and null (P ¼ 0.01). We therefore interpret parameters offered by the qualitative AE model indicating a tendency towards distinct genetic influences between males and females. Finally, for social phobia, females (47%) demonstrated a greater heritability of symptoms compared to males (34%) in the form of a significant quantitative sex difference. 2,495 Twins) ¼

0.003, 0.26) 0.03 ( DISCUSSION This study has examined for the ﬁrst time the prevalence and heritability of both OC-related and anxiety disorder symptoms in the same twin population of male and female twin pairs. Moreover, this population was particularly well balanced in terms of the age, gender, and sociodemographic characteristics of MZ and DZ twins. As a further novelty, no previous study has investigated the existence of potential genetic sex differences—either due to a lack of male twins or small overall sample size—in relation to hoarding, body-dysmorphic and hypochondriasis symptoms. To summarize, our ﬁndings endorse existing evidence for moderate rates of heritability across all of the assessed symptom domains.

, dizygotic female twins; DZos, dizygotic opposite-sex twins; OCI-R, obsessive-compulsive inventory–revised; Significant or trend-level genetic sex differences were detected for ; DASS.Stress, stress subscale of the depression, anxiety, and stress scale; WI, Whiteley index. hoarding, DCQ, panic, and social phobia symptoms. 0.11, 0.25) 0.39 (0.29, 0.49) 0.13 ( 0.05, 0.31) 0.39 (0.29, 0.48) 0.19 (0.05, 0.32) 0.10 ( 0.03, 0.33) 0.42 (0.32, 0.51) 0.23 (0.09, 0.36) 0.06 ( 0.11, 0.25)0.06, 0.30) 0.49 (0.40, 0.56) 0.35 (0.25, 0.44) 0.24 (0.11, 0.36) 0.17 (0.04, 0.31) 0.16 ( 0.19 (0.02, 0.34) Prevalence Almost nine percent of the overall sample reported OCI-R symptoms that were severe enough to cause distress (OCI-R 21). This is consistent with a recent report of experiencing subclinical OCI-R symptoms (8.3%) in the general population [Adam et al., 2012]. Our estimates support the idea that significant OCI-R symptoms are experienced at a much greater rate in the community than is implied by assessment of diagnostic prevalence alone. With regard to compulsive hoarding symptoms, we have characterized a similar prevalence rate (2.6%) to the only other twin study utilizing the HRS-SR [2.3%; Iervolino et al., 2009]. For DCQ, we observed a similar prevalence (2%) compared to studies based on the full diagnostic assessment of community-based samples ranging from 0.7% to 2.4% [Faravelli et al., 1997; Otto et al., 2001; Koran et al., 2008]. In relation to anxiety symptoms, 3.5% reported panic-related symptoms, which is consistent with other studies of general community samples reporting a prevalence between 2.5% and 3.4% based on the assessment of diagnostic criteria [Wittchen et al., 2008; Mosing et al., 2009]. In our cohort, social phobia symptoms were slightly higher (16.9%) than in previous epidemiological surveys where diagnostic prevalence rates have been estimated between 7% and 13% [Furmark, 2002; Kessler et al., 2005]. However, as previ- MZ (95% CI) DZ (95% CI) MZM (95% CI) DZM (95% CI)ously MZF (95% emphasized, CI) DZF (95%our CI) study provides DZos (95% CI) symptom-level as opposed to TABLE III. Cross-Twin—Within-Trait Correlations for Monozygotic and Dizygotic Twins and Stratified By Sex and Zygosity (n diagnostic-level prevalence estimates. In relation to our measure of generalized anxiety, 5% of individuals reported significant and persistent arousal, tension, and irritability with 1.6% reporting extremely severe of these symptoms that would be considered in the range of other population-based estimates of GAD: 1.9% to MZ, monozygotic; DZ, dizygotic; CI, confidence interval; MZM, monozygotic male twins; DZM, dizygotic male twins; MZF, monozygotic female twins; DZF HRS-SR, hoarding rating scale-self report; DCQ, dysmorphic concern questionnaire; ASI, anxiety sensitivity index; SPIN, social phobia inventory DCQ 0.43 (0.36, 0.50) 0.10 (0.006, 0.19) 0.44 (0.32, 0.55) 0.07 ( HRS-RS 0.33 (0.25, 0.41) 0.15 (0.06, 0.24) 0.25 (0.11, 0.37) 0.14 ( OCI-R 0.41 (0.34, 0.48) 0.17 (0.06, 0.26) 0.40 (0.27, 0.51) 0.16 ( Cross-twin- within-trait correlations ASISPINDASS.StressWI 0.36 (0.28, 0.43) 0.33 (0.25, 0.46 0.40) (0.39, 0.52) 0.16 (0.07, 0.25) 0.13 (0.04, 0.34 0.18 0.22) (0.26, (0.09, 0.42) 0.27) 0.32 (0.19, 0.44) 0.29 0.17 (0.15, (0.08, 0.38 0.41) 0.25) (0.25,5.1% 0.49) 0.21 (0.03, 0.38) 0.21 (0.03,[Wittchen, 0.31 0.07 0.38) (0.18, ( 0.43) 0.35 (0.25, 0.12 0.45) 0.34 ( (0.24, 0.43) 2002]. 0.16 (0.03, 0.29) 0.19 (0.05, 0.32) Lastly, 0.10 ( the 0.00 ( prevalence of hypochondriasis

60 Clara López-Solà 320

TABLE IV. Model-Fitting Analyses to Test Sex Differences for Obsessive-Compulsive Spectrum Traits and their Parameter Estimates

Model fitting results Parameters of the models (95% CI)

Model ACE compared Models (S2 m/S2 f) 2LL df Dx2 (Ddf) AIC P with Male/female Male/female Male/female OCI-R (Obsessive-Compulsive Inventory-Revised) 1. Saturated 7,688 2,484 2. Qualitative ACE (rG ¼ FREE) 7,691 2,486 3.54 (2) 2,719 0.17 1 3. Qualitative ACE (rC ¼ FREE) 7,691 2,486 3.78 (2) 2,719 0.15 1 4. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 7,691 2,487 0.24 (1) 2,717 0.63 2 5. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 7,698 2,489 6.89 (3) 2,720 0.08 2 6. Scalar (1.3/1.4) 7,694 2,489 2.51 (2) 2,716 0.29 4 7. Null (1.3) 7,694 2,490 2.8 (3) 2,714 0.42 4 0.39 (0.18–0.45) 0.00 (0.00–0.18) 0.61 (0.55–0.68) HRS-SR (Hoarding Rating Scale–Self Report) 1. Saturated 4,047 2,484 2. Qualitative ACE (rG ¼ FREE) 4,047 2,486 0.03 (2) 925 0.99 1 3. Qualitative ACE (rC ¼ FREE) 4,047 2,486 0.07 (2) 925 0.97 1 4. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 4,047 2,487 0.23 (1) 927 0.63 2 0.07 (0.00–0.23)/0.38 0.17 (0.05–0.27)/0.00 0.76 (0.65–0.88)/0.62 (0.08–0.47) (0.00–0.25) (0.53–0.71) 5. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 4,047 2,489 0.6 (3) 930 0.90 2 0.25 (0.13–37)/0.38 / 0.75 (0.63–0.87)/0.62

Clara López-Solà (0.29–0.47) (0.53–0.71) 6. Scalar (0.3/0.31) 4,050 2,489 2.8 (0) 928 <0.001 5 7. Null (0.31) 4,050 2,490 3.4 (2) 929 0.07 5 DCQ (Dysmorphic Concern Questionnaire) 1. Saturateda 1,046 2,477 2. Qualitative ACE (rG ¼ FREE) 1,063 2,486 16.6 (9) 3,909 0.06 1 0.42 (0.20–0.52)/0.38 0.00 (0.00–0.18)/0.00 0.58 (0.48–0.70)/0.62 (0.17–0.47) (0.00–0.17) (0.53–0.71) 3. Qualitative ACE (rC ¼ FREE) 1,067 2,486 20.8 (9) 3,905 0.01 1 4. Qualitative AE (rG ¼ FREE) 1,063 2,488 16.6(11) 3,913 0.12 1 0.42 (0.30–0.52)/0.38 / 0.58 (0.48–0.70)/0.62 (0.28–0.47) (0.53–0.71) 5. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 1,066 2,487 3.2 (1) 3,908 0.07 2 GENETICS MEDICAL OF JOURNAL AMERICAN 6. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 1,070 2,489 7.06 (1) 3,908 0.01 4 7. Scalar (0.09/0.10) 1,066 2,489 3.69 (1) 3,912 0.05 4 8. Null (.09) 1,074 2,490 11.2 (2) 3,906 <0.001 4 WI (Whiteley Index) 1.Saturated 4,262 2,484 2. Qualitative ACE (rG ¼ FREE) 4,262 2,486 0.37 (2) 710 1 1 3. Qualitative ACE (rC ¼ FREE) 4,262 2,486 0.37 (2) 710 1 1 4. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 4,262 2,487 0 (1) 712 1 2 5. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 4,262 2,489 0.05(3) 716 1 2 6. Scalar (0.31/0.35) 4,262 2,489 0.2 (2) 716 0.90 4 0.29 (0.06–0.39) 0.03 (0.00–0.22) 0.68 (0.61–0.76) 7. Null (0.33) 4,265 2,490 3.1 (3) 715 0.38 4 0.30 (0.06–0.39) 0.02 (0.00–0.21) 0.68 (0.61–0.76)

Model fitting results Parameters of the models (95% CI) AL. ET

Model ACE compared Models (S2 m/S2 f) 2LL df Dx2 (Ddf) AIC P with Male/female Male/female Male/female ASI (Anxiety Sensitivity Index) 1.Saturated 7,886 2,484 2. Qualitative ACE (rG ¼ FREE) 7,885 2,486 0.88 (2) 2,913 1 1 0.27 (0.05–0.41)/0.29 0.03 (0.00–0.20)/0.04 0.70 (0.59–0.82)/0.67 (0.00–0.42) (0.00–0.31) (0.58–0.77) 3. Qualitative ACE (rC ¼ FREE) 7,884 2,486 0.15 (2) 2,912 1 1 4. Qualitative AE (rG ¼ FREE) 7,885 2,488 0.7 (4) 2,909 1 1 0.30 (0.18–0.41)/0.34 / 0.70 (0.59–0.82)/0.66 (0.24–0.42) (0.58–0.76) 5. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 7,887 2,487 2.25 (1) 2,913 0.13 2 0.29 (0.07–0.40)/0.17 0.00 (0.00–0.16)/0.14 0.71 (0.60–0.83)/0.69 (0.00–0.40) (0.00–0.34) (0.59–0.80) 6. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 7,888 2,489 2.85 (1) 2,910 0.09 4 0.28 (0.16–0.40)/0.33 / 0.72 (0.60–0.84)/0.67 (0.23–0.42) (0.58–0.76) 7. Scalar (1.3/1.5) 7,888 2,489 3.05 (1) 2,910 0.08 4 8. Null (1.4) 7,894 2,490 9.44 (2) 2,915 0.01 4 SPIN (Social Phobia Inventory) 1.Saturated 8,803 2,484 2. Qualitative ACE (rG ¼ FREE) 8,804 2,486 1.09 (2) 3,832 0.60 1 3. Qualitative ACE (rC ¼ FREE) 8,804 2,486 1.30 (2) 3,833 0.52 1 4. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 8804.4 2,487 0.20 (1) 3,831 0.65 2 0.35 (0.15–0.45)/0.44 0.00 (0.00–0.14)/0.04 0.65 (0.55–0.77)/0.53 (0.17–0.54) (0.00–0.27) 0.45–0.62) 5. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 8804.5 2,489 0.28 (3) 3,826 0.96 2 0.34 (0.23–0.45)/0.47 / 0.66 (0.55–0.77)/0.53 (0.39–0.55) (0.45–0.61) 6. Scalar (2.06/2.11) 8,808 2,489 3.63 (0) 3,830 <0.001 5 7. Null (2.09) 8,808 2,490 3.85 (1) 3,828 0.05 5 DASS.Stress (Depression, Anxiety, and Stress Scale—Stress Subscale) 1.Saturated 6,615 2,484 2. Qualitative ACE (rG ¼ FREE) 6,614 2,486 0.65 (2) 1,642 1 1 3. Qualitative ACE (rC ¼ FREE) 6,614 2,486 0.34 (2) 1,642 1 1 4. Quantitative ACE (rG ¼ 0.5; rC ¼ 1) 6,614 2,487 0.31 (1) 1,640 0.60 2 5. Quantitative AE (rG ¼ 0.5; rC ¼ 1) 6614.5 2,489 0.54 (3) 1636.5 0.92 2 6. Scalar (0.80/0.89) 6614.5 2,489 0.07 (0) 1636.5 1 5 0.32 (0.09–0.40) 0.006 (0.00–0.20) 0.67 (0.60–0.75) 7. Null (0.85) 6,618 2,490 3.73 (1) 1,638 0.05 5

S2 m, predicted variance in males; S2 f, predicted variance in females; rG, genetic correlation for opposite-sex DZ twins; rC, environmental correlation for opposite-sex twins; 2LL, minus twice the log-likelihood; df, degrees of freedom; Dx2, difference in goodness-of-fit statistic between the submodel and the specified “model compared with”; Ddf, change in degrees of freedom between the submodel and the specified model; AIC, Akaike information criterion [x2 2(df)]; P, probability; A, additive genetic effects; C, shared environmental effects; E, non-shared environmental effects; CI, confidence Interval. The best fitting models based in AIC are represented in bold text. 321 322 AMERICAN JOURNAL OF MEDICAL GENETICS PART B symptoms (6.8%) was similar to that reported in a recent survey ronmental influences operating between adolescence and adult- of health anxiety in Australia (6%) [Sunderland et al., 2013]. hood in order to explain the low heritability rate observed in young Significantly higher prevalence rates in females compared female twins. By adulthood, our results suggest a reversed pattern of to males were observed across all measures with the exception of heritability, although the actual rates being more similar between OCI-R symptoms, which taken together is generally consistent with females and males. Clearly, further studies are needed to understand prior studies in community samples [Faravelli et al., 1997; Rief how gender impacts on the etiology of hoarding taking into account et al., 2006; Koran et al., 2008; Adam et al., 2012; Kessler et al., 2012]. developmental trajectories. The highest prevalence rate in females was in relation to social In relation to DCQ, we observed a similar rate of heritability phobia, which accords well with previous estimates [Magee (42% vs. 44%) to the recent study by Monzani et al. [2012a]. Our et al., 1996; Lampe et al., 2003]. More controversy surrounds results extend their work by indicating a trend towards qualitative hypochondriasis and compulsive hoarding. Epidemiological stud- sex differences, meaning that different biological risk factors may ies of hypochondriasis are in fact very rare. Two initial studies found underlie the manifestation of these symptoms in females and males. no gender differences in hypochondriasis [Gureje et al., 1997; The DCQ, as used in our current study, may be considered to Escobar et al., 1998]. However, a representative study [Rief represent quite a broad phenotype that captures body image et al., 2001] noted significantly higher scores in women, but with concerns also common to eating disorders, which are more preva- a small effect size. Least consistent have been gender-based prevalent in females [Smink et al., 2012]. Interestingly, recent studies lence estimates in compulsive hoarding [Frost et al., 2012]. Two examining putative biological risk factors for such disorders in twin epidemiological studies have reported compulsive hoarding to be populations have provided some evidence for distinct developmen- more prevalent in males than females [Samuels et al., 2008; Iervo- tally mediated sex liability mechanisms, including levels of prenatal lino et al., 2009], although one study [Samuels et al., 2008] did not testosterone exposure [Culbert et al., 2008]. It remains untested use a standardized questionnaire to assess hoarding. In the same whether such mechanisms may contribute to sex differences in risk direction as our results, studies of clinical samples indicate a higher towards body DCQ in addition to eating disorders. prevalence of compulsive hoarding disorder in females [Steketee In relation to anxiety symptoms, we found a similar heritability and Frost, 2003; Pertusa et al., 2008; Mataix-Cols et al., 2010]. for social phobia symptoms in males compared to a recent study based on the full assessment of DSM criteria (34% vs. 39%) [Mosing et al., 2009]. When compared to studies that have assessed social Heritability phobia symptoms using the fear of negative evaluation scale, our Our findings indicate familial aggregation in all symptoms assessed heritability estimate is closest with regard to female twins (47% vs. as observed in the pattern of cross-twin—within-trait correlations. 48%) [Stein et al., 2002]. While some studies have reported no The heritability analyses suggest that this familiarity is primarily heritable sex differences in fear and phobia (including social attributable to genetic factors and not to the shared environment. phobia) [Hettema et al., 2005; Middeldorp et al., 2005], another The results of the twin analyses indicate that genetic factors account study reported that social phobia in males was explained by genetic for between 30% (i.e., hypochondriasis) and 47% (i.e., social risk factors and in females by familial-environmental factors [Ken- phobia in females), which is consistent with moderate genetic dler et al., 2002]. However, two additional twin studies performed factors contributing to the aetiology of the symptom domains separately in males and females reported lower heritability in males assessed. (20%) [Kendler et al., 2001] than females (30%) [Kendler et al., The heritability rates for OCI-R symptoms and hypochondriasis 1992a]. This latter pattern is more in agreement with our finding of appear to be in line with past studies [van Grootheest et al., 2005; a quantitative sex difference and with a recent meta-analysis in Taylor et al., 2006]. Similarly, a recent study of OCI-R symptoms separation anxiety disorder (associated with social phobia in adult- did not report evidence of genetic sex differences [Mataix-Cols hood [Hofmann et al., 2004]), where genetic risk was reported to be et al., 2013]. Ours is the first twin study to suggest no prominent double in females (52%) compared to males (26%) [Scaini et al., genetic sex differences in relation to hypochondriasis symptoms in 2012]. adults, extending the only other twin study of hypochondriasis For panic symptoms, we estimated a similar heritability (30– symptoms [Taylor et al., 2006]. For hoarding symptoms we ob- 34%) compared to previous panic disorder-level estimates [33% in served a lower heritability rate (38%, female; 25%, males) when Tambs et al., 2009; 38% in Mosing et al., 2009], but a lower rate as compared to the recent study by Iervolino et al. (49% female only). compared to a former population-based study of the ASI (45%, These rates may be explained by the prominent age differences 95% CI ¼ 0.33–0.59) [Stein et al., 1999]. This latter difference could between studies, with the latter study including female twins who be due to the reduced number of male twin pairs in the Stein et al. were on average two decades older than our current sample, study, potentially leading to an overestimation of heritability in inclusive of elderly twins. When comparing genders, our results their case [Van Dam et al., 2009]. Regarding gender, we found a indicate a higher heritability of hoarding symptoms in females. This tendency for qualitative differences, which means that a partially result contrasts with the only other twin study of hoarding symp- different set of genes might mediate the risk towards panic-related toms to formally test for genetic sex differences [Ivanov et al., 2013]. symptoms in men and women. Biological sex differences have been In adolescents, Ivanov et al. [2013] reported quantitative sex differ- recently suggested in experimental studies of physical panic attack ences, with genetic influences in boys accounting for considerably symptoms associated with a CO2 challenge [Nillni et al., 2012]. In more phenotypic variance than in girls (32% vs. 2%). These authors this study, sex differences were related to the experience of the invoked the notion of dynamic developmental genetic and envi- physical symptoms of panic rather than its cognitive correlates. Our

Clara López-Solà 63 LO´ PEZ-SOLA` ET AL. 323 results may also be in line with animal studies reporting a role for panic symptoms has some intuitive appeal with regard to sex-specific hormones (i.e., progesterone) in the manifestation of biological-experimental studies of panic. anxiety and panic [Smith et al., 2006]. Along these lines, premen- Multivariate twin studies will now be important for clarifying the strual distress has been shown to predict higher levels of panic extent to which these symptom domains express common or symptoms following a CO2 challenge [Nillni et al., 2010]. distinct genetic risk factors. Such studies are likely to be valuable Lastly, our estimated heritability of 32% for the Stress subscale of in addressing ongoing debate about the optimal diagnostic DASS-21—our proxy measure of GAD symptoms—accords with classification of OCD in relation to anxiety disorders and the other studies reporting the heritability of GAD [28–32.5%; Kendler contribution of anxiety more broadly to the etiology of OCD. et al., 2007] and when we compare to a more broadly trait of neuroticism [30–50%; Calboli et al., 2010]. A lack of evidence for ACKNOWLEDGMENTS genetic sex differences has also been previously noted in GAD [Hettema et al., 2005]. This research was facilitated through access to the Australian Twin Registry, a national resource supported by an Enabling Grant (ID Limitations 628911) from the National Health and Medical Research Council. We extend considerable thanks to staff at the Australian Twin Although the “dimensional liability” approach adopted here and in Registry and all participating twins for their valuable contribution other twin studies is a valid and widely employed method in to this study. We also thank Dr. Fruhling Rijsdijk for her advice on behavioural genetics [Jonnal et al., 2000; Hettema et al., 2001; some of the statistical analyses included herein. This study was van Grootheest et al., 2005], it will nonetheless be important to funded by an Early Career Researcher Grant from The University of replicate these findings in clinical populations. Secondly, the use of Melbourne to BJH. BJH is supported by a National Health and initial screening questions is likely to have precluded our ability to Medical Research Council of Australia (NHMRC) Clinical Career attain a sufficient sample to estimate heritability for skin picking Development Fellowship (I.D. 628509). C.L-S. is supported by the and hair pulling symptoms. However, low response rates may have Spanish Ministry of Education, Culture and Sport (FPU12/01636). been anticipated for these domains compared to others, particularly C.S-M. is funded by a ‘Miguel Servet’ contract from the Carlos III in the case of compulsive hair-pulling symptoms. Thirdly, results Health Institute (CP10/00604). Prof. C.P was supported by a from Stress subscale of DASS-21 are interpreted as a proxy measure NHMRC Senior Principal Research Fellowship (ID: 628386) and of GAD symptoms but there is reason to believe it may index a NARSAD Distinguished Investigator Award. Prof. M.Y was sup- broader vulnerability trait to anxiety and depression—the so-called ported by a NHMRC Senior Research Fellowship (ID: 1021973). “general neurotic syndrome” [Henry and Crawford, 2005]. 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Accepted the 28th of January 2015, British Journal of Psychiatry

(PDLOIURPWKHHGLWRU

BJP/2014/156281 Title: Etiological Overlap between Obsessive-Compulsive Related and Anxiety Disorder Symptoms: A Multivariate Twin Study

Dear Dr. Harrison,

Thank you for sending your paper to the British Journal of Psychiatry. I am pleased to inform you that it has been accepted for publication.

In order to publish your paper, we need the agreement of all authors in writing. Please download the Copyright Transfer and Publication Agreement form from the Author Area and clicking on the 'Manuscripts with Decisions' queue. Copies of this form must be signed by all authors and faxed back to the British > Journal of Psychiatry on +44 (0) 20 3701 2761 or emailed to [email protected] for publication to proceed.

There is no submission or publication fee for papers published in the Journal in the usual way. All papers published in the Journal become freely available online 12 months after publication. In a new initiative to maximise access to original research, authors now have the option to make their papers freely available from the time of publication, on payment of an Open Access charge. This charge is currently £2500 (or > US$4500) per article plus VAT where applicable. If you wish to take up this option, contact the BJP Editorial Assistant.

Please note that the Royal College of Psychiatrists commissions podcasts on selected articles for publication on its e-learning platform, CPD Online. The College's Podcast Editors may be in touch about the possibility of conducting an interview with you on the subject of your article. You may also be contacted regarding a College press release or by other editorial colleagues interested in commissioning articles linked to your manuscript. Any press enquiries about your work must be directed to Deborah Hart ([email protected]).

Francis O'Neill ------British Journal of Psychiatry 21 Prescot Street London, E1 8BB. Phone:+44 (0) 20 7235 2351 Fax:+44 (0) 20 3701 2761 [email protected]

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86 Clara López-Solà OCD and AD Symptoms as Putative Causal Risk Factors

Extending the classical modeling approach, causal pathway modeling has identified novel and potentially important relationships between OCD and AD symptoms. With this approach, the results were more consistent with OCD symptoms being a causal risk factor for PD and GAD symptoms (having OCD symptoms increases the probability of having PD and GAD symptoms, not vice versa), rather than the association between traits being due to unmeasured familial factors such as genes and shared environment. In other studies without twins, OCD checking symptoms – one of the most common OCD symptom dimensions – have been linked to the increased probability of comorbid of PD and GAD diagnoses35. It was proposed that an intolerance of uncertainty, which is present in OCD checking symptoms, but more strongly associated with general worry and anxiety, might explain the link between these domains. Thus, one possibility is that intolerance of uncertainty represents an underlying trait dimension through which OCD etiologically enhances the risk to PD and GAD symptoms.

By contrast, SP symptoms emerged as a potential causal risk factor for OCD symptoms, although this was a more moderate finding compared to the estimated strength of the above associations. Nevertheless, adopting similar logic, one possibility is that a relevant underlying trait factor may explain these findings. In the case of SP symptoms, one obvious candidate would be “behavioral inhibition”.

Although behavioral inhibition has been most strongly characterized a childhood predictor of SP36, it has also been linked to the development of OCD symptoms in adulthood37. Supporting an early etiological link between these domains, mother- reported levels of inhibition/shyness in preschool-aged twins were reported to show substantial overlap with other anxiety-related behaviors, including OCD-like

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OBSESSIVE-COMPULSIVE DISORDER SYMPTOMS

No direct pathway

GAD PD HD SP BDD Supplemental Information

S1. Flowchart of twin recruitment and final sample composition

S2. Expanded description of the ICE FALCON methodology

S3. Principal component analysis (PCA)

S4. Independent Pathway model with 2 latent common additive genetic factors. Model-fitting results and standardised parameters for the best-fitting model.

Clara López-Solà 103

104 Clara López-Solà S2. Expanded description of the ICE FALCON methodology

The above figure provides a step-by-step explanation of the ICE FALCON regression methodology. X represents the predictor variable and Y the outcome variable. Their numbering represents MZ twin 1 or twin 2.

The following 4 conditions must be satisfied to refute the null hypothesis of no causal influence (X on Y):

Condition 1: The predictor (trait X) or outcome (trait Y) is correlated between the twins of a pair (i.e., between-person correlation).

Condition 2 (Model I): there is an association between the predictor (X) and the outcome (Y) within each twin of a pair (i.e., within person).

Condition 3 (Model II): conditions (1) and (2) must be strong enough to find a detectable and statistically significant “cross-twin cross-trait association”; that suggests that there is a family factor (genetic and/or shared environmental) underneath those two traits.

Condition 4 (Model III): there is a reduction in the magnitude of the cross-twin cross-trait regression (beta) coefficient when modeling the within-person association. If the magnitude of beta significantly reduces, “causation” can be inferred because it is the within-person association that is driving this reduction.

Under the null hypothesis, if the regression coefficient for the cross-twin cross-trait association in Model III is the same as that of Model II, potential shared genetic and/or environmental mechanisms may be implicated.

In our analyses, the 3 models were adjusted for age and gender. We focused on the question of whether OCD symptoms demonstrated evidence for potential causal relationships with the remaining symptom domains: OCD-HD, OCD-BDD, OCD-PD, OCD-GAD, OCD-SP. “Causality” was tested in both directions, that is, flipping the predictor and outcome variables, which corresponded to a total of 10 (5x2) regression models (Table 3). An expanded statistical description is provided below.

Clara López-Solà 105 Description of the Statistical Analysis

Let Yij denote a outcome of interest, index by j = 1, 2 (twin 1 and twin 2, respectively) and i =

1,…, m, where m is the number of twin pairs. Associated with the outcomeYij , let X ij denote a corresponding predictor, for example OCD as Y and HD as X. For simplicity let Yiself Yi and YiFRW win Yi , and similarly defined for predictorX ij Note that the choice of Yiself and YiFRW win is arbitrary – data from both possibilities will be used in the analysis; see below.

The first model expresses the relationship between the expected value (E) of an outcome variable and its own predictor to assess the within-person cross-trait association. E Yiself self Xiself Model I E YiFRW win self XiFRW win where α is the intercept and self is the regression coefficient representing the within-person cross-trait association.

The second model expresses the relationship between the expected value of Yij and its co-twin predictor to assess the cross-twin cross-trait association. E Yiself FRW winXiFRW win Model II E YiFRW win FRW winXiself where FRW win is the regression coefficient representing the cross-twin cross-trait association.

The third model expresses the relationship using both predictors by: a a E Yiself self X iself FRW win X iFRW win Model III a a E YiFRW win self XFRW win FRW winXiself a where FRW win is the regression coefficient representing the effect cross-twin cross-trait association a adjusted for its own predictor (self ).

The above Models can be easily extended to allow for the inclusion of multiple predictors, such as age and gender. Note that the intercept coefficient is excluded if we use the standardised Y and X values.

The parameters in Models I-III were estimated using the generalised estimating equations, which take into account the correlation within a twin pair. Under the null hypothesis of no change in a regression coefficients for cross-twin cross-trait in Model II and III, i.e H FRW win FRW win , we a a use the t-test: t FRW win FRW win se FRW win FRW win , where se is the standard error and computes using nonparametric bootstrap method. This involved randomly sampling twin pairs with replacement to obtain the same sample size as the original dataset, then fitting the Models I- III to this new data set to get a new set of estimated parameters. We then repeated the process 1,000 times to yield a sampling distribution of the parameter estimates from which a standard error was estimated by computing the standard deviation. For bootstrap method, we wrote our own programs in R (http://www.R-project.org/). One-sided p-values were derived and considered nominally significant if p < 0.05.

106 Clara López-Solà S3. Principal component analysis (PCA)

Factor Matrix Matrix forced to retain 2 factors Main Factor Factor 1 Factor 2

PD .814 820 ** SP .789 785 ** OCD .786 678 ** GAD .765 734 ** BDD .697 718 ** HD .603 ** .961

The PCA retained 1 phenotypic factor with eigenvalues greater than 1, explaining 55.6% of the total variance. The PCA were forced to retain 2 phenotypic factor explaining 67.8% of the total variance.

Clara López-Solà 107 S4. Independent Pathway model with 2 latent common additive genetic factors. Model-fitting results and standardized parameters for the best- fitting model.

Estimated Parameter Fit Statistic

Model Common Specific -2LL df AIC X2 ∆df P Compared Factors Factors Value with 1 Cholesky ACE ACE 30357.2 14901 555.25 - - - - Saturated 5 2 IP ACE ACE 30390.9 14925 540.99 33.74 24 .09 1 9 3 CP ACE ACE 30450.4 14938 574.46 93.21 37 <.0001 1 6 4 IP ACE AE 30391.4 14931 529.40 .412 6 .998 2 0 5 IP ACE CE 30414.7 14931 552.79 23.80 6 .0005 2 9 6 IP ACE E 30464.9 14937 590.90 73.91 12 <.0001 2 0 7 IP AE ACE 30424.3 14931 562.32 33.33 6 <.0001 2 2 8 IP CE ACE 30463.8 14934 595.84 72.84 9 <.0001 2 4 9 IP E ACE 30554.0 14940 674.06 163.1 15 <.0001 2 6 Standardized Parameters for Best-fitting Model 4 (95% CI) Additive Genetic Factors Shared Non-Shared Environmental Environmental Factors Factors Ac Ac2 As AT Cc Cs Ec Es ET OCD .23 .03 .06 .32 .04 - .27 .37 .64 (.014-.40) (.00-.14) (.00-.13) (.10-.42) (.00-.22) (.20-.35) (.32-.42) (.56-.72) HD .11 .12 .10 .32 .002 - .13 .55 .67 (.02-.17) (.02-.28) (.00-.23) (.22-.39) (.00-.07) (.08-.19) (.49-.61) (.60-.75) BDD .18 .005 .18 .36 .0002 - .19 .44 .63 (.04-.25) (.00-.03) (.12-.23) (.21-.43) (.00-.10) (.14-.27) (.39-.50) (.56-.72) PD .26 - .04 .30 .00 - .37 .33 .70 (.08-.33) (.00-.08) (.11-.37) (.00-.16) (.30-.45) (.28-.38) (.63-.77) GAD .21 - .06 .27 .05 - .28 .40 .68 (.006-.36) (.00-.12) (.02-.39) (.00-.26) (.21-.37) (.35-.45) (.61-.77) SP .30 - .09 .39 .02 - .29 .30 .59 (.03-.44) (.00-.16) (.11-.48) (.00-.24) (.23-.39) (.25-.34) (.52-.67)

-2LL, minus twice the log-likelihood; df, degrees of freedom; AIC, Akaike information criterion; X2, difference in goodness of fit statistic between the sub-model and the full model; ∆df, change in degrees of freedom between the sub-model and the full model; CI, Confidence Intervals; Ac, additive genetic factor common to all disorders; Ac2, additive genetic factor common to Obsessive-Compulsive Related Disorders; As, additive genetic factor specific to each disorder; AT, total additive genetic factor; Cc, shared environmental factor common to all disorders; Cs, shared environmental factor specific to each disorder; Ec, non-shared environmental factor common to all disorders; Es, non-shared environmental factor specific to each disorder; ET, total non-shared environmental factor; IP, independent pathway; CP, common pathway. OCD, Obsessive-Compulsive Disorder Symptoms; HD, Hoarding Disorder Symptoms; BDD, Body Dysmorphic Disorder Symptoms; PD, Panic Disorder Symptoms; GAD, Generalized Anxiety Disorder Symptoms; SP, Social Phobia Symptoms. In boldface type the best-fitting model based on AIC.

108 Clara López-Solà Study 3

Under Review

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116 Clara López-Solà model, which estimates whether the covariance among phenotypes was influenced via one latent factor taking into account the shared contribution of common A, C, and E factors. The Akaike information criterion (AIC) value was used to measure the relatively goodness of fit of these models; the one with the lowest AIC was taken to be the most parsimonious. Reduced sub-models were systematically tested to derive the most parsimonious model fitting results. For the most parsimonious model, confidence intervals for the factor loadings at the path diagram were calculated to provide the best estimate for each parameter of the model. All analyses were carried out in R

(http://www.R-project.org/) using the OpenMx 2.0 package27.

Results

Best Fitting Models & Estimated Factor Loadings

Table 1 and Figure 1 present results for the most parsimonious model for each of the

OC symptom dimensions. Figure 1 also displays the factor loadings (with confidence intervals) for common and specific genetic and environmental influences estimated for each dimension. With reference to Table 1, the four symptom dimensions each demonstrated best fit with the same single factor structure; namely, the independent pathway (IP) model with ACE as common factors and AE as specific factors. Estimates for the best fitting IP model are emphasized in bold text (Table 1). Figure 1 presents the values of the factor loadings for each dimension, indicating a unique pattern of genetic and environmental overlap with ADs and other OCRDs.

------Table 1 & Figure 1 ------

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Clara López-Solà 119 VHSDUDWHO\IRUREVHVVLQJV\PSWRPVDQG2&5'V)RUREVHVVLQJRIWKHWRWDO

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------Tables 5 ------

Estimated Environmental Influences

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Clara López-Solà 121 6HFRQGRUGHULQJZDVWKHKLJKHVWJHQHWLFFRUUHODWLRQZLWK+'DQG%''V\PSWRPVEXW

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Clara López-Solà

CHAPTER 5

DISCUSSION & CONCLUSIONS

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166 Discussion Clara López-Solà

CHAPTER 6

SUMMARY IN SPANISH

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176 Summary in Spanish Clara López-Solà GLPHQVLRQHVREVHVLYDV6yORXQHVWXGLRKDREVHUYDGRTXHORVSUREOHPDVSHULQDWDOHV SDUHFHQVHUXQIDFWRUGHULHVJRSDUDORVVtQWRPDVGHRUGHQVLPHWUtD *ULVKDPHWDO (QUHODFLyQDORVWUDVWRUQRVGHOHVSHFWURREVHVLYRHO7'&HVWDUtDDVRFLDGRD FLHUWRV IDFWRUHV GH ULHVJR FRPXQHV FRQ HO 72& \ ORV WUDVWRUQRV GH DQVLHGDG FRPR KLVWRULDGHDEXVRQHJOLJHQFLDREXUODVHQODLQIDQFLD %XKOPDQQHWDO 'LGLHHWDO1H]LURJOXHWDO 'HOEstudio 2 VH GHVSUHQGH TXH OD PD\RUtD GH ORV IDFWRUHV GH ULHVJR DPELHQWDOHV VRQ HVSHFtILFRV SDUD FDGD WUDVWRUQR HYDOXDGR 3RU HVWH PRWLYR VHUtD FRQYHQLHQWH HVWXGLDU GLFKRV IDFWRUHV HVSHFtILFRV \ DVt GHVDUUROODU SURJUDPDV GH SUHYHQFLyQ\GHWHFFLyQSUHFR]GHWUDVWRUQRVJHQpWLFDPHQWHUHODFLRQDGRVFRQHO72& )DFWRUHVGHLQWHUDFFLyQJHQDPELHQWH /RV UHVXOWDGRV GH HVWD WHVLV VRQ FRQVLVWHQWHV FRQ OD KLSyWHVLV VREUH ³SOHLWURStD´ JHQpWLFDGRQGHP~OWLSOHVJHQHVFRQWULEX\HQDH[SOLFDUXQDSURSRUFLyQLPSRUWDQWHGH OD H[SUHVLyQ IHQRWtSLFD GH XQ JUXSR GH WUDVWRUQRV 1LFROLQL HW DO /D LQWHUDFFLyQ JHQDPELHQWH VH UHILHUH D TXH ORV HIHFWRV GH VHU H[SXHVWR D IDFWRUHV DPELHQWDOHV HVSHFtILFRV GHSHQGHUiQ GHO JHQRWLSR GH FDGD LQGLYLGXR $O PLVPR WLHPSR JHQRWLSRV HVSHFtILFRV DXPHQWDQ R GLVPLQX\HQ OD SUREDELOLGDG GH TXH XQD SHUVRQDVHDH[SXHVWDDFLHUWRWLSRGHDPELHQWHV /DLQWHUDFFLyQJHQDPELHQWHSXHGHGDUOXJDUDPRGLILFDFLRQHVHQODH[SUHVLyQ GHFLHUWRVJHQHV HSLJHQpWLFD /DGLIHUHQFLDSULQFLSDOHQWUHORVSURFHVRVJHQpWLFRV\ HSLJHQpWLFRV HV HQ HVWRV ~OWLPRV VX SRWHQFLDO HIHFWR UHYHUVLEOH PHGLDQWH LQWHUYHQFLRQHVFRQGXFWXDOHVRIDUPDFROyJLFDV 6]\I 'HVGHHOSXQWRGHYLVWD HSLJHQpWLFR HO DPELHQWH LQWUDXWHULQR HV GRQGH VH SURGXFHQ ORV SULPHURV \ PiV UHOHYDQWHV FDPELRV HQ OD H[SUHVLyQ JHQpWLFD 6H KD GHPRVWUDGR OD H[LVWHQFLD GH IDFWRUHVHSLJHQpWLFRVGLVFRUGDQWHVHQJHPHORVJHQpWLFDPHQWHLGpQWLFRV *RUGRQHWDO (O DPELHQWH LQWUDXWHULQR HV SRU WDQWR XQ IDFWRU GH ULHVJR DPELHQWDO QR FRPSDUWLGRDSHVDUGHTXHDPERVJHPHORVVHDQJHVWDGRVHQHOPLVPRPRPHQWR\HQ HOPLVPRYLHQWUHPDWHUQRSDUDHQIHUPHGDGHV\WUDVWRUQRVPHQWDOHVHQODHGDGDGXOWD DWHQHUHQFXHQWDHQIXWXURVHVWXGLRVFRQJHPHORV ,PSOLFDFLRQHV1RVROyJLFDV\&OtQLFDV /RVUHVXOWDGRVGHHVWDWHVLVH[SOLFDQTXHHO72&\VXVGLPHQVLRQHVGHVtQWRPDVVRQ HWLROyJLFDPHQWH XQ FRQVWUXFWR PiV FRPSOHMR TXH HO H[SOLFDGR ~QLFDPHQWH SRU ORV

Clara López-Solà Summary in Spanish 177 VtQWRPDVGHOHVSHFWURREVHVLYR\TXHVXDVRFLDFLyQFRQODDQVLHGDGHVFUXFLDOSDUD HQWHQGHU VX IXQFLRQDPLHQWR 1XHVWURV UHVXOWDGRV DSR\DQ OD YLVLyQ SUHYLD GH RWURV DXWRUHV TXH UHFRPHQGDURQ PDQWHQHU MXQWRV EDMR HO PLVPR FDStWXORGHO'60ORV WUDVWRUQRVGHDQVLHGDGHO72&\DOJXQRVWUDVWRUQRVGHOHVSHFWURFRPRODKLSRFRQGUtD \HO7'& %LHQYHQXHWDO6WHLQHWDO 'HVGH HO SXQWR GH YLVWD FOtQLFR GLIHUHQFLDV GH JpQHUR HM RVFLODFLRQHV GHO FLFORKRUPRQDO GHEHUtDQWHQHUVHHQFXHQWDHQODSUiFWLFDFOtQLFDFRQHOILQGHPHMRUDU ORVSURJUDPDVGHWUDWDPLHQWRSUHYHQFLyQ$GHPiVODSUHVHQFLDGH72&GHEHUtDVHU SDUDHOFOtQLFRXQLQGLFDGRUGHTXHHVDSHUVRQDWLHQHPiVULHVJRGHGHVDUUROODURWURV WUDVWRUQRV GH DQVLHGDG SiQLFR \ DQVLHGDG JHQHUDOL]DGD DVt FRPR VtQWRPDV GH DFXPXODFLyQSRVWHULRUFRQXQDHVSHFLDODWHQFLyQVLODVGLPHQVLRQHVSUHVHQWDGDVVRQ GHSHQVDPLHQWRVSURKLELGRV\OLPSLH]D(VWDYLVLyQKROtVWLFDGHODPDQLIHVWDFLyQGH ORVVtQWRPDVREVHVLYRDQVLRVRVSXHGHD\XGDUDOGLDJQyVWLFRSUHFR]GHRWURVWUDVWRUQRV DVRFLDGRV DVt FRPR SRWHQFLDOPHQWH D\XGDU D GLVPLQXLU ORV IDFWRUHV GH ULHVJR DVRFLDGRVFRQJUXSRVGHVtQWRPDVTXHIUHFXHQWHPHQWHFRRFXUUHQ3RURWURODGROD SUHYHQFLyQ GLULJLGD D ORV SDGUHV GH QLxRV TXH SUHVHQWDQ ULHVJR JHQpWLFR SDUD GHVDUUROODU HO WUDVWRUQR D\XGDUtD D GLVPLQXLU OD DSDULFLyQ GH FLHUWRV WUDVWRUQRV R D FRQWURODUHOLPSDFWRGHORVPLVPRVHQODYLGDGHOSDFLHQWHPHGLDQWHSURJUDPDVGH SVLFRHGXFDFLyQ VREUH ORV VtQWRPDV \ IDFWRUHV GH ULHVJR DPELHQWDO HVWLOR HGXFDWLYR FRPXQLFDFLyQSDUHQWDOHWF /LPLWDFLRQHV /RVVtQWRPDVGHH[FRULDFLyQ\WULFRWLORPDQtDIXHURQLQFOXLGRVHQODHQFXHVWDLQLFLDO VLQHPEDUJRODPDQHUDGHUHFOXWDUORVQRIXHySWLPDLPSLGLHQGRUHFRSLODUXQQ~PHUR VXILFLHQWHGHUHVSXHVWDVILQDOHV6HJXQGRORVUHVXOWDGRVHVWiQEDVDGRVHQVtQWRPDV\ QRHQGLDJQyVWLFRVFOtQLFRV6LQHPEDUJRWRGRVORVFXHVWLRQDULRVXWLOL]DGRVKDQVLGR SUHYLDPHQWH YDOLGDGRV HQ SREODFLyQ QR FOtQLFD \ DGHPiV HO XVR GH PHGLGDV DXWR DGPLQLVWUDGDV VH UHFRPLHQGD HQ ORV DQiOLVLV GH JHQpWLFD GH FRQGXFWD 1HDOH &DUGRQ 7HUFHURORVJHPHORVVRQXQWLSRGHSREODFLyQJHQHUDOTXHQRHVGHO WRGR UHSUHVHQWDWLYR &XDUWR ORV DQiOLVLV FOiVLFRV GH JHPHORV VH EDVDQ HQ GLIHUHQWHV VXSXHVWRV 8QR GH HOORV FRQRFLGR FRPR ³DPELHQWH HTXLYDOHQWH´ DVXPH TXH ORV JHPHORV0=\'=YLYHQFRPSDUWLHQGRDSUR[LPDGDPHQWHHOPLVPRWLSRGHDPELHQWH 6LQHPEDUJRHVWHVXSXHVWRKDVLGRFULWLFDGRSRUGLIHUHQWHVDXWRUHV)LQDOPHQWHWRGRV

178 Summary in Spanish Clara López-Solà ORV DQiOLVLV UHDOL]DGRV VRQ WUDQVYHUVDOHV OR TXH VLJQLILFD TXH VH GHVFRQRFH OD HVWDELOLGDGGHORVPLVPRVDORODUJRGHOWLHPSR &RQFOXVLRQHV (Q FRQFOXVLyQ HV QHFHVDULR SRGHU GLVWLQJXLU HQWUH OD XWLOLGDG TXH SXHGH WHQHU OD FODVLILFDFLyQ GLDJQyVWLFD GHO 72& SDUD ORV SURIHVLRQDOHV FOtQLFRV GHO LPSHGLPHQWR TXH GLFKD FODVLILFDFLyQ SXHGH JHQHUDU HQ HO HVWXGLR GH ORV IDFWRUHV HWLROyJLFRV VXE\DFHQWHV DO WUDVWRUQR 3DUD HOOR VH SUHFLVD GH XQD YLVLyQPiV DPSOLD GRQGH ORV VLVWHPDV GH FODVLILFDFLyQ QR DFW~HQ GH EDUUHUDV \ REVWDFXOLFHQ HO GHVDUUROOR GH VX FRQRFLPLHQWR /RV HVWXGLRV FLHQWtILFRV TXH GH PDQHUD UHSHWLGD VH FHQWUDQ HQ XQD GHILQLFLyQ GHO 72& JXLDGD SRU ORV PRGHORV QRVROyJLFRV D PHQXGR FDPELDQWHV IUDFDVDUiQHQHOGHVFXEULPLHQWRGHVXHWLRORJtD(QVXOXJDUHOHVWXGLRGHJUXSRVGH WUDVWRUQRV UHODFLRQDGRVFRPR ODDQVLHGDGHO 7'&RODKLSRFRQGUtDHQWUHRWURV DVt FRPR IDFWRUHV DPELHQWDOHVWUDXPiWLFRV \QRWUDXPiWLFRV VHUtDXQD DSUR[LPDFLyQ GH PD\RUXWLOLGDGDODKRUDGHGHVJUDQDUFXiOHVVRQORVIDFWRUHVJHQpWLFRV\DPELHQWDOHV HVSHFtILFRVDVRFLDGRVDODPDQLIHVWDFLyQGHOWUDVWRUQR

Clara López-Solà Summary in Spanish 179

CHAPTER 7

REFERENCES

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$PHULFDQ3V\FKLDWU\$VVRFLDWLRQ $3$ Diagnostic and statistical manual of mental disorders WKHG :DVKLQJWRQ'&$XWKRU

$QJVW - *DPPD $ (QGUDVV - +DQWRXFKH ( *RRGZLQ 5 $MGDFLF 9 « 5|VVOHU : 2EVHVVLYHFRPSXOVLYH V\QGURPHV DQG GLVRUGHUV VLJQLILFDQFH RI FRPRUELGLW\ ZLWK ELSRODU DQG DQ[LHW\ V\QGURPHV European Archives of Psychiatry and Clinical Neuroscience255 ±

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