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Finding gene-environment interactions for phobias
Alice M. Gregory
Psychology Department, Goldsmiths College, University of London and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College, University of London
Jennifer Y. F. Lau
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College, University of London
Thalia C. Eley
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College, University of London
Correspondence to: Dr Alice M. Gregory, Psychology Department, Goldsmiths College, University of London, Lewisham Way, New Cross, London, SE14 6NW
Phone: +44 (0)20 7919 7959; Fax: +44 (0)20 7919 7873; Email: a.gregory@gold.ac.uk
Phobias are common disorders causing a great deal of suffering. Studies of gene-environment interaction (G x E) have revealed much about the complex processes underlying the development of various psychiatric disorders but have told us little about phobias. This article describes what is already known about genetic and environmental influences upon phobias and suggests how this information can be used to optimise the chances of discovering G x Es for phobias. In addition to the careful conceptualisation of new studies, it is suggested that data already collected should be re-analysed in light of increased understanding of processes influencing phobias.
Key words: Gene, environment, interaction, phobia, twins
Finding gene-environment interactions for phobias
Despite having saved hard for her trip of a life-time, a friend recently revealed that she was half-dreading her honeymoon because she knew that her new husband would spend the entire 11 hour flight in a state of complete terror a result of his lifelong fear of flying. Specific phobias are one of three main types of phobias highlighted in the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders ADDIN REFMGR.CITE American Psychiatric Association1994763Diagnostic and statistical manual of mental disordersBook, Whole763Diagnostic and statistical manual of mental disordersAmerican Psychiatric Association1994diagnostic and statistical manualmental disordersdisordersDSM-IVNot in FileWashington, DCAmerican Psychiatric Association2(1). The other two are social phobia (characterised by high levels of anxiety resulting from exposure to social or performance situations) and agoraphobia (clinically significant levels of fear or avoidance of certain places or situations which are considered to be difficult or embarrassing from which to escape). Agoraphobia is often co-morbid with panic and agoraphobics may fear places and situations in which they are concerned that they will not receive help if panicking. Unfortunately, these crippling disorders are common. Indeed, estimates from the National Comorbidity Survey-Replication place anxiety disorders as the most common category of mental illness ADDIN REFMGR.CITE Kessler20055571Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replicationJournal5571Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replicationKessler,R.C.Berglund,P.Demler,O.Jin,R.Walters,E.E.2005adolescenceAGEage-of-onsetagedAMERICANAMERICANSanxietyanxiety disordersCAREchildhoodCOHORTcomorbidcomorbiditycourseCRITERIAdiagnosisDIAGNOSTIC INTERVIEWDIFFERENCEDISORDERdisordersDRUG-USEDSM-IVDSM-IV ANXIETYDSM-IV disordersepidemiologyFIRST ONSETGENERAL-POPULATIONHealthinterventioninterviewLIFELIFE-COURSELIFETIMELIFETIME PREVALENCEmeasureMENTAL HEALTHMENTAL-DISORDERSmental-healthMOODmood disorderMOOD DISORDERSMORTALITYNATIONAL COMORBIDITY SURVEYNATIONAL-COMORBIDITY-SURVEYNCS-RNEEDonsetORGANIZATIONoutcomeprevalencepreventionPSYCHIATRIC-DISORDERSpsychiatryREPLICATIONriskSUBSTANCE USESUBSTANCE USE DISORDERStreatmentUNITED-STATESWORLD-HEALTH-ORGANIZATIONYOUTHNot in File593602Archives of General Psychiatry626Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA.ISI:000229628400003Archives of General PsychiatryArch Gen Psychiatry1(21). Of the anxiety disorders, phobias are known to be amongst the most commonly occurring difficulty ADDIN REFMGR.CITE Gregory20075809Juvenile Mental Health Histories of Adults with Anxiety DisordersJournal5809Juvenile Mental Health Histories of Adults with Anxiety DisordersGregory,A.M.Caspi,A.Moffitt,T.E.Koenen,K.Eley,T.C.Poulton,R.2007MENTAL HEALTHmental-healthHealthHISTORIESHISTORYadultsAdultanxietyanxiety disordersanxiety disorderdisordersDISORDERAMERICANpsychiatryNot in File301308American Journal of Psychiatry164American Journal of PsychiatryAm.J.Psychiatry1Kessler20055571Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replicationJournal5571Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replicationKessler,R.C.Berglund,P.Demler,O.Jin,R.Walters,E.E.2005adolescenceAGEage-of-onsetagedAMERICANAMERICANSanxietyanxiety disordersCAREchildhoodCOHORTcomorbidcomorbiditycourseCRITERIAdiagnosisDIAGNOSTIC INTERVIEWDIFFERENCEDISORDERdisordersDRUG-USEDSM-IVDSM-IV ANXIETYDSM-IV disordersepidemiologyFIRST ONSETGENERAL-POPULATIONHealthinterventioninterviewLIFELIFE-COURSELIFETIMELIFETIME PREVALENCEmeasureMENTAL HEALTHMENTAL-DISORDERSmental-healthMOODmood disorderMOOD DISORDERSMORTALITYNATIONAL COMORBIDITY SURVEYNATIONAL-COMORBIDITY-SURVEYNCS-RNEEDonsetORGANIZATIONoutcomeprevalencepreventionPSYCHIATRIC-DISORDERSpsychiatryREPLICATIONriskSUBSTANCE USESUBSTANCE USE DISORDERStreatmentUNITED-STATESWORLD-HEALTH-ORGANIZATIONYOUTHNot in File593602Archives of General Psychiatry626Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA.ISI:000229628400003Archives of General PsychiatryArch Gen Psychiatry1(10,21) Phobias occur more frequently in females than males, may first appear early in life (especially with regards to specific phobias), and occur concurrently and longitudinally with certain internalising and externalising disorders ADDIN REFMGR.CITE Gregory20075809Juvenile Mental Health Histories of Adults with Anxiety DisordersJournal5809Juvenile Mental Health Histories of Adults with Anxiety DisordersGregory,A.M.Caspi,A.Moffitt,T.E.Koenen,K.Eley,T.C.Poulton,R.2007MENTAL HEALTHmental-healthHealthHISTORIESHISTORYadultsAdultanxietyanxiety disordersanxiety disorderdisordersDISORDERAMERICANpsychiatryNot in File301308American Journal of Psychiatry164American Journal of PsychiatryAm.J.Psychiatry1Kessler20055571Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replicationJournal5571Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replicationKessler,R.C.Berglund,P.Demler,O.Jin,R.Walters,E.E.2005adolescenceAGEage-of-onsetagedAMERICANAMERICANSanxietyanxiety disordersCAREchildhoodCOHORTcomorbidcomorbiditycourseCRITERIAdiagnosisDIAGNOSTIC INTERVIEWDIFFERENCEDISORDERdisordersDRUG-USEDSM-IVDSM-IV ANXIETYDSM-IV disordersepidemiologyFIRST ONSETGENERAL-POPULATIONHealthinterventioninterviewLIFELIFE-COURSELIFETIMELIFETIME PREVALENCEmeasureMENTAL HEALTHMENTAL-DISORDERSmental-healthMOODmood disorderMOOD DISORDERSMORTALITYNATIONAL COMORBIDITY SURVEYNATIONAL-COMORBIDITY-SURVEYNCS-RNEEDonsetORGANIZATIONoutcomeprevalencepreventionPSYCHIATRIC-DISORDERSpsychiatryREPLICATIONriskSUBSTANCE USESUBSTANCE USE DISORDERStreatmentUNITED-STATESWORLD-HEALTH-ORGANIZATIONYOUTHNot in File593602Archives of General Psychiatry626Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA.ISI:000229628400003Archives of General PsychiatryArch Gen Psychiatry1Kessler20056114Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey ReplicationJournal6114Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey ReplicationKessler,R.C.Chiu,W.T.Demler,O.Walters,E.E.2005analysisanxietycomorbidcomorbidityDIAGNOSESdiagnosisDIAGNOSTIC INTERVIEWDISORDERdisordersDSM-IVDSM-IV ANXIETYDSM-IV disordersgeneral populationGENERAL-POPULATIONHealthHEALTH SURVEYINTERNATIONAL DIAGNOSTIC INTERVIEWinterviewmeasureMENTAL DISORDERmental disordersMENTAL HEALTHMENTAL-DISORDERSmental-healthMODERATEMOODNATIONAL COMORBIDITY SURVEYNATIONAL-COMORBIDITY-SURVEYORGANIZATIONoutcomePOPULATIONprevalenceREPLICATIONseverityWORLD-HEALTH-ORGANIZATIONNot in File617627Archives of General Psychiatry626ISI:000229628400006Archives of General PsychiatryArch Gen Psychiatry1(10,21,22). In addition to considering phobias in terms of diagnoses, it is possible to examine specific fear symptoms and considering both approaches may be optimal when designing genetic studies ADDIN REFMGR.CITE Smoller19983500Panic and phobic anxiety: Defining phenotypes for genetic studiesJournal3500Panic and phobic anxiety: Defining phenotypes for genetic studiesSmoller,J.W.Tsuang,M.T.1998panicanxietyphenotypesPhenotypeIn File11521162American Journal of Psychiatry155American Journal of PsychiatryAm.J.Psychiatry1(39). Indeed, focusing upon a single measure of phobias may have limitations, as suggested by research demonstrating that information about fear and phobias assessed at personal interviews shows substantial unreliability ADDIN REFMGR.CITE Kendler19996073Fears and phobias: reliability and heritabilityJournal6073Fears and phobias: reliability and heritabilityKendler,K.S.Karkowski,L.M.Prescott,C.A.1999fearFEARSheritabilityphobiaphobiasreliabilityNot in File539553Psychological Medicine293ISI:000080803100004Psychological MedicinePsychol Med1(15).
This article addresses issues relevant to the aetiology of phobias. Specifically, there are now rich data estimating and describing genetic and environmental influences upon phobias. However, there have been few investigations of gene-environment interactions (G x E) in relation to phobias. Given that it is becoming increasingly clear that sensitivity to environmental insults is influenced by genotype and that this information is essential for understanding the complex pathways by which genes influence behaviour ADDIN REFMGR.CITE Rutter20066115Gene-environment interplayBook Chapter6115Gene-environment interplayRutter,M.2006genesgenebehaviorIn File178210Genes and behavior9OxfordBlackwell3(33), this represents a sizeable limitation to knowledge with regards to the aetiology of phobias. In the hope of stimulating research into this area, this article describes what is known about genetic and environmental influences on phobias and discusses issues that need to be considered when designing studies investigating G x E for phobias.
Phobias and other anxiety disorders
When exploring genetic and environmental influences upon anxiety, researchers often combine different types of anxiety based on the findings that there is strong cross-sectional and longitudinal comorbidity between the different disorders and similarities between anxiety disorders in terms of mental health histories ADDIN REFMGR.CITE Gregory20075809Juvenile Mental Health Histories of Adults with Anxiety DisordersJournal5809Juvenile Mental Health Histories of Adults with Anxiety DisordersGregory,A.M.Caspi,A.Moffitt,T.E.Koenen,K.Eley,T.C.Poulton,R.2007MENTAL HEALTHmental-healthHealthHISTORIESHISTORYadultsAdultanxietyanxiety disordersanxiety disorderdisordersDISORDERAMERICANpsychiatryNot in File301308American Journal of Psychiatry164American Journal of PsychiatryAm.J.Psychiatry1(10). Furthermore, factor analyses suggest that different anxiety disorders share a common factor structure ADDIN REFMGR.CITE Krueger19995574The structure of common mental disordersJournal5574The structure of common mental disordersKrueger,R.F.1999AGEanxietycomorbidityDEPENDENCEDIAGNOSTIC INTERVIEWDISORDERdisordersDSM-III-RfearFITFUTURE-DIRECTIONSgeneralized anxiety disorderHealthinterviewINTERVIEWSmajor depressionMENMENTAL DISORDERmental disordersMENTAL HEALTHMENTAL-DISORDERSmental-healthmethodsMinnesotaMODELNATIONAL COMORBIDITY SURVEYNATIONAL-COMORBIDITY-SURVEYpanic disorderPATTERNSPERSPECTIVEPSYCHIATRIC-DISORDERSpsychiatrypsychopathologyreliabilityRISK-FACTORSSAMPLEstructuretreatmentVARIANTwomenNot in File921926Archives of General Psychiatry5610Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA.ISI:000083037300010Archives of General PsychiatryArch Gen Psychiatry1(23). However, there are also reasons to examine phobias separately from other anxiety disorders. For example, factor analyses also suggest that within internalizing disorders it is possible to distinguish between generalized anxiety disorder (GAD) which can be grouped with depression; and a group comprising specific phobias, social phobias, panic and agoraphobia ADDIN REFMGR.CITE Krueger19995574The structure of common mental disordersJournal5574The structure of common mental disordersKrueger,R.F.1999AGEanxietycomorbidityDEPENDENCEDIAGNOSTIC INTERVIEWDISORDERdisordersDSM-III-RfearFITFUTURE-DIRECTIONSgeneralized anxiety disorderHealthinterviewINTERVIEWSmajor depressionMENMENTAL DISORDERmental disordersMENTAL HEALTHMENTAL-DISORDERSmental-healthmethodsMinnesotaMODELNATIONAL COMORBIDITY SURVEYNATIONAL-COMORBIDITY-SURVEYpanic disorderPATTERNSPERSPECTIVEPSYCHIATRIC-DISORDERSpsychiatrypsychopathologyreliabilityRISK-FACTORSSAMPLEstructuretreatmentVARIANTwomenNot in File921926Archives of General Psychiatry5610Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA.ISI:000083037300010Archives of General PsychiatryArch Gen Psychiatry1Vollebergh20015573The structure and stability of common mental disorders - The NEMESIS StudyJournal5573The structure and stability of common mental disorders - The NEMESIS StudyVollebergh,W.A.M.Iedema,J.Bijl,R.V.de Graaf,R.Smit,F.Ormel,J.2001agoraphobiaalcoholalcohol dependenceanxietyanxiety disorderscomorbidityDEPENDENCEdepressionDIAGNOSESDIAGNOSTIC INTERVIEWDIFFERENCEDIMENSIONSDISORDERdisordersDSM-III-RdysthymiaFITGENERAL-POPULATIONGENERALIZED ANXIETYgeneralized anxiety disorderHealthHEALTH SURVEYIncidenceindividual differencesINDIVIDUAL-DIFFERENCESINTERNATIONAL DIAGNOSTIC INTERVIEWinterviewmajor depressionmeasurementMENTAL DISORDERmental disordersMENTAL HEALTHMENTAL-DISORDERSmental-healthmethodsMODELMOODmood disorderMOOD DISORDERSpanicpanic disorderPERIODphobiaPOPULATIONprevalencePSYCHIATRIC-SYMPTOMSpsychiatryQUESTIONSreliabilitysocialSOCIAL PHOBIASTABILITYstructural equation modelingstructureSUBSTANCE USESUBSTANCE USE DISORDERSTIMENot in File597603Archives of General Psychiatry586Netherlands Inst Mental Hlth & Addict, Trimbos Inst, NL-3500 AS Utrecht, Netherlands. Social & Cultural Planning Off, The Hague, Netherlands. Univ Groningen, Dept Social Psychiat, Groningen, Netherlands.ISI:000169136500011Archives of General PsychiatryArch Gen Psychiatry1Watson20055608Rethinking the mood and anxiety disorders: A quantitative hierarchical model for DSM-VJournal5608Rethinking the mood and anxiety disorders: A quantitative hierarchical model for DSM-VWatson,D.2005agoraphobiaAMERICANanxietyanxiety disorderanxiety disordersassociationbipolar disorderCOMMON MENTAL-DISORDERScomorbidityCONFIRMATORY FACTOR-ANALYSESdepressiondiagnostic and statistical manualDISORDERdisordersDISTRESSDSM-Vdysthymic disorderEMOTIONAL DISORDERSfactor analysisfearGENERALIZED ANXIETYgeneralized anxiety disorderIV ANXIETYLATENT STRUCTUREmajor depressionMENTAL DISORDERmental disordersMENTAL-DISORDERSMODELMOODNATIONAL COMORBIDITY SURVEYNEEDOBSESSIVE-COMPULSIVE DISORDERpanicpanic disorderphobiaPOSTTRAUMATIC STRESSPOSTTRAUMATIC STRESS DISORDERPOSTTRAUMATIC-STRESSPOSTTRAUMATIC-STRESS-DISORDERpsychologicalpsychologyPSYCHOPATHOLOGY RESEARCHreviewSIMILARITYsocialSOCIAL PHOBIAstressstructuresyndromeSYSTEMTRIPARTITE MODELNot in File522536Journal of Abnormal Psychology1144Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA.ISI:000233760700004Journal of Abnormal PsychologyJ Abnorm Psychol1(23,43,44). Furthermore, twin studies suggest that the genetic aetiology of specific phobias may differ from that of other anxiety disorders ADDIN REFMGR.CITE Hettema20055509The structure of genetic and environmental risk factors for anxiety disorders in men and womenJournal5509The structure of genetic and environmental risk factors for anxiety disorders in men and womenHettema,J.M.Prescott,C.A.Myers,J.M.Neale,M.C.Kendler,K.S.2005AdultADULT PSYCHIATRIC-DISORDERagoraphobiaAnimalanxietyanxiety disordersassociationCHILDHOOD SEXUAL-ABUSECLASSIFICATIONCOMMUNITYCOMMUNITY SAMPLEcomorbidityDIAGNOSESDIFFERENCEDISORDERdisordersenvironmentalenvironmental factorsenvironmental influenceENVIRONMENTAL-INFLUENCESetiologyFemalegeneGENERALIZED ANXIETYgeneralized anxiety disordergenesgeneticgenetic factorsinterviewLIFETIMEmajor depressionMalemeasureMENMODELoutcomepanicpanic disorderphobiaphobiasPOPULATION-BASED TWINpsychiatryREGISTRYriskrisk factorrisk factorsRISK-FACTORSSAMPLESEXSEX DIFFERENCEsex differencesSEX-DIFFERENCESsocialSOCIAL PHOBIAstructural equation modelingstructureSUBSTANCE USESUBSTANCE USE DISORDERSsymptomstreatmenttwintwin studiestwin studyVARIANCEwomenNot in File182189Archives of General Psychiatry622Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. Virginia Commonwealth Univ, Inst Psychiat & Behav Genet, Richmond, VA USA.ISI:000226742300009Archives of General PsychiatryArch Gen Psychiatry1Kendler20035572The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and womenJournal5572The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and womenKendler,K.S.Prescott,C.A.Myers,J.Neale,M.C.2003abuseAdultalcoholalcohol dependenceALCOHOL-ABUSEAnimalantisocial behaviorANTISOCIAL-BEHAVIORanxietybehaviorcomorbidityconductconduct disorderDEPENDENCEdepressionDIAGNOSESDISORDERdisordersdrug abuseDRUG-ABUSEDSM-III-Renvironmentenvironmentalenvironmental factorsfearFemaleFITGENERALIZED ANXIETYgeneralized anxiety disordergeneticgenetic factorsGENETIC RISKinterviewLIFETIMEmajor depressionMaleMALE TWINSMENmethodsMODELmodelsMxNATIONAL-COMORBIDITY-SURVEYPATTERNSphobiaPOPULATION-BASED SAMPLEPROGRAMpsychiatric syndromespsychiatryREGISTRYriskrisk factorrisk factorsRISK-FACTORSSEX-DIFFERENCESshared environmentstructureSUBSTANCE USESUBSTANCE USE DISORDERSsyndrometwinwomenNot in File929937Archives of General Psychiatry609Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USA.ISI:000185155800010Archives of General PsychiatryArch Gen Psychiatry1(13,19). In terms of developmental pathways, whereas most adult anxiety disorders are largely non-specific in terms of their history of anxiety disorders (they are preceded by a range of juvenile anxiety disorders), adults with specific phobias are unique in having a history of juvenile phobias but not other anxiety disorders ADDIN REFMGR.CITE Gregory20075809Juvenile Mental Health Histories of Adults with Anxiety DisordersJournal5809Juvenile Mental Health Histories of Adults with Anxiety DisordersGregory,A.M.Caspi,A.Moffitt,T.E.Koenen,K.Eley,T.C.Poulton,R.2007MENTAL HEALTHmental-healthHealthHISTORIESHISTORYadultsAdultanxietyanxiety disordersanxiety disorderdisordersDISORDERAMERICANpsychiatryNot in File301308American Journal of Psychiatry164American Journal of PsychiatryAm.J.Psychiatry1(10). This finding is consistent with prior research highlighting specificity within phobias: adolescent simple phobias predicted simple phobias in adulthood, whereas social phobias in adolescence predicted later social phobia ADDIN REFMGR.CITE Pine19985035The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disordersJournal5035The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disordersPine,D.S.Cohen,P.Gurley,D.Brook,J.Ma,Y.J.1998adolescenceAdolescentadolescentsAdultadulthoodadultsanxietyassessmentassociationCHILDREN DISC-2.1depressiondepressive disorderdepressive disordersDEPRESSIVE-DISORDERSDIAGNOSTIC INTERVIEW SCHEDULEdisordersDISRUPTIVE CHILDHOOD BEHAVIORSDSM- III DISORDERSEMOTIONAL-PROBLEMSGROWTH-HORMONE RESPONSEinterviewlatent variablesmethodsmodelsNATIONAL-COMORBIDITY-SURVEYpanic disorderphobiaPSYCHIATRIC-DISORDERSrelationshipsriskSAMPLEsocialSOCIAL PHOBIAspecificityYOUNG-ADULTSNot in File5664Archives of General Psychiatry551ISI:000071301900011Archives of General PsychiatryArch Gen Psychiatry1(28). Furthermore, selective serotonin reuptake inhibitors (SSRIs) are used to treat various anxiety disorders but are not typically used in the treatment of specific phobias, due to their limited effectiveness. Hence, studies focusing exclusively upon phobias (as opposed to studies including phobias as part of a general anxiety scale) are the focus of this report.
Genetic and environmental influences
It has long-since been postulated that both genetic and environmental factors are important in the development of phobias. Indeed, Martin Seligman highlighted in an early paper the importance of environmental influences in the development of specific phobias by pointing out that a neutral stimuli (e.g. a horse) can become aversive when paired with an external negative event (e.g. receiving an electric shock) ADDIN REFMGR.CITE Seligman19716118Phobias and PreparednessJournal6118Phobias and PreparednessSeligman,M.E.1971phobiaphobiasNot in File307320Behavior Therapy23ISI:A1971J712500003Behavior Therapy1(35). This early report also pointed out that it is easier to condition phobias towards certain stimuli (e.g. snakes) than others (e.g. flowers) - which may be due to a genetic predisposition to associate certain objects with fear ADDIN REFMGR.CITE Hettema20036038A twin study of the genetics of fear conditioningmore recently, see for a genetic study of fear conditioningJournal6038A twin study of the genetics of fear conditioningHettema,J.M.Annas,P.Neale,M.C.Kendler,K.S.Fredrikson,M.2003CONDITIONINGfeargeneticgeneticstwintwin studiestwin studyNot in File702708Archives of General Psychiatry607ISI:000184027200006Archives of General PsychiatryArch Gen Psychiatry1(more recently, see 11 for a genetic study of fear conditioning).
While direct conditioning has been the most influential theory of fear acquisition, other pathways are also important. Indeed, Rachman proposed three main pathways to fear conditioning involving direct conditioning; vicarious acquisition and informational/ instructional acquisition ADDIN REFMGR.CITE Rachman19786149Fear and CourageBook, Whole6149Fear and CourageRachman,S.J.1978fearIn FileSan FranciscoW.H.Freeman and Co.2(31). Each of these pathways has received support from various sources ADDIN REFMGR.CITE Field20036147Fear information and the development of fears during childhood: effects on implicit fear responses and behavioural avoidancee.g. for a test of the informational/ instructional pathways see Journal6147Fear information and the development of fears during childhood: effects on implicit fear responses and behavioural avoidanceField,A.P.Lawson,J.2003AVOIDANCEchildhooddevelopmentfearFEARSINFORMATIONRESPONSESNot in File12771293Behaviour Research and Therapy4111ISI:000186383400003Behaviour Research and TherapyBeh Res & Therapy1(e.g. for a test of the informational/ instructional pathways see 6). Although traditional theories have tended to emphasise the importance of experience in the development of phobias, a fourth, complementary, non-associative route also needs to be acknowledged ADDIN REFMGR.CITE Poulton20026148Non-associative fear acquisition: a review of the evidence from retrospective and longitudinal researchfor a review see Journal6148Non-associative fear acquisition: a review of the evidence from retrospective and longitudinal researchPoulton,R.Menzies,R.G.2002ACQUISITIONfearFEAR-ACQUISITIONlongitudinalreviewNot in File127149Behaviour Research and Therapy402ISI:000173262600002Behaviour Research and TherapyBeh Res & Therapy1(for a review see 30). Non-associative theories of fear acquisition emphasise that evolutionary-relevant fears (such as fears of snakes and heights) can appear with minimal or no learning.
Evidence that both genetic and environmental factors are important in explaining individual differences in phobias is provided by data from twin studies. These studies compare similarity between monozygotic twins who are genetic clones, and dizygotic twins who share on average half of their segregating genes ADDIN REFMGR.CITE Plomin20013582Behavioral Genetics 4th Editionfor further discussion of twin methodology see Book, Whole3582Behavioral Genetics 4th EditionPlomin,R.DeFries,J.CMcClearn,G.E.McGuffin,P.2001=in pressbehavioral geneticsgeneticsNot in FileNew YorkWorth Publishers2(for further discussion of twin methodology see 29). Results of studies have shown that phobias are more likely to co-occur in monozygotic than dizygotic twins.
Studies focusing upon children have found significant genetic influence upon fears and specific phobias examined in terms of symptoms ADDIN REFMGR.CITE Stevenson199211Fears and fearfulness in children and adolescents: a genetic analysis of twin dataJournal11Fears and fearfulness in children and adolescents: a genetic analysis of twin dataStevenson,J.Batten,N.Cherner,M.1992fearchildrenadolescentsgeneticsh square gIn File977985Journal of Child Psychology and Psychiatry336Journal of Child Psychology and PsychiatryJ Child Psychol Psychiat1(42) and disorders ADDIN REFMGR.CITE Bolton20065830Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twinsJournal5830Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twinsBolton,D.Eley,T.C.O'Connor,T.G.Perrin,S.Rabe-Hesketh,S.Rijsdijk,F.Smith,P.2006AdolescentadolescentsAGEanxietyanxiety disorderanxiety disorderschildhoodCHILDHOOD ANXIETYchildhood anxiety disorderchildrenCOMMUNITIESCOMMUNITYCOMMUNITY SAMPLECRITERIADIAGNOSTIC INTERVIEWDISORDERdisordersDSM-IVearly onsetEARLY-ONSETenvironmentenvironmentalenvironmental influenceENVIRONMENTAL-INFLUENCESgeneticheritabilityIMPAIRMENTinterviewnon-shared environmentnonshared environmentPATTERNSPhenotypephenotypesphobiaprevalenceRATESSAMPLESEPARATIONseparation anxietyseparation anxiety disordersyndrometwintwinsVARIANCEYOUNGYOUNG-CHILDRENNot in File335344Psychological Medicine363ISI:000235812400005Psychological MedicinePsychol Med1Lichtenstein20004454Heritability and Prevalence of Specific Fears and Phobia in ChildhoodJournal4454Heritability and Prevalence of Specific Fears and Phobia in ChildhoodLichtenstein,P.Annas,P.2000heritabilityprevalencefearphobiachildhoodIn File927937Journal of Child Psychology & Psychiatry417Journal of Child Psychology & Psychiatry1(2,24). Similarly, studies of adult twins have highlighted the importance of genes influencing specific phobias ADDIN REFMGR.CITE Kendler19996073Fears and phobias: reliability and heritabilitye.g. Journal6073Fears and phobias: reliability and heritabilityKendler,K.S.Karkowski,L.M.Prescott,C.A.1999fearFEARSheritabilityphobiaphobiasreliabilityNot in File539553Psychological Medicine293ISI:000080803100004Psychological MedicinePsychol Med1Kendler20016062The genetic epidemiology of irrational fears and phobias in menJournal6062The genetic epidemiology of irrational fears and phobias in menKendler,K.S.Myers,J.Prescott,C.A.Neale,M.C.2001epidemiologyfearFEARSgeneticgenetic epidemiologyMENphobiaphobiasNot in File257265Archives of General Psychiatry583ISI:000167339600007Archives of General PsychiatryArch Gen Psychiatry1Skre20006005The heritability of common phobic fear: A twin study of a clinical sampleJournal6005The heritability of common phobic fear: A twin study of a clinical sampleSkre,I.Onstad,S.Torgersen,S.Lygren,S.Kringlen,E.2000fearheritabilitySAMPLEtwintwin studiestwin studyNot in File549562Journal of Anxiety Disorders146ISI:000166157800002Journal of Anxiety Disorders1(e.g. 15,17,38), social phobias ADDIN REFMGR.CITE Kendler19996073Fears and phobias: reliability and heritabilitye.g. Journal6073Fears and phobias: reliability and heritabilityKendler,K.S.Karkowski,L.M.Prescott,C.A.1999fearFEARSheritabilityphobiaphobiasreliabilityNot in File539553Psychological Medicine293ISI:000080803100004Psychological MedicinePsychol Med1Kendler20016062The genetic epidemiology of irrational fears and phobias in menJournal6062The genetic epidemiology of irrational fears and phobias in menKendler,K.S.Myers,J.Prescott,C.A.Neale,M.C.2001epidemiologyfearFEARSgeneticgenetic epidemiologyMENphobiaphobiasNot in File257265Archives of General Psychiatry583ISI:000167339600007Archives of General PsychiatryArch Gen Psychiatry1Skre20006005The heritability of common phobic fear: A twin study of a clinical sampleJournal6005The heritability of common phobic fear: A twin study of a clinical sampleSkre,I.Onstad,S.Torgersen,S.Lygren,S.Kringlen,E.2000fearheritabilitySAMPLEtwintwin studiestwin studyNot in File549562Journal of Anxiety Disorders146ISI:000166157800002Journal of Anxiety Disorders1(e.g. 15,17,38) and agoraphobia ADDIN REFMGR.CITE Kendler19996073Fears and phobias: reliability and heritabilitye.g. Journal6073Fears and phobias: reliability and heritabilityKendler,K.S.Karkowski,L.M.Prescott,C.A.1999fearFEARSheritabilityphobiaphobiasreliabilityNot in File539553Psychological Medicine293ISI:000080803100004Psychological MedicinePsychol Med1Kendler20016062The genetic epidemiology of irrational fears and phobias in menJournal6062The genetic epidemiology of irrational fears and phobias in menKendler,K.S.Myers,J.Prescott,C.A.Neale,M.C.2001epidemiologyfearFEARSgeneticgenetic epidemiologyMENphobiaphobiasNot in File257265Archives of General Psychiatry583ISI:000167339600007Archives of General PsychiatryArch Gen Psychiatry1Skre20006005The heritability of common phobic fear: A twin study of a clinical sampleJournal6005The heritability of common phobic fear: A twin study of a clinical sampleSkre,I.Onstad,S.Torgersen,S.Lygren,S.Kringlen,E.2000fearheritabilitySAMPLEtwintwin studiestwin studyNot in File549562Journal of Anxiety Disorders146ISI:000166157800002Journal of Anxiety Disorders1(e.g. 15,17,38).
In addition to distinguishing genetic and environmental influences, most twin studies also distinguish shared environmental influences (those that make family members alike) and nonshared environmental influences (those that make family members differ). Nonshared environment appears to have a robust influence on phobias ADDIN REFMGR.CITE Bolton20065830Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twinse.g. Journal5830Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twinsBolton,D.Eley,T.C.O'Connor,T.G.Perrin,S.Rabe-Hesketh,S.Rijsdijk,F.Smith,P.2006AdolescentadolescentsAGEanxietyanxiety disorderanxiety disorderschildhoodCHILDHOOD ANXIETYchildhood anxiety disorderchildrenCOMMUNITIESCOMMUNITYCOMMUNITY SAMPLECRITERIADIAGNOSTIC INTERVIEWDISORDERdisordersDSM-IVearly onsetEARLY-ONSETenvironmentenvironmentalenvironmental influenceENVIRONMENTAL-INFLUENCESgeneticheritabilityIMPAIRMENTinterviewnon-shared environmentnonshared environmentPATTERNSPhenotypephenotypesphobiaprevalenceRATESSAMPLESEPARATIONseparation anxietyseparation anxiety disordersyndrometwintwinsVARIANCEYOUNGYOUNG-CHILDRENNot in File335344Psychological Medicine363ISI:000235812400005Psychological MedicinePsychol Med1Kendler19956007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationJournal6007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationKendler,K.S.Walters,E.E.Truett,K.R.Heath,A.C.Neale,M.C.Martin,N.G.Eaves,L.J.1995self-reportSOMATIZATIONsymptomsNot in File499515Behavior Genetics256ISI:A1995TC66700001Behavior GeneticsBehav Genet1Kendler20016062The genetic epidemiology of irrational fears and phobias in menJournal6062The genetic epidemiology of irrational fears and phobias in menKendler,K.S.Myers,J.Prescott,C.A.Neale,M.C.2001epidemiologyfearFEARSgeneticgenetic epidemiologyMENphobiaphobiasNot in File257265Archives of General Psychiatry583ISI:000167339600007Archives of General PsychiatryArch Gen Psychiatry1(e.g. 2,20,17). However, research has produced mixed results with regards to shared environmental influence. For example, one study of children highlighted shared environmental influence on phobias ADDIN REFMGR.CITE Lichtenstein20004454Heritability and Prevalence of Specific Fears and Phobia in ChildhoodJournal4454Heritability and Prevalence of Specific Fears and Phobia in ChildhoodLichtenstein,P.Annas,P.2000heritabilityprevalencefearphobiachildhoodIn File927937Journal of Child Psychology & Psychiatry417Journal of Child Psychology & Psychiatry1(24) whereas another did not find this type of influence to be significant ADDIN REFMGR.CITE Bolton20065830Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twinsJournal5830Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twinsBolton,D.Eley,T.C.O'Connor,T.G.Perrin,S.Rabe-Hesketh,S.Rijsdijk,F.Smith,P.2006AdolescentadolescentsAGEanxietyanxiety disorderanxiety disorderschildhoodCHILDHOOD ANXIETYchildhood anxiety disorderchildrenCOMMUNITIESCOMMUNITYCOMMUNITY SAMPLECRITERIADIAGNOSTIC INTERVIEWDISORDERdisordersDSM-IVearly onsetEARLY-ONSETenvironmentenvironmentalenvironmental influenceENVIRONMENTAL-INFLUENCESgeneticheritabilityIMPAIRMENTinterviewnon-shared environmentnonshared environmentPATTERNSPhenotypephenotypesphobiaprevalenceRATESSAMPLESEPARATIONseparation anxietyseparation anxiety disordersyndrometwintwinsVARIANCEYOUNGYOUNG-CHILDRENNot in File335344Psychological Medicine363ISI:000235812400005Psychological MedicinePsychol Med1(2). Similarly, there have been mixed results from studies of adults with a study of males revealing possible shared environmental influence on agoraphobia and social phobia but not specific phobia ADDIN REFMGR.CITE Kendler20016062The genetic epidemiology of irrational fears and phobias in menJournal6062The genetic epidemiology of irrational fears and phobias in menKendler,K.S.Myers,J.Prescott,C.A.Neale,M.C.2001epidemiologyfearFEARSgeneticgenetic epidemiologyMENphobiaphobiasNot in File257265Archives of General Psychiatry583ISI:000167339600007Archives of General PsychiatryArch Gen Psychiatry1(17). A further report showed negligible shared environmental influence on panic-phobia in males but a more modest influence on females ADDIN REFMGR.CITE Kendler19956007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationJournal6007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationKendler,K.S.Walters,E.E.Truett,K.R.Heath,A.C.Neale,M.C.Martin,N.G.Eaves,L.J.1995self-reportSOMATIZATIONsymptomsNot in File499515Behavior Genetics256ISI:A1995TC66700001Behavior GeneticsBehav Genet1(20). The distinction between shared and nonshared environmental influences is relevant to studies of G x E. Indeed, most twin analyses do not estimate G x E and if positive interactions between genetic and shared environmental influences are present but ignored they artificially inflate estimates of genetic influence. In contrast, positive interactions between genetic and nonshared environmental influence are estimated as nonshared environmental influence ADDIN REFMGR.CITE Rijsdijk20025310Analytic approaches to twin data using structural equation modelsJournal5310Analytic approaches to twin data using structural equation modelsRijsdijk,F.V.Sham,P.C.2002twinmodelsMODELNot in File119133Briefings in bioinformatics32In fileBriefings in bioinformatics1(32).
Studies of both children and adults have highlighted differences between the sexes in terms of the magnitude of influences on different types of phobias ADDIN REFMGR.CITE Kendler19956007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and Somatizatione.g. Journal6007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationKendler,K.S.Walters,E.E.Truett,K.R.Heath,A.C.Neale,M.C.Martin,N.G.Eaves,L.J.1995self-reportSOMATIZATIONsymptomsNot in File499515Behavior Genetics256ISI:A1995TC66700001Behavior GeneticsBehav Genet1Lichtenstein20004454Heritability and Prevalence of Specific Fears and Phobia in ChildhoodJournal4454Heritability and Prevalence of Specific Fears and Phobia in ChildhoodLichtenstein,P.Annas,P.2000heritabilityprevalencefearphobiachildhoodIn File927937Journal of Child Psychology & Psychiatry417Journal of Child Psychology & Psychiatry1(e.g. 20,24). Further studies have also revealed that some of the genes influencing phobic disorders may differ between males and females. For example, a study of over 3000 adult twin pairs found that exactly the same set of genes influenced animal fears in both males and females ADDIN REFMGR.CITE Kendler20026050Sex differences in genetic and environmental risk factors for irrational fears and phobiasJournal6050Sex differences in genetic and environmental risk factors for irrational fears and phobiasKendler,K.S.Jacobson,K.C.Myers,J.Prescott,C.A.2002DIFFERENCEenvironmentalfearFEARSgeneticphobiaphobiasriskrisk factorrisk factorsRISK-FACTORSSEXSEX DIFFERENCEsex differencesSEX-DIFFERENCESNot in File209217Psychological Medicine322ISI:000173990900003Psychological MedicinePsychol Med1(14). In contrast, for agoraphobia, situational phobia and blood/injury phobia there was some genetic overlap although different genes also influenced these traits in males and females separately. Hence, the impact of sex differences appears to vary across phobia subtype. To add further complexity, sex differences have also been found in the magnitude of influences accounting for stability of symptoms. Specifically, one study found that, for males, genes account for 73% of the stability of panic-phobic symptoms over a mean 14-month period, as compared to 24% for females ADDIN REFMGR.CITE Kendler19956007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationJournal6007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationKendler,K.S.Walters,E.E.Truett,K.R.Heath,A.C.Neale,M.C.Martin,N.G.Eaves,L.J.1995self-reportSOMATIZATIONsymptomsNot in File499515Behavior Genetics256ISI:A1995TC66700001Behavior GeneticsBehav Genet1(20). Genetic and environmental influences clearly differ by phenotype and sex and these variables therefore need to be considered when planning G x E studies for phobias.
Twin studies have also increased understanding of comorbidity. For example, a twin study of different phobias in males revealed that genetic risks were partly common and partly specific across different types of phobias ADDIN REFMGR.CITE Kendler20016062The genetic epidemiology of irrational fears and phobias in menJournal6062The genetic epidemiology of irrational fears and phobias in menKendler,K.S.Myers,J.Prescott,C.A.Neale,M.C.2001epidemiologyfearFEARSgeneticgenetic epidemiologyMENphobiaphobiasNot in File257265Archives of General Psychiatry583ISI:000167339600007Archives of General PsychiatryArch Gen Psychiatry1(17). Studies examining the overlap between different types of anxiety have also highlighted an overlap between genes influencing different types of anxiety ADDIN REFMGR.CITE Eley20035101A twin study of anxiety-related behaviours in pre-school childrenfor a study of anxiety-related behaviours in pre-school twins see Journal5101A twin study of anxiety-related behaviours in pre-school childrenEley,T.C.Bolton,D.O'Connor,T.G.Perrin,S.Smith,P.Plomin,R.2003anxietyanxiety disordersassessmentbehaviourbehavioural inhibitionChildchildhoodchildrenCOMMUNITY SAMPLEDISORDERdisordersenvironmentenvironmental influenceENVIRONMENTAL-INFLUENCESfearFEARSGENETIC-ANALYSISgeneticsheritabilityinternalisinglife eventsmethodsMIDDLEMIDDLE CHILDHOODnon-shared environmentOBSESSIVE-COMPULSIVE DISORDERpanic disorderphobiapre-school childrenpre-schoolersPRESCHOOLSAMPLESCALESCALESseparation anxietySOCIAL PHOBIAstructuresymptomstwintwin studiestwin studytwinsYOUNG TWINSYOUNG-CHILDRENNot in File945960Journal of Child Psychology and Psychiatry and Allied Disciplines447ISI:000185573900003Journal of Child Psychology and Psychiatry and Allied Disciplines1(for a study of anxiety-related behaviours in pre-school twins see 5), although such studies have also suggested that the aetiology of specific phobias may be largely distinct from that of other anxiety disorders ADDIN REFMGR.CITE Hettema20055509The structure of genetic and environmental risk factors for anxiety disorders in men and womenJournal5509The structure of genetic and environmental risk factors for anxiety disorders in men and womenHettema,J.M.Prescott,C.A.Myers,J.M.Neale,M.C.Kendler,K.S.2005AdultADULT PSYCHIATRIC-DISORDERagoraphobiaAnimalanxietyanxiety disordersassociationCHILDHOOD SEXUAL-ABUSECLASSIFICATIONCOMMUNITYCOMMUNITY SAMPLEcomorbidityDIAGNOSESDIFFERENCEDISORDERdisordersenvironmentalenvironmental factorsenvironmental influenceENVIRONMENTAL-INFLUENCESetiologyFemalegeneGENERALIZED ANXIETYgeneralized anxiety disordergenesgeneticgenetic factorsinterviewLIFETIMEmajor depressionMalemeasureMENMODELoutcomepanicpanic disorderphobiaphobiasPOPULATION-BASED TWINpsychiatryREGISTRYriskrisk factorrisk factorsRISK-FACTORSSAMPLESEXSEX DIFFERENCEsex differencesSEX-DIFFERENCESsocialSOCIAL PHOBIAstructural equation modelingstructureSUBSTANCE USESUBSTANCE USE DISORDERSsymptomstreatmenttwintwin studiestwin studyVARIANCEwomenNot in File182189Archives of General Psychiatry622Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. Virginia Commonwealth Univ, Inst Psychiat & Behav Genet, Richmond, VA USA.ISI:000226742300009Archives of General PsychiatryArch Gen Psychiatry1Kendler20035572The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and womenJournal5572The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and womenKendler,K.S.Prescott,C.A.Myers,J.Neale,M.C.2003abuseAdultalcoholalcohol dependenceALCOHOL-ABUSEAnimalantisocial behaviorANTISOCIAL-BEHAVIORanxietybehaviorcomorbidityconductconduct disorderDEPENDENCEdepressionDIAGNOSESDISORDERdisordersdrug abuseDRUG-ABUSEDSM-III-Renvironmentenvironmentalenvironmental factorsfearFemaleFITGENERALIZED ANXIETYgeneralized anxiety disordergeneticgenetic factorsGENETIC RISKinterviewLIFETIMEmajor depressionMaleMALE TWINSMENmethodsMODELmodelsMxNATIONAL-COMORBIDITY-SURVEYPATTERNSphobiaPOPULATION-BASED SAMPLEPROGRAMpsychiatric syndromespsychiatryREGISTRYriskrisk factorrisk factorsRISK-FACTORSSEX-DIFFERENCESshared environmentstructureSUBSTANCE USESUBSTANCE USE DISORDERSsyndrometwinwomenNot in File929937Archives of General Psychiatry609Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USA.ISI:000185155800010Archives of General PsychiatryArch Gen Psychiatry1(13,19). In addition to providing information about the co-occurrence of anxiety disorders, studies of comorbidity examine different types of disorders. For example, those with phobias are at increased risk of major depressive disorder ADDIN REFMGR.CITE Hettema20035513The effects of anxiety, substance use and conduct disorders on risk of major depressive disorderJournal5513The effects of anxiety, substance use and conduct disorders on risk of major depressive disorderHettema,J.M.Prescott,C.A.Kendler,K.S.2003Adultalcoholalcohol dependenceanxietyAXIS-ICO-OCCURRENCEcomorbidityconductconduct disorderconduct disordersDEPENDENCEdepressiondepressive disorderdevelopmentDIFFERENCEDISORDERdisordersDSM-IIIFemaleGENDERGENDER DIFFERENCESGENDER-DIFFERENCESGENERAL-POPULATIONGENERALIZED ANXIETYgeneralized anxiety disordergenetic epidemiologyLIFETIMElongitudinalMAJOR DEPRESSIVE DISORDERMaleMDDMENMODELonsetpanicpanic disorderPERIODphobiaphobiasPOPULATION-BASED SAMPLEprevalencepsychiatric disorderpsychiatric disordersPSYCHIATRIC-DISORDERPSYCHIATRIC-DISORDERSpsychiatrypsychologyRATESriskrisk factorrisk factorsRISK-FACTORSSAMPLEsensitivitySEX-DIFFERENCESSUBSTANCE USESUBSTANCE USE DISORDERSTIMEtwinwomenNot in File14231432Psychological Medicine338Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Coll Med,Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Coll Med,Virginia Inst Psychiat & Behav Genet, Dept Human Genet, Richmond, VA 23298 USA.ISI:000186981000010Psychological MedicinePsychol Med1(12) and comorbidity between the two types of illness appears to be influenced by genetic and environmental influences to different degrees depending upon the type of phobia being examined in association with depression ADDIN REFMGR.CITE Kendler1993189Major depression and phobias: the genetic and environmental sources of comorbidityJournal189Major depression and phobias: the genetic and environmental sources of comorbidityKendler,K.S.Neale,M.C.Kessler,R.C.Heath,A.C.Eaves,L.J.1993=bmajor depressiondepressionphobiasgeneticscomorbiditytwin studyIn File361371Psychological Medicine23Psychological MedicinePsychol Med1Nelson20004826Social phobia in population-based female adolescent twin sample: co-morbidity and associated suicide-related symptoms. see also Journal4826Social phobia in population-based female adolescent twin sample: co-morbidity and associated suicide-related symptoms.Nelson,E.C.Grant,J.D.Bucholz,K.K.Glowinski,A.Madden,P.A.F.Reich,W.Heath,A.C.2000AdolescentcomorbidityFemalephobiasocialsymptomstwinNot in File797804Psychological Medicine30Psychological MedicinePsychol Med1(18, see also 26). Longitudinal associations between phobias and depression have also been reported and genetic decomposition of this association in a sample of over 600 female twin pairs revealed that genetic influences on depression after 14 years of age reflect liability to symptoms of phobias before the age of 14, whereas shared environmental influences on depression before 14 years of age influenced phobias after the age of 14 ADDIN REFMGR.CITE Silberg20014951Genetic and environmental influences on the temporal association between earlier anxiety and later depression in girlsJournal4951Genetic and environmental influences on the temporal association between earlier anxiety and later depression in girlsSilberg,J.L.Rutter,M.Eaves,L.2001adolescenceAdolescentADOLESCENT BEHAVIORAL-DEVELOPMENTaffectAGEanxietyanxiety symptomsassociationbehavioral developmentchildhooddepressiondepressive symptomsdevelopmentdisordersenvironmentenvironmental factorsenvironmental influenceFemalegeneticsgirlsinterviewmajor depressionmethodsMIDDLEmodel-fittingmodelsPARTLY DIFFERENT ENVIRONMENTSphobiaphobiasPSYCHIATRIC-ASSESSMENT CAPApsychopathologyriskRISK-FACTORSseparation anxietysymptomssyndrometwintwin studiestwin studyVIRGINIA TWINNot in File10401049Biological Psychiatry4912ISI:000169568900010Biological PsychiatryBiol Psychiatry1(36) highlighting the role of development in the complex links between phobias and depression. Twin studies of co-occurring traits are useful when planning studies of G x E, as strong correlations between the influences (e.g. genes) on different traits (e.g. depression and phobias) suggest that once a specific influence on one trait (e.g. depression) has been identified, this same influence may also be a good candidate to explore in models of G x E with regards to the co-occurring trait (e.g. phobias).
Genetic models have also been used to shed light on links between phobias and cognitive dimensions and one study reported a strong genetic correlation between fear of negative evaluation (a cognitive construct central to social phobia) and social anxiety related personality traits ADDIN REFMGR.CITE Stein20026048Heritability of social anxiety-related concerns and personality characteristics: A twin studyJournal6048Heritability of social anxiety-related concerns and personality characteristics: A twin studyStein,M.B.Jang,K.L.Livesley,W.J.2002heritabilitypersonalitysocialtwintwin studiestwin studyNot in File219224Journal of Nervous and Mental Disease1904ISI:000175096500002Journal of Nervous and Mental DiseaseJ Nerv Ment Dis1(40). It may be fruitful to measure cognition (in addition to phobias) in G x E models as it is possible that cognitive style mediates some of the genetic risk on phobic symptoms. Measuring cognitions central to phobias may therefore allow testing of theories underlying the development and maintenance of these difficulties. Furthermore, certain central cognitive aspects of phobias may be more directly influenced by genes than the symptoms of phobias themselves. Such endophenotypes for phobias need to be proposed and tested empirically ADDIN REFMGR.CITE Gottesman20035644The endophenotype concept in psychiatry: Etymology and strategic intentions(for further discussion of endophenotypes in genetic research see Journal5644The endophenotype concept in psychiatry: Etymology and strategic intentionsGottesman,I.I.Gould,T.D.2003analysisAnimalanimal modelsANIMAL-MODELSassociationATTENTION-DEFICITHYPERACTIVITY DISORDERcandidate geneCLASSIFICATIONCOMPLEXCRITERIAdevelopmentDIAGNOSESdiagnosisDISEASEDISEASESDISORDERdisordersDORSOLATERAL PREFRONTAL CORTEXEyeEYE-MOVEMENT DYSFUNCTIONFIRST-DEGREE RELATIVESFRONTAL-LOBE FUNCTIONgenegeneticGENETIC-ANALYSISgeneticsGenotypeheritabilityLONG-QT SYNDROMEMinnesotaMODELmodelsnaturePARAMETERSPOSITRON-EMISSION-TOMOGRAPHYpsychiatric disorderpsychiatric disordersPSYCHIATRIC-DISORDERPSYCHIATRIC-DISORDERSpsychiatryREGIONRELATIVESreviewriskSCHIZOPHRENIC-PATIENTSSCHIZOTYPAL PERSONALITY-DISORDERself-reportSTRATEGIESsyndromeWORKING-MEMORY PERFORMANCENot in File636645American Journal of Psychiatry1604Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55454 USA. NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA.ISI:000182096300008American Journal of PsychiatryAm.J.Psychiatry1(for further discussion of endophenotypes in genetic research see 9).
There has been extensive debate concerning the adequacy of the twin methodology. Critics of twin research claim that the assumptions underlying the methodology are unfounded and so estimates provided by studies employing twin methodology are inaccurate. Twin researchers justify assumptions made and point out that this is amongst the best methodologies available whilst emphasising the need for cautious general interpretation of estimates from twin data ADDIN REFMGR.CITE Plomin20013582Behavioral Genetics 4th Editionsee for further discussion of this topicBook, Whole3582Behavioral Genetics 4th EditionPlomin,R.DeFries,J.CMcClearn,G.E.McGuffin,P.2001=in pressbehavioral geneticsgeneticsNot in FileNew YorkWorth Publishers2(see 29 for further discussion of this topic). Although it is beyond the scope of this review to represent this highly charged debate, it is important to mention criticisms which have focused upon phobias. One such criticism concerns generalizability. In order to extrapolate results from twin studies to the non-twin population, it must be assumed that twins are similar to non-twins. However, this is not necessarily the case for phobias as one study including both twin and sibling pairs revealed higher levels of heritability for panic-phobia when focusing upon twins exclusively than when including non-twins ADDIN REFMGR.CITE Kendler19956007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationJournal6007A Twin-Family Study of Self-Report Symptoms of Panic-Phobia and SomatizationKendler,K.S.Walters,E.E.Truett,K.R.Heath,A.C.Neale,M.C.Martin,N.G.Eaves,L.J.1995self-reportSOMATIZATIONsymptomsNot in File499515Behavior Genetics256ISI:A1995TC66700001Behavior GeneticsBehav Genet1(20). Other studies have emphasised similarities between twins and non-twins however, and the prevalence rate for psychiatric disorders is similar in twins and non-twins ADDIN REFMGR.CITE Simonoff19971623The Virginia Twin Study of Adolescent Behavioral Development. Influences of age, sex, and impairment on rates of disorderJournal1623The Virginia Twin Study of Adolescent Behavioral Development. Influences of age, sex, and impairment on rates of disorderSimonoff,E.Pickles,A.Meyer,J.Silberg,J.L.Maes,H.Loeber,R.Rutter,M.Hewitt,J.K.Eaves,L.J.1997twintwin studytwin studiesAdolescentbehavioral developmentdevelopmentIn File801808Archives of General Psychiatry54Archives of General PsychiatryArch Gen Psychiatry1(37). Despite criticisms, twin studies have revealed a great deal about genetic and environmental influences on phobias. Together with early conditioning studies which suggest that phobias may arise from genetic propensities which are expressed following exposure to certain environmental stimuli, twin studies have stimulated hypotheses concerning G x E for phobias.
Finding G x Es for phobias
The finding from twin studies that environmental factors are influential (albeit to varying degrees) sits well with clinical observations that patients with phobias often report early traumatic experiences associated with their phobias. However, such observations may not demonstrate purely environmental influences on phobias as it is known that genes may influence both exposure and sensitivity to environmental insults. Imagine for example that a child has genes associated with high levels of behavioural inhibition. Perhaps these genes influence the way in which the child interacts with unfamiliar animals and the awkward stroking of a dog may lead to the child being bitten (an example of gene-environment correlation, rGE). Based on the childs genetic propensity, this environmental trauma may make this child (as compared to certain other children) particularly vulnerable for developing a dog phobia (an example of G x E).
There is little evidence of rGE and G x E for phobias. However, one study explored the possibility of a stress-diathesis model for phobias in 7500 twin pairs ADDIN REFMGR.CITE Kendler20026049The etiology of phobias - An evaluation of the stress-diathesis modelJournal6049The etiology of phobias - An evaluation of the stress-diathesis modelKendler,K.S.Myers,J.Prescott,C.A.2002etiologyMODELphobiaphobiasNot in File242248Archives of General Psychiatry593ISI:000174300800005Archives of General PsychiatryArch Gen Psychiatry1(16). The authors examined whether phobic individuals who reported higher levels of environmental stress (e.g. experiencing a severe trauma) had a lower genetic loading (i.e. were phobias were less heritable in this sub-group?) as compared to those who reported lower levels of environmental stress (e.g. observing a trauma occurring to another or experiencing a mild trauma). The results did not support the stress-diathesis model and the authors proposed that this is most likely because the model is not applicable to phobias and instead argue that vulnerability to phobias may be largely innate without the need for environmental experiences.
An alternative suggestion of these null results concerns the measure of the environment which could have been inappropriate. While the authors point out that this explanation is unlikely given the adequate reliability and validity of their assessment of stress the issue of how best to conceptualise the environment is of central importance when designing studies of G x E. For example, it is important to decide upon the optimum aspect of the environment on which to focus and there are distinctions between negative life events influencing anxiety and depression, with threat events associated with anxiety and loss events associated with depression ADDIN REFMGR.CITE Finlay-Jones1981117Types of stressful life events and the onset of anxiety and depressive disorderse.g. Journal117Types of stressful life events and the onset of anxiety and depressive disordersFinlay-Jones,R.Brown,G.W.1981anxietydepressive disorderslife eventsanxiety disorderslossdangerIn File803815Psychological Medicine11Psychological MedicinePsychol Med1(e.g. 7). Additionally, there may be differences between anxiety disorders with regards to environmental influences. For example, while elevated rates of abuse have been reported in individuals with different types of anxiety disorders, two studies suggest that there may be a particularly strong association between abuse and panic as compared to certain other anxiety disorders ADDIN REFMGR.CITE Safren20025596History of childhood abuse in panic disorder, social phobia, and generalized anxiety disorderJournal5596History of childhood abuse in panic disorder, social phobia, and generalized anxiety disorderSafren,S.A.Gershuny,B.S.Marzol,P.Otto,M.W.Pollack,M.H.2002abuseAdultanxietyanxiety disorderanxiety disorderschildhoodcomorbidCOMORBID ANXIETYdepressiondevelopmentDISORDERDISORDER PATIENTSdisordersEXPERIENCEGENERALIZED ANXIETYgeneralized anxiety disorderHISTORIESHISTORYintelligencemajor depressionpanicpanic disorderPATIENTphobiaPOSTTRAUMATIC-STRESS-DISORDERprevalencepsychiatryRATESSAMPLESEXUAL ABUSEsocialSOCIAL PHOBIAsymptomsTRAUMAtreatmentNot in File453456Journal of Nervous and Mental Disease1907Harvard Univ, Sch Med, MGH Psychiat, Boston, MA 02114 USA.ISI:000177060800005Journal of Nervous and Mental DiseaseJ Nerv Ment Dis1Stein19965104Childhood physical and sexual abuse in patients with anxiety disorders and in a community sampleJournal5104Childhood physical and sexual abuse in patients with anxiety disorders and in a community sampleStein,M.B.Walker,J.R.Anderson,G.Hazen,A.L.Ross,C.A.Eldridge,G.Forde,D.R.1996abuseAGEanxietyanxiety disordersASSAULTassociationchildhoodCOMMUNITYCOMMUNITY SAMPLEDISORDERdisordersDSM-IVHISTORYillnessinterviewMENTAL-DISORDERSpanicpanic disorderphobiaPOPULATIONSAMPLESEXUAL ABUSEsocialSOCIAL PHOBIAsymptomsTRAUMAwomenNot in File275277American Journal of Psychiatry1532ISI:A1996TT55700024American Journal of PsychiatryAm.J.Psychiatry1(34,41). Further still there are likely to be distinctions between different types of phobias in terms of environmental influences. For example, Kenneth Kendler and colleagues identified differences in the mode of acquisition of different types of phobias ADDIN REFMGR.CITE Kendler20026049The etiology of phobias - An evaluation of the stress-diathesis modelJournal6049The etiology of phobias - An evaluation of the stress-diathesis modelKendler,K.S.Myers,J.Prescott,C.A.2002etiologyMODELphobiaphobiasNot in File242248Archives of General Psychiatry593ISI:000174300800005Archives of General PsychiatryArch Gen Psychiatry1(16). Whereas experiencing a trauma was identified as the mode of acquisition for 48% of participants with animal fears, it accounted for just 23% of cases of social fears.
In addition to consideration of the optimal environmental phenotype to measure in G x E models, the timing of environmental experiences also needs to be considered. First, the impact of certain life events may vary with age. For example, being bitten by a dog may represent a more traumatic experience for a young child who has not yet developed the cognitive capacity to deal with this event, as compared to an adult. A further consideration concerns latent inhibition which refers to a phenomenon whereby being pre-exposed to a neutral stimulus results in subsequent difficulty when attempting to condition that stimulus to be aversive. This theory would explain increased susceptibility of dog phobia in a bitten child as compared to a bitten adult by pointing to greater neutral exposure to dogs in adults as compared to children. As environmental events associated with phobias may have occurred early in life care needs to be taken when measuring events that have occurred a long time ago. In particular, use of prospective longitudinal data eliminates the need for retrospective reporting, which is notoriously unreliable. Research also suggests that phobias may develop as an acute reaction to an event and genetic moderation of response to experimental manipulations of the environment (e.g. requesting patients with social phobia to give a public presentation; using novel paradigms to eliciting an acute response in real-time) is therefore likely to be scientifically important. Ethical considerations in relation to eliciting or inducing stress in participants suggests that animal studies are likely to continue being used in order to establish responses to certain environmental manipulations (e.g. classical conditioning studies of phobias).
In addition to environmental explanations for the lack of evidence for G x E for phobias, a further explanation could be that previous studies have not assessed genetic influence appropriately. For example, sample size must be considered in order to ensure appropriate power to identify the interactions being sought. While previous studies employ large sample sizes and are therefore appropriate with regards to this issue ADDIN REFMGR.CITE Kendler20026049The etiology of phobias - An evaluation of the stress-diathesis modelJournal6049The etiology of phobias - An evaluation of the stress-diathesis modelKendler,K.S.Myers,J.Prescott,C.A.2002etiologyMODELphobiaphobiasNot in File242248Archives of General Psychiatry593ISI:000174300800005Archives of General PsychiatryArch Gen Psychiatry1(16), these studies have estimated as opposed to measured genetic influence, and the latter approach has obvious advantages. Consequently, in addition to identifying statistical G x E, studies of other phenotypes have begun to examine associations between specific genes and environmental factors ADDIN REFMGR.CITE Caspi20035084Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT genee.g. the short allele of the 5-HTT promoter polymorphism has been associated with greater sensitivity to life events in the development of depression,Journal5084Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT geneCaspi,A.Sugden,K.Moffitt,T.E.Taylor,A.Craig,I.W.Harrington,H.McClay,J.Mill,J.Martin,J.Braithwaite,A.Poulton,R.20035HTTdepressiongeneLIFEpolymorphismstressNot in File386389Science3015631ISI:000184207300050Science1(e.g. the short allele of the 5-HTT promoter polymorphism has been associated with greater sensitivity to life events in the development of depression, 4). When designing studies of G x E for phobias, researchers should capitalise upon what is already known about specific genes linked with phobias in order to select candidate genes to examine in models of G x E. For example, there have been associations between phobias and the val/val genotype of the catechol-O-methyltransterase (COMT) Val158Met polymorphism ADDIN REFMGR.CITE McGrath20045887Association between catechol-O-methyltransferase and phobic anxietyJournal5887Association between catechol-O-methyltransferase and phobic anxietyMcGrath,M.Kawachi,I.Ascherio,A.Colditz,G.A.Hunter,D.J.De Vivo,I.2004anxietyassociationCATECHOL-O-METHYLTRANSFERASEdevelopmentgeneGene DosageGenotypegenotypesINDEXPHOBIC ANXIETYpolymorphismSCALEwomenNot in File17031705American Journal of Psychiatry1619ISI:000223800600027American Journal of PsychiatryAm.J.Psychiatry1(25) and with genes involved in thyroid hormone receptor function ADDIN REFMGR.CITE Philibert20026046The association of a HOPA polymorphism with major depression and phobiaJournal6046The association of a HOPA polymorphism with major depression and phobiaPhilibert,R.Caspers,K.Langbehn,D.Troughton,E.P.Yucuis,R.Sandhu,H.K.Cadoret,R.J.2002associationdepressionmajor depressionphobiapolymorphismNot in File404410Comprehensive Psychiatry435ISI:000177944600011Comprehensive PsychiatryCompr Psychiatry1(27). Candidate genes may also come from other types of studies, such as twin studies of comorbidity as knowledge of strong genetic overlap between disorders suggests that once a gene has been associated with one disorder it may also be associated with the comorbid disorder.
Conclusion
Twin studies have been essential in advancing understanding of genetic and environmental influences on phobias - although previous research is limited in that it largely ignores associations between genes and the environment. Studies of G x E inevitably involve measurement of three components: genes; the environment; and phobias. Given developing knowledge of all three, it is increasingly likely that novel studies utilising this knowledge and designed to identify G x E for phobias will succeed.
In addition to the careful conceptualisation of new studies designed to find G x Es for phobias, researchers may also benefit from re-examining data which have already been collected. Indeed, distinctions between phobias and other types of anxiety suggest that it may be beneficial to regroup data already collected in order to focus upon: 1) specific types of phobias (rather than anxiety as a whole); 2) environmental factors which have been directly linked to phobias (rather than more general measures of stress); and 3) genes that have been associated with phobias (rather than more generally with anxiety). This approach is likely to be particularly fruitful in light of continuous growth in knowledge of genes and environmental factors linked to phobias.
In order to develop a more comprehensive understanding of phobias, it may also be worthwhile acknowledging other disciplines. Twin studies have already used important information provided by cognitive psychologists to increase understanding of the aetiology of phobias. Furthermore, reviews have stressed the mutual benefit of combining gene-environment interactions and neuroscience in psychiatry ADDIN REFMGR.CITE Caspi20065872Opinion - Gene-environment interactions in psychiatry: joining forces with neuroscienceJournal5872Opinion - Gene-environment interactions in psychiatry: joining forces with neuroscienceCaspi,A.Moffitt,T.E.2006affectDIFFERENCEDISEASEDISORDERdisordersDNAenvironmentenvironmentalepidemiologygenegene-environment interactiongeneticHETEROGENEITYLEVELMECHANISMMECHANISMSMENTAL DISORDERmental disordersMENTAL-DISORDERSnatureOPPORTUNITYpsychiatryNot in File583590Nature Reviews Neuroscience77ISI:000238476600018Nature Reviews Neuroscience1(3). For example, based partly on G x E findings that genetic influence on a trait may only appear following a stressful experience, one study explored an association between a specific polymorphism and a brain response, finding that the 5-HTT candidate gene is associated with individual differences in amygdala responsiveness to social anxiety provocation in patients with social phobia ADDIN REFMGR.CITE Furmark20045286Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobiaJournal5286Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobiaFurmark,T.Tillfors,M.Garpenstrand,H.Marteinsdottir,I.Langstrom,B.Oreland,L.Fredrikson,M.20045- HTTLPR5HTTACTIVATIONactivityaffectAllelesamygdalaanxietyANXIETY-RELATED TRAITSassociationDISORDERemotionFUNCTIONAL POLYMORPHISMgeneGENE REGULATORY REGIONgeneticgenotypingHumanlinkagePATIENTPETphobiapolymorphismPOSITRON EMISSION TOMOGRAPHYPROMOTERREGIONserotoninserotonin transportersocialsocial anxietySOCIAL PHOBIAtransporterNot in File189192Neuroscience Letters3623Uppsala Univ, Dept Psychol, Box 1225, SE-75142 Uppsala, Sweden Uppsala Univ, Dept Psychol, SE-75142 Uppsala, Sweden Univ Orebro, Dept Behav Social & Legal Sci, S-70130 Orebro, Sweden Uppsala Univ, Dept Neurosci Pharmacol, SE-75142 Uppsala, Sweden Uppsala Univ, Dept Neurosci Psychiat, SE-75142 Uppsala, Sweden Univ Hosp, Uppsala Imanet AB, Uppsala, SwedenISI:000221679100006Neuroscience Letters1(8). In turn, such findings provide inspiration to researchers developing studies of G x E for phobias.
Acknowledgements
Thalia C. Eley is funded by a Medical Research Council Career Development Award. The authors thank Megan Crawford, Jessica Holland and Thomas Willis for their feedback on an earlier draft of this manuscript and for their assistance in preparing this article.
ADDIN REFMGR.REFLIST Reference List
1. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edition. American Psychiatric Press, Washington, DC
2. Bolton D, Eley TC, O'Connor TG, Perrin S, Rabe-Hesketh S, Rijsdijk F, Smith P (2006) Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twins. Psychological Medicine 36:335-344
3. Caspi A, Moffitt TE (2006) Opinion - Gene-environment interactions in psychiatry: joining forces with neuroscience. Nature Reviews Neuroscience 7:583-590
4. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386-389
5. Eley TC, Bolton D, O'Connor TG, Perrin S, Smith P, Plomin R (2003) A twin study of anxiety-related behaviours in pre-school children. Journal of Child Psychology and Psychiatry and Allied Disciplines 44:945-960
6. Field AP, Lawson J (2003) Fear information and the development of fears during childhood: effects on implicit fear responses and behavioural avoidance. Behaviour Research and Therapy 41:1277-1293
7. Finlay-Jones R, Brown GW (1981) Types of stressful life events and the onset of anxiety and depressive disorders. Psychological Medicine 11:803-815
8. Furmark T, Tillfors M, Garpenstrand H, Marteinsdottir I, Langstrom B, Oreland L, Fredrikson M (2004) Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neuroscience Letters 362:189-192
9. Gottesman II and Gould TD (2003) The endophenotype concept in psychiatry: Etymology and strategic intentions. American Journal of Psychiatry 160:636-645
10. Gregory AM, Caspi A, Moffitt TE, Koenen K, Eley TC, Poulton R (2007) Juvenile mental health histories of adults with anxiety disorders. American Journal of Psychiatry 164:301-308
11. Hettema JM, Annas P, Neale MC, Kendler KS, Fredrikson M (2003) A twin study of the genetics of fear conditioning. Archives of General Psychiatry 60:702-708
12. Hettema JM, Prescott CA, Kendler KS (2003) The effects of anxiety, substance use and conduct disorders on risk of major depressive disorder. Psychological Medicine 33:1423-1432
13. Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS (2005) The structure of genetic and environmental risk factors for anxiety disorders in men and women. Archives of General Psychiatry 62:182-189
14. Kendler KS, Jacobson KC, Myers J, Prescott CA (2002) Sex differences in genetic and environmental risk factors for irrational fears and phobias. Psychological Medicine 32:209-217
15. Kendler KS, Karkowski LM, Prescott CA (1999) Fears and phobias: reliability and heritability. Psychological Medicine 29:539-553
16. Kendler KS, Myers J, Prescott CA (2002) The etiology of phobias - an evaluation of the stress-diathesis model. Archives of General Psychiatry 59:242-248
17. Kendler KS, Myers J, Prescott CA, Neale MC (2001) The genetic epidemiology of irrational fears and phobias in men. Archives of General Psychiatry 58:257-265
18. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ (1993) Major depression and phobias: the genetic and environmental sources of comorbidity. Psychological Medicine 23:361-371
19. Kendler KS, Prescott CA, Myers J, Neale MC (2003) The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry 60:929-937
20. Kendler KS, Walters EE, Truett KR, Heath AC, Neale MC, Martin NG, Eaves LJ (1995) A twin-family study of self-report symptoms of panic-phobia and Somatization. Behavior Genetics 25:499-515
21. Kessler RC, Berglund P, Demler O, Jin R, Walters EE (2005) Lifetime prevalence and age-of-onset distributions' of DSM-IV disorders in the national comorbidity survey replication. Archives of General Psychiatry 62:593-602
22. Kessler RC, Chiu WT, Demler O, Walters EE (2005) Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62:617-627
23. Krueger RF (1999) The structure of common mental disorders. Archives of General Psychiatry 56:921-926
24. Lichtenstein P and Annas P (2000) Heritability and prevalence of specific fears and phobia in childhood. Journal of Child Psychology & Psychiatry 41:927-937
25. McGrath M, Kawachi I, Ascherio A, Colditz GA, Hunter DJ, De Vivo I (2004) Association between catechol-O-methyltransferase and phobic anxiety. American Journal of Psychiatry 161:1703-1705
26. Nelson EC, Grant JD, Bucholz KK, Glowinski A, Madden PAF, Reich W, Heath AC (2000) Social phobia in population-based female adolescent twin sample: co-morbidity and associated suicide-related symptoms. Psychological Medicine 30:797-804
27. Philibert R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK, Cadoret RJ (2002) The association of a HOPA polymorphism with major depression and phobia. Comprehensive Psychiatry 43:404-410
28. Pine DS, Cohen P, Gurley D, Brook J, Ma YJ (1998) The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Archives of General Psychiatry 55:56-64
29. Plomin R, DeFries JC, McClearn GE, McGuffin P (2001) Behavioral Genetics 4th Edition, Worth Publishers, New York
30. Poulton R, Menzies RG (2002) Non-associative fear acquisition: a review of the evidence from retrospective and longitudinal research. Behaviour Research and Therapy 40:127-149
31. Rachman SJ (1978) Fear and Courage, WH Freeman & Co, San Francisco
32. Rijsdijk FV and Sham PC (2002) Analytic approaches to twin data using structural equation models. Briefings in bioinformatics 3:119-133
33. Rutter M (2006) Gene-environment interplay in Genes and Behaviour, Blackwell, Oxford: 178-210
34. Safren SA, Gershuny BS, Marzol P, Otto MW, Pollack MH (2002) History of childhood abuse in panic disorder, social phobia, and generalized anxiety disorder. Journal of Nervous and Mental Disease 190:453-456
35. Seligman ME (1971) Phobias and preparedness. Behavior Therapy 2:307-320
36. Silberg JL, Rutter M, Eaves L (2001) Genetic and environmental influences on the temporal association between earlier anxiety and later depression in girls. Biological Psychiatry 49:1040-1049
37. Simonoff E, Pickles A, Meyer J, Silberg JL, Maes H, Loeber R, Rutter M, Hewitt JK, Eaves LJ (1997) The Virginia twin study of adolescent behavioral development. Influences of age, sex, and impairment on rates of disorder. Archives of General Psychiatry 54:801-808
38. Skre I, Onstad S, Torgersen S, Lygren S, Kringlen E (2000) The heritability of common phobic fear: a twin study of a clinical sample. Journal of Anxiety Disorders 14:549-562
39. Smoller JW, Tsuang MT (1998) Panic and phobic anxiety: defining phenotypes for genetic studies. American Journal of Psychiatry 155:1152-1162
40. Stein MB, Jang KL, Livesley WJ (2002) Heritability of social anxiety-related concerns and personality characteristics: a twin study. Journal of Nervous and Mental Disease 190:219-224
41. Stein MB, Walker JR, Anderson G, Hazen AL, Ross CA, Eldridge G, Forde DR (1996) Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample. American Journal of Psychiatry 153:275-277
42. Stevenson J, Batten N, Cherner M (1992) Fears and fearfulness in children and adolescents: a genetic analysis of twin data. Journal of Child Psychology and Psychiatry 33:977-985
43. Vollebergh WAM, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J (2001) The structure and stability of common mental disorders - The NEMESIS study. Archives of General Psychiatry 58:597-603
44. Watson D (2005) Rethinking the mood and anxiety disorders: a quantitative hierarchical model for DSM-V. Journal of Abnormal Psychology 114:522-536
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