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    RORA Polymorphism Interacts with Childhood Maltreatment in Determining Anxiety Sensitivity by Sex: A Preliminary Study in Healthy Young Adults

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    https://www.riss.kr/link?id=A104303529

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    Objective: Recent studies have reported associations of retinoid-related orphan receptor alpha (RORA) gene single nucleotide polymorphisms (SNPs) with depression and anxiety disorders. Based on these, we attempt to test whether RORA polymorphism is associated with anxiety sensitivity (AS), the intermediate phenotype of depression and anxiety disorders. Considering gene-environment interactions and sex differences in AS, childhood maltreatment (CM) and sex were considered as confounders. Methods: Two-hundred and five healthy young Korean adults (female: 98, male: 107; age, 23.0±3.2 years) completed genotyping for the RORA SNP rs11071547, as well as measures for AS and CM. Generalized linear models were used to examine the main and interaction effects of RORA genotype, CM, and sex in determining AS. Results: The main effect of RORA polymorphisms was not found ( p =0.760) whereas the main effect of CM and interaction effects among sex, genotype, and maltreatment were significant on AS. In separate analyses by sex, the interaction effect between RORA genotype and maltreatment was significant only in males ( p <0.001). In females, the main effects of genotype and CM were significant (both were p <0.001), in which both a history of CM and C genotype tended to be associated with higher AS. Conclusion: The association between RORA polymorphism and AS might differ by sex. The interaction between RORA polymorphism and CM was significant only in males whereas RORA genotype and CM independently associated with AS in females. Further studies are encouraged to confirm the relationship between RORA polymorphism and AS.
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    Objective: Recent studies have reported associations of retinoid-related orphan receptor alpha (RORA) gene single nucleotide polymorphisms (SNPs) with depression and anxiety disorders. Based on these, we attempt to test whether RORA polymorphism is as...

    Objective: Recent studies have reported associations of retinoid-related orphan receptor alpha (RORA) gene single nucleotide polymorphisms (SNPs) with depression and anxiety disorders. Based on these, we attempt to test whether RORA polymorphism is associated with anxiety sensitivity (AS), the intermediate phenotype of depression and anxiety disorders. Considering gene-environment interactions and sex differences in AS, childhood maltreatment (CM) and sex were considered as confounders. Methods: Two-hundred and five healthy young Korean adults (female: 98, male: 107; age, 23.0±3.2 years) completed genotyping for the RORA SNP rs11071547, as well as measures for AS and CM. Generalized linear models were used to examine the main and interaction effects of RORA genotype, CM, and sex in determining AS. Results: The main effect of RORA polymorphisms was not found ( p =0.760) whereas the main effect of CM and interaction effects among sex, genotype, and maltreatment were significant on AS. In separate analyses by sex, the interaction effect between RORA genotype and maltreatment was significant only in males ( p <0.001). In females, the main effects of genotype and CM were significant (both were p <0.001), in which both a history of CM and C genotype tended to be associated with higher AS. Conclusion: The association between RORA polymorphism and AS might differ by sex. The interaction between RORA polymorphism and CM was significant only in males whereas RORA genotype and CM independently associated with AS in females. Further studies are encouraged to confirm the relationship between RORA polymorphism and AS.

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    참고문헌 (Reference)

    1 Hettema JM, "The structure of genetic and environmental risk factors for anxiety disorders in men and women" 62 : 182-189, 2005

    2 Carr CP, "The role of early life stress in adult psychiatric disorders : a systematic review according to childhood trauma subtypes" 201 : 1007-1020, 2013

    3 Miller MW, "The retinoidrelated orphan receptor alpha(RORA)gene and fearrelated psychopathology" 151 : 702-708, 2013

    4 Easton A, "The circadian Clock mutation increases exploratory activity and escape-seeking behavior" 2 : 11-19, 2003

    5 Amstadter AB, "Support for association of RORA variant and post traumatic stress symptoms in a population-based study of hurricane exposed adults" 18 : 1148-1149, 2013

    6 Fergusson DM, "Structural equation modeling of repeated retrospective reports of childhood maltreatment" 20 : 93-104, 2011

    7 Coles ME, "Sleep, circadian rhythms, and anxious traits" 17 : 73-, 2015

    8 Klauke B, "Serotonin transporter gene and childhood trauma--a G × E effect on anxiety sensitivity" 28 : 1048-1057, 2011

    9 김대호, "Reliability and Validity of the Korean Version of the Childhood Trauma Questionnaire-Short Form for Psychiatric Outpatients" 대한신경정신의학회 8 (8): 305-311, 2011

    10 Polanczyk G, "Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment : replication and extension" 66 : 978-985, 2009

    1 Hettema JM, "The structure of genetic and environmental risk factors for anxiety disorders in men and women" 62 : 182-189, 2005

    2 Carr CP, "The role of early life stress in adult psychiatric disorders : a systematic review according to childhood trauma subtypes" 201 : 1007-1020, 2013

    3 Miller MW, "The retinoidrelated orphan receptor alpha(RORA)gene and fearrelated psychopathology" 151 : 702-708, 2013

    4 Easton A, "The circadian Clock mutation increases exploratory activity and escape-seeking behavior" 2 : 11-19, 2003

    5 Amstadter AB, "Support for association of RORA variant and post traumatic stress symptoms in a population-based study of hurricane exposed adults" 18 : 1148-1149, 2013

    6 Fergusson DM, "Structural equation modeling of repeated retrospective reports of childhood maltreatment" 20 : 93-104, 2011

    7 Coles ME, "Sleep, circadian rhythms, and anxious traits" 17 : 73-, 2015

    8 Klauke B, "Serotonin transporter gene and childhood trauma--a G × E effect on anxiety sensitivity" 28 : 1048-1057, 2011

    9 김대호, "Reliability and Validity of the Korean Version of the Childhood Trauma Questionnaire-Short Form for Psychiatric Outpatients" 대한신경정신의학회 8 (8): 305-311, 2011

    10 Polanczyk G, "Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment : replication and extension" 66 : 978-985, 2009

    11 Lavebratt C, "PER2 variantion is associated with depression vulnerability" 153B : 570-581, 2010

    12 Bouayed J, "Oxidative stress and anxiety : relationship and cellular pathways" 2 : 63-67, 2009

    13 E Bouvier, "Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression" Springer Nature 22 (22): 1701-1713, 2016

    14 Klauke B, "Neuropeptide S receptor gene(NPSR)and life events : G × E effects on anxiety sensitivity and its subdimensions" 15 : 17-25, 2014

    15 Lim YJ, "Korean Anxiety Sensitivity Index-Revised: its factor structure, reliability, and validity in clinical and nonclinical samples." 24 : 331-341, 2007

    16 Ino H, "Immunohistochemical characterization of the orphan nuclear receptor ROR alpha in the mouse nervous system" 52 : 311-323, 2004

    17 Boukhtouche F, "Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis" 96 : 1778-1789, 2006

    18 Stein MB, "Heritability of anxiety sensitivity : a twin study" 156 : 246-251, 1999

    19 Nguyen A, "Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brai" 24 : 3036-3051, 2010

    20 Terracciano A, "Genome-wide association scan of trait depression" 68 : 811-817, 2010

    21 Kripke DF, "Genetic variants associated with sleep disorders" 16 : 217-224, 2015

    22 Grabe HJ, "Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse" 36 : 264-270, 2012

    23 Ratnu VS, "Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain" 95 : 301-310, 2017

    24 Stein MB, "Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders" 33 : 312-319, 2008

    25 Jang KL, "Gender differences in the etiology of anxiety sensitivity : a twin study" 2 : 39-44, 1999

    26 Stewart SH, "Gender differences in dimensions of anxiety sensitivity" 11 : 179-200, 1997

    27 Lake RI, "Further evidence against the environmental transmission of individual differences in neuroticism from a collaborative study of 45,850 twins and relatives on two continents" 30 : 223-233, 2000

    28 Bernstein DP, "Development and validation of a brief screening version of the Childhood Trauma Questionnaire" 27 : 169-190, 2003

    29 Partonen T, "Clock gene variants in mood and anxiety disorders" 119 : 1133-1145, 2012

    30 Bernstein DP, "Childhood trauma questionnaire: a restrospective self-report: manual"

    31 Heim C, "Childhood trauma and risk for chronic fatigue syndrome : association with neuroendocrine dysfunction" 66 : 72-80, 2009

    32 Maglione JE, "Associations of PER3 and RORA circadian gene polymorphisms and depressive symptoms in older adults" 23 : 1075-1087, 2015

    33 Schmidt NB, "Anxiety sensitivity : prospective prediction of panic attacks and Axis I pathology" 40 : 691-699, 2006

    34 Taylor S, "An expanded anxiety sensitivity index : evidence for a hierarchic structure in a clinical sample" 12 : 463-483, 1998

    35 Sipilä T, "An association analysis of circadian genes in anxiety disorders" 67 : 1163-1170, 2010

    36 Logue MW, "A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha(RORA)gene as a significant risk locus" 18 : 937-942, 2013

    37 Sato TK, "A functional genomics strategy reveals Rora as a component of the mammalian circadian clock" 43 : 527-537, 2004

    38 Duncan LE, "A critical review of the first 10years of candidate gene-by-environment interaction research in psychiatry" 168 : 1041-1049, 2011

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