Variation in the CD38 gene, which regulates secretion of the neuropeptide oxytocin, has been associated with several social phenotypes. Specifically, rs3796863 A allele carriers have demonstrated increased social sensitivity. In 400 older adolescents, we used trait-state-occasion modeling to investigate how rs3796863 genotype, baseline ratings of chronic interpersonal stress, and their gene–environment (G×E) interaction predicted trait social anxiety and depression symptoms over 6 years. We found significant G×E effects for CD38 A-carrier genotypes and chronic interpersonal stress at baseline predicting greater social anxiety and depression symptoms. A significant G×E effect of smaller magnitude was also found for C/C genotype and chronic interpersonal stress predicting greater depression; however, this effect was small compared with the main effect of chronic interpersonal stress. Thus, in the context of chronic interpersonal stress, heightened social sensitivity associated with the rs3796863 A allele may prospectively predict risk for social anxiety and (to a lesser extent) depression.
BartzJ. A.McInnesL. A. (2007). CD38 regulates oxytocin secretion and complex social behavior. Bioessays, 29, 837–841.
2.
BartzJ. A.ZakiJ.BolgerN.OchsnerK. N. (2011). Social effects of oxytocin in humans: Context and person matter. Trends in Cognitive Sciences, 15, 301–309.
3.
BenjaminiY.HochbergY. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological), 57, 289–300.
4.
BoyceP.ParkerG.BarnettB.CooneyM.SmithF. (1991). Personality as a vulnerability factor to depression. British Journal of Psychiatry, 159, 106–114.
5.
BruzzoneS.BodratoN.UsaiC.GuidaL.MoreschiI.NanoR.. . . ZocchiE. (2008). Abscisic acid is an endogenous stimulator of insulin release from human pancreatic islets with cyclic ADP ribose as second messenger. Journal of Biological Chemistry, 283, 32188–32197.
6.
CardosoC.LinnenA. M.JooberR.EllenbogenM. A. (2012). Coping style moderates the effect of intranasal oxytocin on the mood response to interpersonal stress. Experimental and Clinical Psychopharmacology, 20, 84–91.
7.
CaspiA.HaririA. R.HolmesA.UherR.MoffittT. E. (2010). Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167, 509–527.
8.
ChevallierC.KohlsG.TroianiV.BrodkinE. S.SchultzR. T. (2012). The social motivation theory of autism. Trends in Cognitive Science, 16, 231–239.
9.
ClarkD. M.McManusF. (2002). Information processing in social phobia. Biological Psychiatry, 51, 92–100.
10.
ColeD. A.MartinN. C.SteigerJ. H. (2005). Empirical and conceptual problems with longitudinal trait-state models: Introducing a trait-state-occasion model. Psychological Methods, 10, 3–20.
11.
CuthbertB. N.KozakM. J. (2013). Constructing constructs for psychopathology: The NIMH research domain criteria. Journal of Abnormal Psychology, 122, 928–937.
12.
CyranowskiJ. M.HofkensB. A.FrankE.SeltmanH.CaiH.AmicoJ. (2008). Evidence of dysregulated peripheral oxytocin release among depressed women. Psychosomatic Medicine, 70, 967–975.
13.
DemirkanA.PenninxB. W. J. H.HekK.WrayN. R.AminN.AulchenkoY. S.. . . MiddeldorpC. M. (2011). Genetic risk profiles for depression and anxiety in adult and elderly cohorts. Molecular Psychiatry, 16, 773–783.
14.
Di NardoP. A.BarlowD. H. (1988). Anxiety Disorders Interview Schedule–Revised (ADIS-R). Albany, NY: Phobia and Anxiety Disorders Clinic.
15.
DomschkeK.DannlowskiU. (2010). Imaging genetics of anxiety disorders. NeuroImage, 53, 822–831.
16.
DuncanL. E.KellerM. C. (2011). A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. American Journal of Psychiatry, 168, 1041–1049.
17.
EysenckS. B. G.EysenckH. J.BarrettP. (1985). A revised version of the psychoticism scale. Personality and Individual Differences, 6, 21–29.
18.
FeldmanR.GordonI.InflusM.GutbirT.EbsteinR. P. (2013). Parental oxytocin and early caregiving jointly shape children’s oxytocin response and social reciprocity. Neuropsychopharmacology, 38, 1154–1162.
19.
FeldmanR.Zagoory-SharonO.WeismanO.SchneidermanI.GordonI.MaozR.. . . EbsteinR. P. (2012). Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biological Psychiatry, 72, 175–181.
20.
FirstM.SpitzerR.GibbonM.WilliamsJ. (2001). Structured Clinical Interview for DSM-IV-TR Axis I disorders–Non-Patient Edition. New York, NY: New York State Psychiatric Institute.
21.
GuastellaA. J.HowardA. L.DaddsM. R.MitchellP.CarsonD. S. (2009). A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology, 34, 917–923.
22.
HammenC. (1991). Generation of stress in the course of unipolar depression. Journal of Abnormal Psychology, 100, 555–561.
23.
HammenC. (2005). Stress and depression. Annual Review of Clinical Psychology, 1, 293–319.
24.
HammenC.HazelN. A.BrennanP. A.NajmanJ. (2012). Intergenerational transmission and continuity of stress and depression: Depressed women and their offspring in 20 years of follow-up. Psychological Medicine, 42, 931–942.
25.
HaunerK. K.RevelleW.ZinbargR. E. (2013). A latent variable model approach to estimating systematic bias in the oversampling method. Behavioral Research Methods, 46, 786–797.
26.
HeinrichsM.GaabJ. (2007). Neuroendocrine mechanisms of stress and social interaction: Implications for mental disorders. Current Opinion in Psychiatry, 20, 158–162.
27.
HigashidaH.YokoyamaS.KikuchiM.MunesueT. (2012). CD38 and its role in oxytocin secretion and social behavior. Hormones and Behavior, 61, 351–358.
28.
HogeE. A.PollackM. H.KaufmanR. E.ZakP. J.SimonN. M. (2008). Oxytocin levels in social anxiety disorder. CNS Neuroscience and Therapeutics, 14, 165–170.
29.
HollingsheadA. B. (1975). A four factor index of social status. Unpublished manuscript. Yale University, New Haven, CT.
30.
HuL.BentlerP. M. (1999). Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives. Structural Equation Modeling, 6, 1–55.
31.
JinD.LiuH. X.HiraiH.TorashimaT.NagaiT.LopatinaO.. . . HigashidaH. (2007). CD38 is critical for social behaviour by regulating oxytocin secretion. Nature, 446, 41–45.
32.
KellerM. C. (2014). Gene × environment interaction studies have not properly controlled for potential confounders: The problem and the (simple) solution. Biological Psychiatry, 75, 18–24.
33.
KendlerK. S.PrescottC. A.MyersJ.NealeM. C. (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.
34.
KesslerR. C.BerglundP.DemlerO.JinR.MerikangasK. R.WaltersE. E. (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.
35.
KissI.Levy-GigiE.KeriS. (2011). CD 38 expression, attachment style and habituation of arousal in relation to trust-related oxytocin release. Biological Psychology, 88, 223–226.
36.
KruegerR. F. (1999). Personality traits in late adolescence predict mental disorders in early adulthood: A prospective-epidemiological study. Journal of Personality, 67, 39–65.
37.
LabuschagneI.PhanK. L.WoodA.AngstadtM.ChuaP.HeinrichsM.. . . NathanP. J. (2010). Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology, 35, 2403–2413.
38.
LererE.LeviS.IsraelS.YaariM.NemanovL.MankutaD.. . . EpsteinR. P. (2010). Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study. Autism Research, 3, 293–302.
39.
LinP. I.VanceJ. M.Pericak-VanceM. A.MartinE. R. (2007). No gene is an island: The flip-flop phenomenon. American Journal of Human Genetics, 80, 531–538.
40.
LiuR. T.AlloyL. B. (2010). Stress generation in depression: A systematic review of the empirical literature and recommendations for future study. Clinical Psychology Review, 30, 582–593.
41.
MalavasiF.DeaglioS.FunaroA.FerreroE.HorensteinA. L.OrtolanE.. . . AydinS. (2008). Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiological Reviews, 88, 841–886.
42.
MattickR. P.ClarkJ. C. (1998). Development and validation of measures of social phobia scrutiny fear and social interaction anxiety. Behaviour Research and Therapy, 36, 455–470.
43.
McGrathL. M.WeillS.RobinsonE. B.MacraeR.SmollerJ. W. (2012). Bringing a developmental perspective to anxiety genetics. Development and Psychopathology, 24, 1179–1193.
44.
McLaughlinK. A.BreslauJ.GreenJ. G.LakomaM. D.SampsonN. A.ZaslavskyA. M.KesslerR. C. (2011). Childhood socio-economic status and the onset, persistence, and severity of DSM-IV mental disorders in a US national sample. Social Science and Medicine, 73, 1088–1096.
45.
McQuaidR. J.McInnisO. A.SteadJ. D.MathesonK.AnismanH. (2013). A paradoxical association of an oxytocin receptor gene polymorphism: Early-life adversity and vulnerability to depression. Frontiers in Neuroscience, 7, 128.
46.
MiddeldorpC. M.CathD. C.Van DyckR.BoomsmaD. I. (2005). The co-morbidity of anxiety and depression in the perspective of genetic epidemiology. A review of twin and family studies. Psychological Medicine, 35, 611–624.
47.
MunesueT.YokoyamaS.NakamuraK.AnithaA.YamadaK.HayashiK.. . . HigashidaH. (2010). Two genetic variants of CD38 in subjects with autism spectrum disorder and controls. Neuroscience Research, 67, 181–191.
48.
MuthénL. K.MuthénB. O. (1998–2012). Mplus User’s Guide (7th ed.). Los Angeles, CA: Muthén & Muthén.
49.
Naragon-GaineyK.GallagherM. W.BrownT. A. (2013). Stable “trait” variance of temperament as a predictor of the temporal course of depression and social phobia. Journal of Abnormal Psychology, 122, 611–623.
50.
NeumannI. D.LandgrafR. (2012). Balance of brain oxytocin and vasopressin: Implications for anxiety, depression, and social behaviors. Trends in Neuroscience, 35, 649–659.
51.
PrenoveauJ. M.CraskeM. G.ZinbargR. E.MinekaS.RoseR. D.GriffithJ. W. (2011). Are anxiety and depression just as stable as personality during late adolescence? Results from a three-year longitudinal latent variable study. Journal of Abnormal Psychology, 120, 832–843.
52.
PrenoveauJ. M.ZinbargR. E.CraskeM. G.MinekaS.GriffithJ. W.EpsteinA. M. (2010). Testing a hierarchical model of anxiety and depression in adolescents: A tri-level model. Journal of Anxiety Disorders, 24, 334–344.
53.
SauerC.MontagC.WornerC.KirschP.ReuterM. (2012). Effects of a common variant in the CD38 gene on social processing in an oxytocin challenge study: Possible links to autism. Neuropsychopharmacology, 37, 1474–1482.
54.
Shamay-TsooryS. G.FischerM.DvashJ.HaririA. R.Perach-BloomN.LevkovitzY. (2009). Intranasal administration of oxytocin increases envy and schadenfreude (gloating). Biological Psychiatry, 66, 864–870.
55.
SimonG.OrmelJ.VonKorffM.BarlowW. (1995). Health care costs associated with depressive and anxiety disorders in primary care. American Journal of Psychiatry, 152, 352–357.
56.
SlavichG. M.O’DonovanA.EpelE. S.KemenyM. E. (2010). Black sheep get the blues: A psychobiological model of social rejection and depression. Neuroscience and Biobehavioral Reviews, 35, 39–45.
57.
SmollerJ. W.Gardner-SchusterE.MisiaszekM. (2008). Genetics of anxiety: Would the genome recognize the DSM?Depression and Anxiety, 25, 368–377.
58.
StarrL. R.DavilaJ. (2008). Differentiating interpersonal correlates of depressive symptoms and social anxiety in adolescence: Implications for models of comorbidity. Journal of Clinical Child and Adolescent Psychology, 37, 337–349.
59.
SullivanP. F.NealeM. C.KendlerK. S. (2000). Genetic epidemiology of major depression: Review and meta-analysis. American Journal of Psychiatry, 157, 1552–1562.
60.
SuttonJ. M.MinekaS.ZinbargR. E.CraskeM. G.GriffithJ. W.RoseR. D.. . . MorN. (2011). The relationships of personality and cognitive styles with self-reported symptoms of depression and anxiety. Cognitive Therapy and Research, 35, 381–393.
61.
SzetoA.McCabeP. M.NationD. A.TabakB. A.RossettiM. A.McCulloughM. E.. . . MendezA. J. (2011). Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin. Psychosomatic Medicine, 73, 393–400.
62.
TabakB. A. (2013). Oxytocin and social salience: A call for gene–environment interaction research. Frontiers in Neuroscience, 7, 199.
63.
TabakB. A.McCulloughM. E.SzetoA.MendezA. J.McCabeP. M. (2011). Oxytocin indexes relational distress following interpersonal harms in women. Psychoneuroendocrinology, 36, 115–122.
64.
TangH.QuertermousT.RodriguezB.KardiaS. L.ZhuX.BrownA.. . . RischN. J. (2005). Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. American Journal of Human Genetics, 76, 268–275.
65.
Vrshek-SchallhornS.MinekaS.ZinbargR. E.CraskeM. G.GriffithJ. W.SuttonJ.. . . AdamE. K. (2014). Refining the candidate environment: Interpersonal stress, the serotonin transporter polymorphism, and gene–environment interactions in major depression. Clinical Psychological Science, 2, 235–248.
66.
WatsonD.WeberK.AssenheimerJ. S.ClarkL. A.StraussM. E.McCormickR. A. (1995). Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. Journal of Abnormal Psychology, 104, 3–14.
67.
WongM. Y.DayN. E.LuanJ. A.ChanK. P.WarehamN. J. (2003). The detection of gene–environment interaction for continuous traits: Should we deal with measurement error by bigger studies or better measurement?International Journal of Epidemiology, 32, 51–57.
68.
ZimmermanM.CoryellW.CorenthalC.WilsonS. (1986). A self-report scale to diagnose major depressive disorder. Archives of General Psychiatry, 43, 1076–1081.
69.
ZinbargR. E.MinekaS.CraskeM. G.GriffithJ. W.SuttonJ.RoseR. D.. (2010). The Northwestern-UCLA Youth Emotion Project: Associations of cognitive vulnerabilities, neuroticism and gender with past diagnoses of emotional disorders in adolescents. Behaviour Research and Therapy, 48, 347–358.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
