Gene–environment interactions: early life stress and risk for depressive and anxiety disorders

“Of the 13 studies including physical abuse as an ELS, ten found support for GxE with risk associated with the s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008; Xie et al.…”

“The short (s) allele of this polymorphism confers lower transcriptional efficiency than the long (l) allele, and is associated with decreased transporter expression and serotonin reuptake (Lesch et al. 1996).”

“Converging findings from preclinical and clinical studies indicate that exposure to excessive glucocorticoid concentrations impedes neuroprotection and neurogenesis in the hippocampus, effects linked to the pathogenesis of depression and anxiety disorders (De Kloet et al. 2005).”

“The Met allele of the functional BDNF Val66Met polymorphism confers abnormal intracellular packaging and secretion of BDNF (Egan et al. 2003), and has been implicated in impaired extinction of conditioned fear response and atypical frontoamygdala activity in humans (Soliman et al. 2010), as well as…”

“A study of depressed inpatients found that those with two copies of the Met allele of BDNF Val66Met had elevated adrenocorticotropic hormone and cortisol responses to the Dex/CRH text (Schule et al. 2006).”

“It is also possible for certain genes to confer environmentally sensitive “plasticity” such that the same genetic variant may confer risk under harmful environmental circumstances but provide benefit under auspicious conditions (Belsky et al. 2009; Belsky and Pluess 2009; Fox et al. 2007).”

“Consistent with early theory (Bronfenbrenner and Ceci 1994), twin models of both internalizing and externalizing have suggested that socioeconomically disadvantaged environments may obscure genetic effects (Raine 2002; South and Krueger 2010; Tuvblad et al.”

“…may be a critical determinant of the sequelae, while the method of assessment (i.e., prospective, retrospective; interview, records, questionnaire) may be similarly critical in permitting detection of any moderation by candidate risk genes (Hardt and Rutter 2004; Moffitt et al. 2005; Paivio 2001).”

“…disorders Early life stress (ELS) is an established predictor of adverse outcomes across the lifespan encompassing neurocognitive, behavioral, health, and psychiatric domains (Danese et al. 2009; Gunnar and Quevedo 2007; Heim and Nemeroff 2002; Irish et al. 2009; Roth and Friedman 1993; Terr 1991).”

“Anxiety Early life stress and risk for depressive and anxiety disorders Early life stress (ELS) is an established predictor of adverse outcomes across the lifespan encompassing neurocognitive, behavioral, health, and psychiatric domains (Danese et al. 2009; Gunnar and Quevedo 2007; Heim and Nemeroff 2002; Irish et al.…”

“Since altered sensitivity of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“Candidate gene research is predicated on the assumption that common diseases are influenced by common genetic variants (Lohmueller et al. 2003).”

“Another important consideration is that individuals may shape their environments or elicit certain types of responses or stimuli in their environment, resulting in gene–environment correlation (rGE) (Plomin et al. 1977; Rutter 2009).”

“Although no published meta-analyses have focused on gene by ELS interactions, a recent meta-analysis by Risch et al. (2009) examined GxE between stressful life events and 5-HTTLPR on depression using 14 studies (N=14,250).”

“(Binder et al. 2008) examined four SNPs of the FKBP5 gene in a sample of predominantly low-income, urban, African American adult patients seeking medical care.”

“The use of logistic regression techniques to identify interactions in GxE studies is widespread, but it is important to note that this technique can lead to both false-positive and false-negative findings (Eaves 2006; Moffit et al. 2006; Kraft et al. 2007; Munafo et al. 2009; Caspi et al. 2010).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“However, the influence of poverty or socioeconomic status may differ across psychiatric outcomes (Dohrenwend et al. 1992; Johnson et al. 1999).”

“Other candidate genes Dopaminergic genes Dopamine, which plays a central role in motivation and pleasure, has also been implicated in the pathophysiology of depression (Dunlop and Nemeroff 2007).”

“…disorders Early life stress (ELS) is an established predictor of adverse outcomes across the lifespan encompassing neurocognitive, behavioral, health, and psychiatric domains (Danese et al. 2009; Gunnar and Quevedo 2007; Heim and Nemeroff 2002; Irish et al. 2009; Roth and Friedman 1993; Terr 1991).”

“It is also possible for certain genes to confer environmentally sensitive “plasticity” such that the same genetic variant may confer risk under harmful environmental circumstances but provide benefit under auspicious conditions (Belsky et al. 2009; Belsky and Pluess 2009; Fox et al. 2007).”

“A substantially elevated risk of internalizing (i.e., depressive and anxiety) disorders following ELS is particularly well documented (Harrington 2001; Hicks et al. 2009; Kendler et al. 1995, 2003; Kessing et al. 2003).”

“Animal models demonstrate increased serotonin neuronal activity, as indicated by increased gene expression and serotonin concentrations, in brain areas implicated in the stress response (e.g., Amat et al. 2005; Grahn et al. 1999; Takase et al. 2004).”

“Consistent with early theory (Bronfenbrenner and Ceci 1994), twin models of both internalizing and externalizing have suggested that socioeconomically disadvantaged environments may obscure genetic effects (Raine 2002; South and Krueger 2010; Tuvblad et al. 2006).”

“This may be particularly problematic in studies of later-life internalizing, as research supports a progression of externalizing concerns to internalizing concerns, whereas the opposite is rarely seen (Brook et al. 1998; Fergusson and Horwood 2002; Rao et al. 1999; Rutter et al. 2006).”

“Yet another concern when testing for interaction effects is the potential for artifactual interactions that can occur secondary to subtle changes in definition and scaling of the variables (Jinks and Fulker 1970; Kraft et al. 2007; Mather and Jinks 1982; Moffit et al. 2006; Neale and Cardon 1992).”

“…emotional abuse, nearly all (n=10) reported GxE with increased risk conferred by s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Gibb et al. 2009; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008).”

“…may be a critical determinant of the sequelae, while the method of assessment (i.e., prospective, retrospective; interview, records, questionnaire) may be similarly critical in permitting detection of any moderation by candidate risk genes (Hardt and Rutter 2004; Moffitt et al. 2005; Paivio 2001).”

“A recent systematic review of genetic influences on environmental measures found estimated heritabilities of 39% for negative life events, 36% for trauma, and 27% across environmental measures (Kendler and Baker 2007).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“Eley et al. (2004) examined TPH1, in addition to other genes in the serotonin pathway, including 5-HTTLPR, in their investigation of depressive symptoms in adolescents.”

“Ressler et al. (2010) extended their prior GxE analyses of a CRHR1 haplotype and childhood maltreatment (Bradley et al. 2008) by examining the triallelic 5-HTTLPR as a further moderator of these interactions.”

“A third functional allele has been identified for this gene, LG, (Nakamura et al. 2000); this allele results in transcriptional capacity comparable to the s allele.”

“2003), and has been implicated in impaired extinction of conditioned fear response and atypical frontoamygdala activity in humans (Soliman et al. 2010), as well as reduced amygdala and hippocampus volume (Montag et al.”

“Achieving sufficient statistical power presents a special challenge because interaction effects require larger numbers of subjects for adequate power (Brookes et al. 2001; Luan et al. 2001; Uher 2008), and power depends on allele frequencies in addition to exposure to ELS (Munafo et al.”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“Gatt et al. (2009) studied the relationship between ELS and BDNF in predicting depressive and anxiety symptoms, cognitive function, and heart rate in resting and arousal states in 374 healthy adults, with volumetric brain imaging in a subset of 89 participants.”

“Anxiety Early life stress and risk for depressive and anxiety disorders Early life stress (ELS) is an established predictor of adverse outcomes across the lifespan encompassing neurocognitive, behavioral, health, and psychiatric domains (Danese et al. 2009; Gunnar and Quevedo 2007; Heim and Nemeroff 2002; Irish et al.…”

“The effects of genetic and environmental factors on symptoms of depression and anxiety have also been shown to differ as a function of age (Tambs and Mourn 1993) and gender (Eaves et al. 1997), so these factors should be considered in GxE analyses.”

“…supports differences in neurobiological and treatment-response characteristics of depression with onset in childhood, adolescence, and adulthood (Rutter et al. 2006), and there is evidence that the ELS profiles of individuals with childhood- vs. adult-onset depression differ (Jaffee et al. 2002).”

“2009), decreased academic and occupational opportunities (Dubow and Ippolito 1994; Fiscella and Kitzman 2009), decreased resiliency (Campbell-Sills et al. 2009), decreased adult monitoring (Horowitz et al.”

“2004; McCormick and Mathews 2010), with further influences exerted by a host of moderating factors (Bagner et al. 2010; Brown and Harris 2008; Monk et al. 2003; Silberg et al. 1999).”

“Yet another concern when testing for interaction effects is the potential for artifactual interactions that can occur secondary to subtle changes in definition and scaling of the variables (Jinks and Fulker 1970; Kraft et al. 2007; Mather and Jinks 1982; Moffit et al. 2006; Neale and Cardon 1992).”

“…emotional abuse, nearly all (n=10) reported GxE with increased risk conferred by s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Gibb et al. 2009; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008).”

“…adequate numbers of subjects exposed and unexposed to the stressful environment to ensure adequate power, because only a main effect of genotype can be identified if nearly all participants have experienced high levels of the environmental factor (Munafo et al. 2009; Uher and McGuffin 2010).”

“2004; McCormick and Mathews 2010), with further influences exerted by a host of moderating factors (Bagner et al. 2010; Brown and Harris 2008; Monk et al. 2003; Silberg et al. 1999).”

“However, the influence of poverty or socioeconomic status may differ across psychiatric outcomes (Dohrenwend et al. 1992; Johnson et al. 1999).”

“Reciprocal interactions between BDNF and serotonin have also been well documented (Duman 2002; MacQueen et al. 2003), underscoring the viability of genes that regulate BDNF as candidates for study.”

“Since altered sensitivity of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“…of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“Of note in the present review, evidence suggests that variation in the serotonin system (especially in the serotonin transporter and 1A receptor) may be particularly important during early development (Holmes et al. 2003; Ansorge et al. 2007).”

“This may be particularly problematic in studies of later-life internalizing, as research supports a progression of externalizing concerns to internalizing concerns, whereas the opposite is rarely seen (Brook et al. 1998; Fergusson and Horwood 2002; Rao et al. 1999; Rutter et al. 2006).”

“This may be particularly problematic in studies of later-life internalizing, as research supports a progression of externalizing concerns to internalizing concerns, whereas the opposite is rarely seen (Brook et al. 1998; Fergusson and Horwood 2002; Rao et al. 1999; Rutter et al. 2006).”

“Anxiety Early life stress and risk for depressive and anxiety disorders Early life stress (ELS) is an established predictor of adverse outcomes across the lifespan encompassing neurocognitive, behavioral, health, and psychiatric domains (Danese et al. 2009; Gunnar and Quevedo 2007; Heim and Nemeroff 2002; Irish et al.…”

“Animal models demonstrate increased serotonin neuronal activity, as indicated by increased gene expression and serotonin concentrations, in brain areas implicated in the stress response (e.g., Amat et al. 2005; Grahn et al. 1999; Takase et al. 2004).”

“Polanczyk et al. (2009) examined this GxE interaction effect with the three most significant SNPs identified by Bradley et al. using data from two longitudinal cohort studies.”

“Similarly, Aguilera et al. (2009) showed a GxE effect of the 5-HTTLPR s allele and a history of childhood sexual abuse on depressive symptoms, but also observed rGE, in which the l/l genotype was more strongly associated with childhood sexual abuse than the l/s genotype.”

“…Cicchetti et al. 2007; Eley et al. 2004; Gibb et al. 2009; Hammen et al. 2010; Kaufman et al. 2004, 2006; Laucht et al. 2009; Nobile et al. 2009; Ritchie et al. 2009; Sjoberg et al. 2006; Stein et al. 2008; Surtees et al. 2006; Taylor et al. 2006; Wichers et al. 2008; Xie et al. 2009) (Table 1).”

“Of the 13 studies including physical abuse as an ELS, ten found support for GxE with risk associated with the s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008; Xie et al.…”

“Polanczyk et al. concluded that the GxE effect was supported, but with the effect specific to depression-relevant emotional memories assessed with the CTQ. Tyrka et al. (2009) examined the interactions of two of these three polymorphisms in the CRHR1 gene and childhood maltreatment, as measured by the CTQ, in predicti…”

“Moreover, there is strong evidence from human and animal studies that the stress response is modulated in part by serotonergic neurotransmission (for reviews, see El Hage et al. 2009; Holmes 2008).”

“All but one (Chorbov et al. 2007) of the studies reporting GxE effects with increased risk conferred by l/l′ included socioeconomic status in their definition of ELS (Chipman et al. 2007; Laucht et al. 2009; Ritchie et al. 2009; Sjoberg et al. 2006).”

“…emotional abuse, nearly all (n=10) reported GxE with increased risk conferred by s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Gibb et al. 2009; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008).”

“Moreover, research suggests that differences in the chronicity and developmental timing of ELS may influence the nature and timing of outcomes (Maercker et al. 2004; McCormick and Mathews 2010), with further influences exerted by a host of moderating factors (Bagner et al.”

“Moreover, research suggests that differences in the chronicity and developmental timing of ELS may influence the nature and timing of outcomes (Maercker et al. 2004; McCormick and Mathews 2010), with further influences exerted by a host of moderating factors (Bagner et al.”

“2009), decreased academic and occupational opportunities (Dubow and Ippolito 1994; Fiscella and Kitzman 2009), decreased resiliency (Campbell-Sills et al.”

“2004; McCormick and Mathews 2010), with further influences exerted by a host of moderating factors (Bagner et al. 2010; Brown and Harris 2008; Monk et al. 2003; Silberg et al. 1999).”

“This may be particularly problematic in studies of later-life internalizing, as research supports a progression of externalizing concerns to internalizing concerns, whereas the opposite is rarely seen (Brook et al. 1998; Fergusson and Horwood 2002; Rao et al. 1999; Rutter et al. 2006).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“Consistent with early theory (Bronfenbrenner and Ceci 1994), twin models of both internalizing and externalizing have suggested that socioeconomically disadvantaged environments may obscure genetic effects (Raine 2002; South and Krueger 2010; Tuvblad et al. 2006).”

“…22 samples to date (Aguilera et al. 2009; Araya et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Chipman et al. 2007; Chorbov et al. 2007; Cicchetti et al. 2007; Eley et al. 2004; Gibb et al. 2009; Hammen et al. 2010; Kaufman et al. 2004, 2006; Laucht et al. 2009; Nobile et al. 2009;…”

“Since altered sensitivity of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“…1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al. 2005; Laaris et al. 1995, 1997; Lanfumey et al. 1999; Li et al. 1999, 2004, 2006; Pehek et al. 2006; Pezawas et al. 2005; Preece et al. 2004; Tjurmina et al. 2004; Tyrka et al. 2004).”

“For example, Eaves’ (2006) simulation of GxE interactions in depression and antisocial behavior suggested that dichotomization (i.e., using a “clinical cutoff” to assign a yes/no diagnosis) and sampling from the extremes of a distribution can significantly inflate the likelihood of potential…”

“…influences that can increase long-term risk for depression, such as exposure to neighborhood violence (Freisthler et al. 2008) and deviant peers (McCart et al. 2007; Zinzow et al. 2009), decreased academic and occupational opportunities (Dubow and Ippolito 1994; Fiscella and Kitzman 2009),…”

“Consistent with this, the s′ allele of 5-HTTLPR has been associated with an exaggerated cortisol response to a standardized psychosocial stressor in children and adults (Alexander et al. 2009; Gotlib et al. 2008).”

“2010), as well as reduced amygdala and hippocampus volume (Montag et al. 2009).”

“Since altered sensitivity of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“2009), decreased academic and occupational opportunities (Dubow and Ippolito 1994; Fiscella and Kitzman 2009), decreased resiliency (Campbell-Sills et al.”

“Many of the polymorphisms with replicated effects are thought to be functional variants that influence relevant neurobiological systems (Fu et al. 2007; Koenen et al. 2008; Rutter 2008; Rutter 2010).”

“2009), decreased adult monitoring (Horowitz et al. 2005), increased caregiver depression and aggression (Mitchell et al.”

“Even emotional abuse is endorsed by only 12% of nonclinical populations (Cohen et al. 2006).”

“…by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al.…”

“Ressler et al. (2010) extended their prior GxE analyses of a CRHR1 haplotype and childhood maltreatment (Bradley et al. 2008) by examining the triallelic 5-HTTLPR as a further moderator of these interactions.”

“Bet et al. (2009) examined polymorphisms of the GR gene NR3C1 in 906 older adults who retrospectively reported on stressful life events in childhood.”

“2005), increased caregiver depression and aggression (Mitchell et al. 2009; Scaramella et al. 2008), and increased difficulty coping with trauma (Kawachi and Subramanian 2006).”

“…emotional abuse, nearly all (n=10) reported GxE with increased risk conferred by s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Gibb et al. 2009; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008).”

“…(Gibb et al. 2009; Hammen et al. 2010; Nobile et al. 2009; Stein et al. 2008; Xie et al. 2009), 3 studies found full or partial support for risk effects of the l′ allele (Chorbov et al. 2007; Laucht et al. 2009; Ritchie et al. 2009), and 1 found no evidence for GxE effects (Araya et al. 2009).”

“…et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al. 2005; Laaris et al. 1995, 1997; Lanfumey et al. 1999; Li et al. 1999, 2004, 2006; Pehek et al. 2006; Pezawas et al. 2005; Preece et al. 2004; Tjurmina et…”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“Achieving sufficient statistical power presents a special challenge because interaction effects require larger numbers of subjects for adequate power (Brookes et al. 2001; Luan et al. 2001; Uher 2008), and power depends on allele frequencies in addition to exposure to ELS (Munafo et al.”

“Since altered sensitivity of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“All but one (Chorbov et al. 2007) of the studies reporting GxE effects with increased risk conferred by l/l′ included socioeconomic status in their definition of ELS (Chipman et al. 2007; Laucht et al. 2009; Ritchie et al. 2009; Sjoberg et al. 2006).”

“…may be a critical determinant of the sequelae, while the method of assessment (i.e., prospective, retrospective; interview, records, questionnaire) may be similarly critical in permitting detection of any moderation by candidate risk genes (Hardt and Rutter 2004; Moffitt et al. 2005; Paivio 2001).”

“…(e.g., transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004;…”

“A substantially elevated risk of internalizing (i.e., depressive and anxiety) disorders following ELS is particularly well documented (Harrington 2001; Hicks et al. 2009; Kendler et al. 1995, 2003; Kessing et al. 2003).”

“Another important consideration is that individuals may shape their environments or elicit certain types of responses or stimuli in their environment, resulting in gene–environment correlation (rGE) (Plomin et al. 1977; Rutter 2009).”

“Although a survey of epigenetic methods and findings is outside the scope of this review, emerging epigenetic research suggests that timing of stress may be linked to functional alterations of genes implicated in depression (Murgatroyd et al. 2010).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“The MAOA gene is located on the short arm of the X chromosome, and this is consistent with other evidence of gender-related effects of the MAOA polymorphism (Biederman et al. 2008).”

“…Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Gibb et al. 2009; Kaufman et al. 2004, 2006; Nobile et al. 2009; Stein et al. 2008; Taylor et al. 2006; Xie et al. 2009) or in a subset of participants (Eley et al. 2004; Hammen et al. 2010, Sjoberg et al. 2006; Wichers et al. 2008).”

“Reciprocal interactions between BDNF and serotonin have also been well documented (Duman 2002; MacQueen et al. 2003), underscoring the viability of genes that regulate BDNF as candidates for study.”

“…increase long-term risk for depression, such as exposure to neighborhood violence (Freisthler et al. 2008) and deviant peers (McCart et al. 2007; Zinzow et al. 2009), decreased academic and occupational opportunities (Dubow and Ippolito 1994; Fiscella and Kitzman 2009), decreased resiliency…”

“A study of depressed inpatients found that those with two copies of the Met allele of BDNF Val66Met had elevated adrenocorticotropic hormone and cortisol responses to the Dex/CRH text (Schule et al. 2006).”

“…Fiscella and Kitzman 2009), decreased resiliency (Campbell-Sills et al. 2009), decreased adult monitoring (Horowitz et al. 2005), increased caregiver depression and aggression (Mitchell et al. 2009; Scaramella et al. 2008), and increased difficulty coping with trauma (Kawachi and Subramanian 2006).”

“Preclinical models of ELS in laboratory animals have become increasingly popular in studies on the pathogenesis of mood and anxiety disorders and the development of novel pharmacological approaches to these conditions (Alleva and Francia 2009; Coplan et al. 2010; Gardner et al. 2009; Kolber et al. 2010; Musazzi et al.…”

“Many of the polymorphisms with replicated effects are thought to be functional variants that influence relevant neurobiological systems (Fu et al. 2007; Koenen et al. 2008; Rutter 2008; Rutter 2010).”

“Preclinical models of ELS in laboratory animals have become increasingly popular in studies on the pathogenesis of mood and anxiety disorders and the development of novel pharmacological approaches to these conditions (Alleva and Francia 2009; Coplan et al. 2010; Gardner et al. 2009; Kolber et al. 2010; Musazzi et al.…”

“…of GRs is thought to mediate HPA axis dysregulation in depression and PTSD (Raison and Miller 2003), genes regulating components of this system are likely candidates for GxE investigations of the etiopathology of depression and anxiety (Charney 2004; Wust et al. 2004a; Wust et al. 2004b).”

“…increase long-term risk for depression, such as exposure to neighborhood violence (Freisthler et al. 2008) and deviant peers (McCart et al. 2007; Zinzow et al. 2009), decreased academic and occupational opportunities (Dubow and Ippolito 1994; Fiscella and Kitzman 2009), decreased resiliency…”

“(Nelson et al. 2009) examined 4 SNPs encoding GABAA receptors (GABRA2) in a subset of 259 participants in a family study of adult twins.”

“Preclinical models of ELS in laboratory animals have become increasingly popular in studies on the pathogenesis of mood and anxiety disorders and the development of novel pharmacological approaches to these conditions (Alleva and Francia 2009; Coplan et al. 2010; Gardner et al. 2009; Kolber et al. 2010; Musazzi et al.…”

“All but one (Chorbov et al. 2007) of the studies reporting GxE effects with increased risk conferred by l/l′ included socioeconomic status in their definition of ELS (Chipman et al. 2007; Laucht et al. 2009; Ritchie et al. 2009; Sjoberg et al. 2006).”

“A substantially elevated risk of internalizing (i.e., depressive and anxiety) disorders following ELS is particularly well documented (Harrington 2001; Hicks et al. 2009; Kendler et al. 1995, 2003; Kessing et al. 2003).”

“…1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al. 2005; Laaris et al. 1995, 1997; Lanfumey et al. 1999; Li et al. 1999, 2004, 2006; Pehek et al. 2006; Pezawas et al. 2005; Preece et al. 2004; Tjurmina et al. 2004; Tyrka et al. 2004).”

“Animal models demonstrate increased serotonin neuronal activity, as indicated by increased gene expression and serotonin concentrations, in brain areas implicated in the stress response (e.g., Amat et al. 2005; Grahn et al. 1999; Takase et al. 2004).”

“Of the 13 studies including physical abuse as an ELS, ten found support for GxE with risk associated with the s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008; Xie et al.…”

“…(Gibb et al. 2009; Hammen et al. 2010; Nobile et al. 2009; Stein et al. 2008; Xie et al. 2009), 3 studies found full or partial support for risk effects of the l′ allele (Chorbov et al. 2007; Laucht et al. 2009; Ritchie et al. 2009), and 1 found no evidence for GxE effects (Araya et al. 2009).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“…emotional abuse, nearly all (n=10) reported GxE with increased risk conferred by s/s′ allele (Aguilera et al. 2009; Åslund et al. 2009; Caspi et al. 2003; Cicchetti et al. 2007; Gibb et al. 2009; Kaufman et al. 2006; Kaufman et al. 2004; Stein et al. 2008; Taylor et al. 2006; Wichers et al. 2008).”

“Preclinical models of ELS in laboratory animals have become increasingly popular in studies on the pathogenesis of mood and anxiety disorders and the development of novel pharmacological approaches to these conditions (Alleva and Francia 2009; Coplan et al. 2010; Gardner et al. 2009; Kolber et al. 2010; Musazzi et al.…”

“Poverty provides a context for numerous influences that can increase long-term risk for depression, such as exposure to neighborhood violence (Freisthler et al. 2008) and deviant peers (McCart et al.”

“Against this backdrop, there has been a surge of interest in using genetic differences to inform understanding of how ELS exerts its pathogenic effects (Koenen and Galea 2009; Moffitt et al. 2005; Munafo and Flint 2009; Risch et al. 2009; Rutter 2009).”

“…1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al. 2005; Laaris et al. 1995, 1997; Lanfumey et al. 1999; Li et al. 1999, 2004, 2006; Pehek et al. 2006; Pezawas et al. 2005; Preece et al. 2004; Tjurmina et al. 2004; Tyrka et al. 2004).”

“…(Gibb et al. 2009; Hammen et al. 2010; Nobile et al. 2009; Stein et al. 2008; Xie et al. 2009), 3 studies found full or partial support for risk effects of the l′ allele (Chorbov et al. 2007; Laucht et al. 2009; Ritchie et al. 2009), and 1 found no evidence for GxE effects (Araya et al. 2009).”

“…et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al. 2005; Laaris et al. 1995, 1997; Lanfumey et al. 1999; Li et al. 1999, 2004, 2006; Pehek et al. 2006; Pezawas et al. 2005; Preece et al. 2004; Tjurmina et…”

“Research with children of alcoholics has reported increased levels of child aggressive behavior and increased anxious/depressed symptoms in children with the l/l genotype relative to other genotypes (Twitchell et al. 2001).”

“Preclinical models of ELS in laboratory animals have become increasingly popular in studies on the pathogenesis of mood and anxiety disorders and the development of novel pharmacological approaches to these conditions (Alleva and Francia 2009; Coplan et al. 2010; Gardner et al. 2009; Kolber et al. 2010; Musazzi et al.…”

“Examination of continuous measures affords greater statistical power and may decrease statistical error due to miscategorization of “subthreshold” individuals (Caspi et al. 2010; Plomin and Davis 2009).”

“Many of the polymorphisms with replicated effects are thought to be functional variants that influence relevant neurobiological systems (Fu et al. 2007; Koenen et al. 2008; Rutter 2008; Rutter 2010).”

“Moreover, there is strong evidence from human and animal studies that the stress response is modulated in part by serotonergic neurotransmission (for reviews, see El Hage et al. 2009; Holmes 2008).”

“The effects of genetic and environmental factors on symptoms of depression and anxiety have also been shown to differ as a function of age (Tambs and Mourn 1993) and gender (Eaves et al.”

“Consistent with early theory (Bronfenbrenner and Ceci 1994), twin models of both internalizing and externalizing have suggested that socioeconomically disadvantaged environments may obscure genetic effects (Raine 2002; South and Krueger 2010; Tuvblad et al. 2006).”

“…have become increasingly popular in studies on the pathogenesis of mood and anxiety disorders and the development of novel pharmacological approaches to these conditions (Alleva and Francia 2009; Coplan et al. 2010; Gardner et al. 2009; Kolber et al. 2010; Musazzi et al. 2010; Vinkers et al. 2010).”

“2005), increased caregiver depression and aggression (Mitchell et al. 2009; Scaramella et al. 2008), and increased difficulty coping with trauma (Kawachi and Subramanian 2006).”

“…Chorbov et al. 2007; Cicchetti et al. 2007; Eley et al. 2004; Gibb et al. 2009; Hammen et al. 2010; Kaufman et al. 2004, 2006; Laucht et al. 2009; Nobile et al. 2009; Ritchie et al. 2009; Sjoberg et al. 2006; Stein et al. 2008; Surtees et al. 2006; Taylor et al. 2006; Wichers et al. 2008; Xie et…”

“Many of the polymorphisms with replicated effects are thought to be functional variants that influence relevant neurobiological systems (Fu et al. 2007; Koenen et al. 2008; Rutter 2008; Rutter 2010).”

“A substantially elevated risk of internalizing (i.e., depressive and anxiety) disorders following ELS is particularly well documented (Harrington 2001; Hicks et al. 2009; Kendler et al. 1995, 2003; Kessing et al. 2003).”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“, transporters and receptors) both influence and are influenced by the functioning of other stress systems in the brain and periphery (e.g., Adamec et al. 2006; Ansorge et al. 2007; Bhatnagar et al. 2004; Carola et al. 2007; Crayton et al. 1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-L…”

“5-HT1A, 5-HT2A, 5-HT2C receptors Chipman et al. (2010) examined the potential interactive effects of the gene coding for the serotonin 1A receptor (HTR1A) and childhood adversity on symptoms of anxiety and depression in a large sample of adults.”

“Achieving sufficient statistical power presents a special challenge because interaction effects require larger numbers of subjects for adequate power (Brookes et al. 2001; Luan et al. 2001; Uher 2008), and power depends on allele frequencies in addition to exposure to ELS (Munafo et al.”

“…1996; Froger et al. 2004; Gross and Hen 2004; Hariri and Holmes 2006; Hemrick-Luecke and Evans 2002; Herman et al. 2005; Laaris et al. 1995, 1997; Lanfumey et al. 1999; Li et al. 1999, 2004, 2006; Pehek et al. 2006; Pezawas et al. 2005; Preece et al. 2004; Tjurmina et al. 2004; Tyrka et al. 2004).”

“Extensive research supports a role for the serotonin system in the development of both mood and anxiety disorders (for review, see Ressler and Nemeroff 2000).”

“…in stress response, also have been implicated as potential moderators of trauma response in geneby-environment (G x E) studies, including research on the corticotropin-releasing hormone type 1 receptor and glucocorticoid receptor genes (Cicchetti 2010, Nugent et al. 2011, Pratchett & Yehuda 2011).”

“particular relevance because acute, repeated, or chronic stress exposures are common triggers for these psychiatric disorders [273, 286], because women may have an inherently increased stress vulnerability, and because key symptoms of these disorders have been successfully modeled in animals.”

“There are excellent examples of the moderate impact of specific genes, particularly from the monoaminergic system and the HPA axis, in defining subsequent behavioral adaptations (Nugent et al., 2011; Scheuer et al., 2016; Zannas and Binder, 2014).”

“Recently, genome-wide association studies have implicated several SNPs associated with major depression (Hek et al., 2013; Lewis et al., 2010; Nugent et al., 2011; Sullivan et al., 2009).”

“Stressful life events can facilitate and exacerbate anxiety disorders (ADs), substance use disorder (SUD), and major depressive disorder (MDD; Hammen, 2005; Andersen and Teicher, 2009; Nugent et al., 2011).”

“This literature has been thoroughly and carefully reviewed and goes beyond the scope of this review (See for example Nugent et al., 2011; Tyrka et al., 2013).”

“Stress in a child’s early caregiving environment has been linked to lasting adverse effects on both physiological and psychological domains of development (National Scientific Council on the Developing Child, 2005; Gunnar and Quevedo, 2007; Nugent et al., 2011).”

“Investigations of gene–gene and gene– environment interactions (Nugent et al., 2011), copy number variations (Bersani et al., 2016; Fung et al., 2010; Kawamura et al., 2011), and epigenetic factors (Cappi et al., 2016; Kim et al., 2017) have yielded some additional insights into the molecular…”

“…from mothers with depression or neglected/abused infants, is associated with increased susceptibility to the effects of stress later in life and vulnerability to develop stress-related psychiatric disorders (Graham et al., 1999; Nugent et al., 2011) and cardiovascular diseases (Loria et al., 2014).”

“GxEIs are core elements within current theories of schizophrenia (van Os and Kapur, 2009; van Os et al., 2008, 2010), depression (Keers and Uher, 2012), anxiety disorders (Gregory et al., 2008; Nugent et al., 2011) and OCD (Nicolini et al., 2009; Pauls, 2010).”

“…in humans is associated with increased risk for developing severe psychological disorders including schizophrenia, depression, and anxiety disorders, as well as risk for abusing and becoming addicted to drugs such as psychostimulants (Scheller-Gilkey et al., 2004; Nugent et al., 2011; Enoch, 2012).”

“…susceptibility to depression has lead to recent theories proposing a role of gene-by-environment interactions in the etiology of depression, in which genetic predisposition modulates vulnerability in the depressogenic response to environmental stressors (Kas et al., in press; Nugent et al., 2011).”

“Second, the mouse models described so far mostly reflect either genetic or environmental manipulations rather than mimicking the interaction of these two risk factors, though such interaction seems to be critical in the clinical manifestation of anxiety disorders [7,159].”

“Anxiety and depression are stress-related common mental disorders and are caused by a combination of multiple genetic and environmental factors affecting certain brain circuits [3].”

“In humans, however, so far only very few studies have been dedicated to G E in anxiety (see Nugent et al. 2011), mostly focussing on variation in the serotonin transporter gene (Stein et al. 2008; Laucht et al. 2009; e.g., Grabe et al. 2009; Klauke et al., 2011).”

“This vulnerability becomes exposed when triggered by enhanced environmental stress such as childhood trauma.(37) This could be the result of long-lasting trauma-”

“For G × E interaction studies focused on adverse early life events, more precise measures of childhood trauma should be investigated to better understand the type, timing, perpe‐ trator, and amount of trauma that increases impulsivity later in life (Nugent et al., 2011).”

“GeneeEnvironment interactions Gene and environment (G E) interactions are another set of variables that need to be taken into consideration when discussing resilience and vulnerability to stressors (Nugent et al., 2011; Caspi and Moffitt, 2006).”

“In humans, ELS has long been linked to anxiety disorders and depression in adulthood (Nugent et al. 2011, Shapero et al. 2013).”

“Although, threatening experiences and life stress have been reported to increase the risk for anxiety disorders (Watanabe et al., 2005; Melchior et al., 2007), the effect of environmental stress is also moderated by a genetic diathesis (Nugent et al., 2011).”

“Such behavioral traits are the product of interactions between genes and early life experiences (Nugent et al., 2011).”

“ISSN:2157-7412 JGSGT, an open access journal traumatic stress [130,135,136], and frequently are accompanied by relative elevations of glucocorticoid stress hormones.”

“Depression and anxiety are stress-related common mental disorders and are caused by a combination of multiple environmental and genetic factors affecting certain brain circuits [3].”

“Although there have been some mixed findings, there is growing evidence that genes influencing serotonergic and hypothalamic–pituitary–adrenal (HPA) axis functioning moderate the impact of environmental stress on depression risk (see Karg, Burmeister, Shedden, & Sen, 2011; Nugent, Tyrka, Carpenter, & Price, 2011 , for…”

“…field, where greater traumatic life events, including childhood abuse, have been found to interact with 5-HTTLPR to predict depression (Karg et al., 2011; Nugent et al., 2011), although the interaction between life events and 5-HTTLPR is not undisputed (Munaf o et al., 2009; Risch et al., 2009).”

“Previous studies suggest that stress is strongly linked to smoking, (Kassel et al., 2003; Tsourtos et al., 2008) as well as to depressive and anxiety symptoms (Hicks et al., 2009; Kessing et al., 2003; Nugent et al., 2011).”

“Gene–environment interaction (GxE) research provides a potential pathway of understanding how genetic differences influence the likelihood that exposure to environmental stress will result in psychopathology (Nugent et al., 2011).”

“‘Anxious temperament’ is considered to be a stable trait across time, and those with extreme levels of such traits are at a higher risk for developing clinical or pathological anxiety (Arnaudova et al., 2013; Jones, 2013; Nugent et al., 2011).”

“Depression is a heterogeneous disorder with multiple complex etiologies originating from interactions between environmental and genetic factors [1].”

“Recent studies suggest a substantially increased risk of internalizing depressive and anxiety disorders into adulthood following early life stress in childhood (Kendler et al., 2003; Nugent et al., 2011).”

“This was demonstrated for psychiatric conditions such as depression and anxiety disorders (Heim & Nemeroff 2001; Tennant, 2002; Nemeroff, 2004; Hulbert-Williams & Hastings, 2008; Nugent et al., 2011), but also cardiovascular disease, asthma, and exacerbations of multiple sclerosis have been shown to be more common in…”

“In most research to date, early life stress has been defi ned as exposure to objective stressors such as childhood maltreatment ( Goldney, 1981 ; Green, et al ., 2010 ; Pechtel & Pizzagalli, 2011 ).”

“Notably, several methodological considerations about GxE analyses have been raised in recent literature (Koenen et al. 2008; Dick 2011; Duncan and Keller 2011; Nugent et al. 2011).”

“Anxiety and depression are stress-related common mental disorders and are caused by a combination of multiple genetic and environmental factors affecting certain brain circuits (Nugent et al., 2011).”

“Some of these comorbid psychiatric problems may actually be related to early stressful life experiences.(22,23)”