Stress sensitization to depression following childhood adversity: Moderation by HPA axis and serotonergic multilocus profile scores

Abstract Childhood adversity appears to sensitize youth to stress, increasing depression risk following stressful life events occurring throughout the lifespan. Some evidence suggests hypothalamic–pituitary–adrenal (HPA) axis-related and serotonergic genetic variation moderates this effect, in a “gene-by-environment-by-environment” interaction (G × E × E). However, prior research has tested single genetic variants, limiting power. The current study uses a multilocus genetic profile score (MGPS) approach to capture polygenic risk relevant to HPA axis and serotonergic functioning. Adolescents (N = 241, Mage = 15.90) completed contextual-threat-based interviews assessing childhood adversity and acute life events, and diagnostic interviews assessing depression. Established MGPSs indexed genetic variation linked to HPA axis (10 single nucleotide polymorphisms [SNPs]) and serotonergic (five SNPs) functioning. Results showed significant MGPS × Childhood Adversity × Recent Life Stress interactions predicting depression for both HPA axis and serotonergic MGPSs, with both risk scores predicting stronger Childhood Adversity × Recent Stress interactions. Serotonergic genetic risk specifically predicted sensitization to major interpersonal stressors. The serotonergic MGPS G × E × E was re-tested in an independent replication sample of early adolescent girls, with comparable results. Findings support the notion that genetic variation linked to these two neurobiological symptoms alters stress sensitization, and that gene-by-environment (G × E) interactions may be qualified by environmental exposures occurring at different points in development.

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Interpersonal childhood adversity and stress generation in adolescence: Moderation by HPA axis multilocus genetic variation

Development and Psychopathology ◽

10.1017/s0954579419001123 ◽

2019 ◽

Vol 32 (3) ◽

pp. 865-878 ◽

Cited By ~ 1

Author(s):

Meghan Huang ◽

Lisa R. Starr

Keyword(s):

Genetic Variation ◽

Hpa Axis ◽

Childhood Adversity ◽

Stress Generation ◽

Genetic Profile ◽

Environment Interaction ◽

Interpersonal Stress ◽

Nucleotide Polymorphisms ◽

Wide Range ◽

Profile Score

AbstractResearch suggests that childhood adversity (CA) is associated with a wide range of repercussions, including an increased likelihood of interpersonal stress generation. This may be particularly true following interpersonal childhood adversity (ICA) and for youth with high hypothalamic-pituitary-adrenal (HPA) axis-related genetic risk. In the current study, we applied a multilocus genetic profile score (MGPS) approach to measuring HPA axis-related genetic variation and examined its interaction with ICA to predict interpersonal stress generation in a sample of adolescents aged 14–17 (N = 241, Caucasian subsample n = 192). MGPSs were computed using 10 single nucleotide polymorphisms from HPA axis-related genes (CRHR1, NRC31, NRC32, and FKBP5). ICA significantly predicted greater adolescent interpersonal dependent stress. Additionally, MGPS predicted a stronger association between ICA and interpersonal dependent (but not independent or noninterpersonal dependent) stress. No gene–environment interaction (G×E) effects were found for noninterpersonal CA and MGPS in predicting adolescent interpersonal dependent stress. Effects remained after controlling for current depressive symptoms and following stratification by race. Findings extend existing G×E research on stress generation to HPA axis-related genetic variation and demonstrate effects specific to the interpersonal domain.

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HPA-axis multilocus genetic variation moderates associations between environmental stress and depressive symptoms among adolescents

Development and Psychopathology ◽

10.1017/s0954579418000779 ◽

2018 ◽

Vol 31 (04) ◽

pp. 1339-1352 ◽

Cited By ~ 6

Author(s):

Lisa R. Starr ◽

Meghan Huang

Keyword(s):

Genetic Variation ◽

Depressive Symptoms ◽

Chronic Stress ◽

Hpa Axis ◽

Acute Stress ◽

Childhood Adversity ◽

Genetic Profile ◽

Acute And Chronic Stress ◽

Adolescent Depressive Symptoms ◽

Gene Environment

AbstractResearch suggests that genetic variants linked to hypothalamic-pituitary-adrenal (HPA)-axis functioning moderate the association between environmental stressors and depression, but examining gene–environment interactions with single polymorphisms limits power. The current study used a multilocus genetic profile score (MGPS) approach to measuring HPA-axis–related genetic variation and examined interactions with acute stress, chronic stress, and childhood adversity (assessed using contextual threat interview methods) with depressive symptoms as outcomes in an adolescent sample (ages 14–17, N = 241; White subsample n = 192). Additive MGPSs were calculated using 10 single nucleotide polymorphisms within HPA-axis genes (CRHR1, NR3C2, NR3C1, FKBP5). Higher MGPS directly correlated with adolescent depressive symptoms. Moreover, MGPS predicted stronger associations between acute and chronic stress and adolescent depressive symptoms and also moderated the effect of interpersonal, but not noninterpersonal, childhood adversity. Gene–environment interactions individually accounted for 5%–8% of depressive symptom variation. All results were retained following multiple test correction and stratification by race. Results suggest that using MGPSs provides substantial power to examine gene–environmental interactions linked to affective outcomes among adolescents.

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Life stress, 5-HTTLPR and mental disorder: findings from a 30-year longitudinal study

The British Journal of Psychiatry ◽

10.1192/bjp.bp.110.085993 ◽

2011 ◽

Vol 198 (2) ◽

pp. 129-135 ◽

Cited By ~ 70

Author(s):

David M. Fergusson ◽

L. John Horwood ◽

Allison L. Miller ◽

Martin A. Kennedy

Keyword(s):

Longitudinal Study ◽

Mental Disorders ◽

Life Events ◽

Life Stress ◽

Additive Models ◽

Stable Gene ◽

Environment Interaction ◽

Adverse Life Events ◽

Gene Environment ◽

S Alleles

BackgroundRecent meta-analyses have raised concerns about the replicability of gene × environment interactions involving the serotonin transporter gene (5-HTTLPR) in moderating the associations between adverse life events and mental disorders.AimsTo use data gathered over the course of a 30-year longitudinal study of a New Zealand birth cohort to test the hypothesis that the presence of short (‘s’) alleles of 5-HTTLPR are associated with an increased response to life stress.MethodParticipants were 893 individuals from the Christchurch Health and Development Study who had complete data on: the 5-HTTLPR genotype; psychiatric disorders up to the age of 30; and exposure to childhood and adult adverse life events.ResultsA series of 104 regression models were fitted to four mental health outcomes (depressive symptoms, major depression, anxiety disorder and suicidal ideation) observed at ages 18, 21, 25 and 30 using 13 measures of life-course stress that spanned childhood and adult stressors. Both multiplicative and additive models were fitted to the data. No evidence was found that would support the hypothesis that ‘s' alleles of 5-HTTLPR are associated with increased responsivity to life stressors.ConclusionsThe present findings add to the evidence suggesting that it is unlikely that there is a stable gene × environment interaction involving 5-HTTLPR, life stress and mental disorders.

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Genetic risk for neuroticism predicts emotional health depending on childhood adversity

Psychological Medicine ◽

10.1017/s0033291718000715 ◽

2018 ◽

Vol 49 (2) ◽

pp. 260-267 ◽

Cited By ~ 1

Author(s):

Kelli Lehto ◽

Ida Karlsson ◽

Cecilia Lundholm ◽

Nancy L. Pedersen

Keyword(s):

Depressive Symptoms ◽

Emotional Health ◽

Association Studies ◽

Childhood Adversity ◽

Total Sample ◽

Risk Scores ◽

Environment Interaction ◽

Genome Wide Association Studies ◽

Twin Design ◽

Variance Explained

AbstractBackgroundExisting evidence for gene × environment interaction (G × E) in neuroticism largely relies on candidate gene studies, although neuroticism is highly polygenic. This study aimed to investigate the long-term associations between polygenic risk scores for neuroticism (PRSN), objective childhood adversity and their interplay on emotional health aspects such as neuroticism itself, depressive symptoms, anxiety symptoms, loneliness and life satisfaction.MethodsThe sample consisted of reared-apart (TRA) and reared-together (TRT) middle- and old age twins (N= 699; median age at separation = 2). PRSNwere created under ninepvalue cut-off thresholds (pT-s) and thepTwith the highest degree of neuroticism variance explained was chosen for subsequent analyses. Linear regressions were used to assess the associations between PRSN, childhood adversity (being reared apart) and emotional health. G × E was further investigated using a discordant twin design.ResultsPRSNexplained up to 1.7% (pT< 0.01) of phenotypic neuroticism in the total sample. Analyses across two separation groups revealed substantial heterogeneity in the variance explained by PRSN; 4.3% was explained in TRT, but almost no effect was observed in TRA. Similarly, PRSNexplained 4% and 1.7% of the variance in depressive symptoms and loneliness, respectively, only in TRT. A significant G × E interaction was identified for depressive symptoms.ConclusionsBy taking advantage of a unique sample of adopted twins, we demonstrated the presence of G × E in neuroticism and emotional health using PRSNand childhood adversity. Our results may indicate that genome-wide association studies are detecting genetic main effects associated with neuroticism, but not those susceptible to early environmental influences.

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Stressful life events in early life and suicidal behaviour

European Psychiatry ◽

10.1016/s0924-9338(11)73865-2 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 2162-2162

Author(s):

P.A. Saiz

Keyword(s):

Life Events ◽

Suicidal Behaviour ◽

Life Stress ◽

Stressful Life Events ◽

Negative Emotion ◽

Association Studies ◽

Stressful Life ◽

Environment Interaction ◽

Biological Stress ◽

S Allele

There is robust evidence that stressful life events (SLE) are associated with an increase in risk of developing depression. However, humans display wide variation in response to adversity. Caspi et al (2003) reported that a functional length polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene moderated the influence of SLE on depressive symptoms, major depression, and suicidality, suggesting evidences of a gene-by-environment interaction.Neuroimage data from healthy, non-depressed, s allele carriers of the 5-HTTLPR show an exaggerated amygdale response to threatening visual stimuli as well as reduced gray matter volume in limbic regions critical for processing of negative emotion compared with individuals with the LL genotype. These data suggest a potent modulatory effect of the 5-HTTLPR on amygdala reactivity to environmental threat.In recent years, a growing number of molecular genetic studies have focused on the serotonin system, suggesting that this system may be involved in the pathogenesis of suicidal behaviour. Meta-analytic evidences support a link between the s allele of the 5-HTTLPR and the risk of suicidal behaviour. However, several case-control association studies show an association between the short allele and the violence, the number, and the medical lethality of the attempts.On the other hand, recent data suggest that biological stress reactivity, mediated by the hypothalamic-pituitary-adrenocortical axis, might be a plausible mechanism underlying the association between the 5-HTTLPR genotype and exposure to life stress in predicting psychopathology.In this presentation we discuss data regarding the complex relationship between the above mentioned systems, stress, and suicidal behaviour.

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Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland

Translational Psychiatry ◽

10.1038/s41398-021-01644-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Claire Green ◽

Aleks Stolicyn ◽

Mathew A. Harris ◽

Xueyi Shen ◽

Liana Romaniuk ◽

...

Keyword(s):

Hpa Axis ◽

Life Stress ◽

Early Life ◽

Childhood Adversity ◽

Later Life ◽

Early Life Adversity ◽

Brain Volumes ◽

Stable Measure ◽

Regional Brain ◽

Generation Scotland

AbstractHypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = −0.057 to −0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = −0.059, P = 0.043; nucleus accumbens: β = −0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

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Abstract 500: Assessing the Impact of Cardiovascular Disease-Related Genetic Variation on Clinical Cognitive Impairment

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a500 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Joseph B Dube ◽

Christopher T Johansen ◽

John Robinson ◽

Joan Lindsay ◽

Vladimir Hachinski ◽

...

Keyword(s):

Cardiovascular Disease ◽

Genetic Variation ◽

Cognitive Impairment ◽

Genetic Markers ◽

Vascular Dysfunction ◽

Risk Scores ◽

Study Cohort ◽

Nucleotide Polymorphisms ◽

Apoe Ε4 ◽

The Impact

Introduction: “Cognitive impairment, no dementia” (CIND) is a prodromal stage of cognitive decline which marks the onset of dementia and is due most commonly to 1) Alzheimer disease (AD) or 2) vascular dysfunction. In order to assess the genetic component of CIND susceptibility, we investigated cardiovascular disease (CVD) and AD-associated genetic variation in CIND patients, hypothesizing that the genetic variation affecting CVD and AD susceptibility is also associated with CIND susceptibility. Methods: Our study cohort was taken from the Canadian Study of Health and Aging (CSHA) and was comprised of patients >65 years old with CIND (n=274) and matched normal controls (n=301). We genotyped ∼200,000 CVD-related SNPs using the Cardio-Metabochip genotyping array (Illumina). We also genotyped a panel of the top 11 AD-associated single nucleotide polymorphisms (SNPs) and APOE isotype. We tested for association between CIND status and genotypes using a logistic regression model adjusted for appropriate covariates. Genetic risk scores (GRSs) evaluated associations between CIND status and the accumulation of multiple genetic markers. Results: From our Cardio-Metabochip analysis, we identified 5 novel CIND susceptibility loci, with rs16901621 in FLJ22536 as our most significantly associated SNP (P=1.05E-06, OR=2.51, 95%CI=1.73-3.63). APOE ε4 isotype was modestly associated with CIND status (P<0.05), while AD SNP risk alleles were not associated (P>0.1). Conclusion: Using a high-throughput CVD microarray, we found novel genetic markers for CIND approaching genome-wide levels of significance. In contrast, known genetic markers for AD, such as APOE ε4 showed only modest associations in this cohort. Follow-up of variants in a CSHA replication cohort (n=370) is currently underway.

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Supplemental Material for Amygdala Functional Connectivity, HPA Axis Genetic Variation, and Life Stress in Children and Relations to Anxiety and Emotion Regulation

Journal of Abnormal Psychology ◽

10.1037/abn0000094.supp ◽

2015 ◽

Keyword(s):

Emotion Regulation ◽

Genetic Variation ◽

Functional Connectivity ◽

Hpa Axis ◽

Life Stress

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Cumulative risk and protection effect of serotonergic genes on male antisocial behaviour: results from a prospective cohort assessed in adolescence and early adulthood

The British Journal of Psychiatry ◽

10.1192/bjp.2018.251 ◽

2018 ◽

Vol 214 (3) ◽

pp. 137-145

Author(s):

Stephanie Langevin ◽

Sara Mascheretti ◽

Sylvana M. Côté ◽

Frank Vitaro ◽

Michel Boivin ◽

...

Keyword(s):

Partner Violence ◽

Early Adulthood ◽

Cumulative Risk ◽

Cumulative Effect ◽

Antisocial Behaviour ◽

Kindergarten Children ◽

Risk Scores ◽

Genetic Profile ◽

Nucleotide Polymorphisms ◽

Structured Interviews

BackgroundHeritability of antisocial behaviour is estimated at approximately 50% and involves multiple genes.AimsTo investigate the cumulative genetic effects of 116 single nucleotide polymorphisms mapping to 11 candidate serotonergic genes and antisocial behaviours, in adolescence and in early adulthood.MethodParticipants were 410 male members of the Quebec Longitudinal Study of Kindergarten Children, a population-based cohort followed up prospectively from age 6 to age 23. The serotonergic genes were selected based on known physiological processes and prior associations with antisocial behaviours. Antisocial behaviours were self-reported and assessed by using semi-structured interviews in adolescence and in adulthood.ResultsCumulative, haplotype-based contributions of serotonergic genes conferring risk and protection for antisocial behaviours were detected by using multilocus genetic profile risk scores (MGPRSs) and multilocus genetic profile protection scores (MGPPSs). Cumulatively, haplotype-based MGPRSs and MGPPSs contributed to 9.6, 8.5 and 15.2% of the variance in general delinquency in adolescence, property/violent crimes in early adulthood and physical partner violence in early adulthood, respectively.ConclusionsThis study extends previous research by showing a cumulative effect of multiple haplotypes conferring risk and protection to antisocial behaviours in adolescence and early adulthood. The findings further support the relevance of concomitantly considering multiple serotonergic polymorphisms to better understand the genetic aetiology of antisocial behaviours. Future studies should investigate the interplay between risk and protective haplotype-based multilocus genetic profile scores with the environment.Declaration of interest:I.O.-M. holds a Canada Research Chair in the developmental origins of vulnerability and resilience.

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