Multilocus Genetic Profile Research Articles

Examining hypothalamic-pituitary-adrenal axis genetic variation on cortisol and alpha-amylase reactivity during an explicit negative-evaluative stress induction.

Prior work consistently links additive genetic variation in the hypothalamic-pituitary-adrenal (HPA) axis-a multilocus genetic profile score (MGPS)-to depression risk in the context of stress exposure. However, despite that HPA MGPS variants were selected based on evidence that they elevate cortisol reactivity, there are surprisingly few tests of whether an HPA MGPS elevates cortisol reactivity to lab-based stress. Similarly, despite neurobiological connections and coordination between the HPA axis and the sympathetic nervous system (e.g., in the paraventricular nucleus and locus coeruleus), no work has tested whether an HPA MGPS influences sympathetic nervous system reactivity to stress. We investigated whether an HPA MGPS moderates the relation between lab-based stress and: (1) HPA activity indexed by cortisol, and/or (2) sympathetic activity indexed by salivary alpha-amylase, sAA. Emerging adults (N=152; mean age=19.5, largest subsample 44.4% Black/African American) were randomly assigned to one of two Trier Social Stress Test variations, a non-evaluative control, or an explicitly negative-evaluative condition. Participants provided DNA and repeated saliva samples for sAA and cortisol. The HPA MGPS did not significantly moderate the relationship between stress condition and cortisol or sAA reactivity, respectively; moreover, post-hoc tests highlight that individual polymorphisms showed non-significant effects in opposite directions from each other, cancelling out in aggregate. Findings suggest that the HPA MGPS's associations with cortisol reactivity are not as straightforward as initially believed. We speculate that the relationships of some HPA variants to biomarker reactivity may vary between modest lab-based stressors and the explicit negative-evaluative induction used here.

The Effects of Variation in the GABAA Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus.

γ-aminobutyric acid (GABA) and its main receptor, the GABAA receptor, are implicated in major depressive disorder (MDD). Anxious depression (AD) is deemed to be a primary subtype of MDD. The amygdala and the dorsolateral prefrontal cortex (DLPFC) are key brain regions involved in emotional regulation. These regions contain the most GABAA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABAA receptor gene polymorphisms affect the functions of specific brain regions, in particular, the amygdala and the DLPFC. The sample comprised 83 patients with AD, 70 patients with non-anxious depression (NAD), and 62healthy controls (HC).All participants underwent genotyping for polymorphisms of GABAA receptor subunit genes, followed by a resting-state fMRI scan. The HAMD-17 was used to evaluate the severity of MDD. ANOVA was performed to obtain the difference in the imaging data, GABAA receptor multi-locus genetic profile scores (MGPS), and HAMD-17 scores among three groups, then the significant differences between AD and NAD groups were identified. Mediating effect analysis was used to explore the role of functional connectivity (FC) between the amygdala and DLPFC in the association between the GABAA receptor gene MGPS and AD clinical features. Compared with the NAD group, the AD group had a higher GABAA receptor MGPS. AD patients exhibited a negative correlation between the MGPS and FC of the right centromedial (CM) subregion, and the right middle frontal gyrus (MFG). A negative correlation was also observed between the MGPS and anxiety/somatic symptoms. More importantly, the right CM and right MFG connectivity mediated the association between the GABAA receptor MGPS and anxiety/somatic symptoms in patients with AD. The decreased FC between the right MFG and right CM subregion mediates the association between GABAA receptor MGPS and AD.

Polygene by environment interactions predicting depressive outcomes.

Depression is a major public health problem with a continued need to uncover its etiology. Current models of depression contend that gene-by-environment (G × E) interactions influence depression risk, and further, that depression is polygenic. Thus, recent models have emphasized two polygenic approaches: a hypothesis-driven multilocus genetic profile score (MGPS; "MGPS × E") and a polygenic risk score (PRS; "PRS × E") derived from genome-wide association studies (GWAS). This review for the first time synthesizes current knowledge on polygene by environment "P × E" interaction research predicting primarily depression-related outcomes, and in brief, neurobiological outcomes. The "environment" of focus in this project is stressful life events. It further discusses findings in the context of differential susceptibility and diathesis-stress theories-two major theories guiding G × E work. This synthesis indicates that, within the MGPS literature, polygenic scores based on the serotonin system, the HPA axis, or across multiple systems, interact with environmental stress exposure to predict outcomes at multiple levels of analyses and most consistently align with differential susceptibility theory. Depressive outcomes are the most studied, but neuroendocrine, and neuroimaging findings are observed as well. By contrast, vast methodological differences between GWAS-based PRS studies contribute to mixed findings that yield inconclusive results.

The effects of childhood maltreatment, recent interpersonal and noninterpersonal stress, and HPA-axis multilocus genetic variation on prospective changes in adolescent depressive symptoms: A multiwave longitudinal study.

Based on a multiwave, two-year prospective design, this study is the first to examine the extent to which multilocus hypothalamic-pituitary-adrenal axis (HPA axis)-related genetic variants, childhood maltreatment, and recent stress jointly predicted prospective changes in adolescent depressive symptoms. A theory-driven multilocus genetic profile score (MGPS) was calculated to combine the effects of six common polymorphisms within HPA-axis related genes (CRHR1, NR3C1, NR3C2, FKBP5, COMT, and HTR1A) in a sample of Chinese Han adolescents (N = 827; 50.2% boys; Mage = 16.45 ± 1.36 years). The results showed that the three-way interaction of HPA-axis related MGPS, childhood maltreatment and recent interpersonal, but not noninterpersonal, stress significantly predicted prospective changes in adolescent depressive symptoms. For adolescents with high but not low HPA-axis related MGPS, exposure to severe childhood maltreatment predisposed individuals more vulnerable to recent interpersonal stress, exhibiting greater prospective changes in adolescent depressive symptoms. The findings provide preliminary evidence for the cumulative risk mechanism regarding gene-by-environment-by-environment (G × E1 × E2) interactions that underlie the longitudinal development of adolescent depressive symptoms and show effects specific to interpersonal stress.

Dopamine multilocus genetic profile influence on reward network in chronic insomnia disorder with depression

BackgroundChronic insomnia disorder (CID) is frequently comorbid with depression, and both conditions are believed to involve disruptions in the reward network. However, the potential effects of genetic polymorphisms in modulating this network remain largely unexplored. MethodsIn this study, we recruited 50 CID patients with high (CID-HD) and low (CID-LD) depressive symptoms and assessed their reward networks using resting-state functional MRI. Additionally, we calculated the multilocus genetic profile score (MGPS) to examine the influence of depression and dopamine genetic variation on the nucleus accumbens functional connectivity (NAFC) network in CID patients. ResultsAlthough the MGPS did not show a significant difference between the two CID groups, its influence on the NAFC network was observed in the salience network (SN) and visual network (VN) in CID patients. When comparing CID-HD patients to CID-LD patients, we found that CID-HD patients exhibited decreased NAFC in the internal reward network, default mode network, SN, and sensorimotor network, while showing increased NAFC in the executive control network (ECN) and VN. Furthermore, the influence of MGPS on the reward network was only significant in CID-HD patients, specifically in the internal reward network and ECN. ConclusionThese findings suggest that genetic variations related to dopamine may modulate the reward network differently in CID patients with and without depressive symptoms. These results contribute to our understanding of the pathophysiology of polygenic effects underlying brain network abnormalities in CID patients with depression.

Serotonergic multilocus genetic variation moderates the association between interpersonal relationship and adolescent depressive symptoms

BackgroundResearch suggests that genetic variants linked to serotonin functioning moderate the association between environmental stressors and depressive symptoms, but examining gene–environment interactions with single polymorphisms limits power. MethodsA multilocus genetic profile score (MGPS) approach to measuring serotonergic multilocus genetic variation and examined interactions with interpersonal relationship, insomnia with depressive symptoms as outcomes in an adolescent sample (average age = 14.15 ± 0.63 years since first measurement; range: 13 to 15). Results(1) interpersonal relationship predicted adolescent depressive symptoms; (2) insomnia mediated the effect of interpersonal relationships on adolescent depressive symptoms; (3) the THP2 gene rs4570625 polymorphism G allele was a key risk factor for depressive symptom, and the MGPS moderated the effects of teacher-student relationship and insomnia on adolescent depressive symptom. Specifically, as the MGPS increased, the effects of insomnia on adolescent depressive symptom were enhanced; further, when the MGPS score increased, the effect of teacher-student relationship on depression showed a similar phenomenon with an increased slope and enhanced prediction; and (4) the results of sensitivity analysis showed that multilocus genetic interaction with the environment had a better explanatory power and stability for depression than single polymorphism studies. ConclusionMGPS provides substantial power to examine gene–environmental interactions linked to affective outcomes among adolescents.

Multilocus Genetic Profile Reflecting Low Dopaminergic Signaling Is Directly Associated with Obesity and Cardiometabolic Disorders Due to Antipsychotic Treatment.

Treatment with second-generation antipsychotics (SGAs) can cause obesity and other cardiometabolic disorders linked to D2 receptor (DRD2) and to genotypes affecting dopaminergic (DA) activity, within reward circuits. We explored the relationship of cardiometabolic alterations with single genetic polymorphisms DRD2 rs1799732 (NG_008841.1:g.4750dup -> C), DRD2 rs6277 (NG_008841.1:g.67543C>T), COMT rs4680 (NG_011526.1:g.27009G>A), and VNTR in both DRD4 NC_000011.10 (637269-640706) and DAT1 NC_000005.10 (1392794-1445440), as well as with a multilocus genetic profile score (MLGP). A total of 285 psychiatric patients treated with SGAs for at least three months were selected. Cardiometabolic parameters were classified according to ATP-III and WHO criteria. Blood samples were taken for routinely biochemical assays and PCR genotyping. Obesity (BMI, waist (W)), high diastolic blood pressure (DBP), and hypertriglyceridemia (HTG) were present in those genetic variants related to low dopaminergic activity: InsIns genotype in rs1799732 (BMI: OR: 2.91 [1.42-5.94]), DRD4-VNTR-L allele (W: OR: 1.73 [1.04-2.87]) and 9R9R variant in DAT1-VNTR (W: OR: 2.73 [1.16-6.40]; high DBP: OR: 3.33 [1.54-7.31]; HTG: OR: 4.38 [1.85-10.36]). A low MLGP score indicated a higher risk of suffering cardiometabolic disorders (BMI: OR: 1.23 [1.05-1.45]; W: OR: 1.18 [1.03-1.34]; high DBP: OR: 1.22 [1.06-1.41]; HTG: OR: 1.20 [1.04-1.39]). The MLGP score was more sensitive for detecting the risk of suffering these alterations. Low dopaminergic system function would contribute to increased obesity, BDP, and HTG following long-term SGA treatment.

Examining the influence of an additive genetic risk score of HPA axis polymorphisms with recent stress on depression onset in emerging adults

Prior research suggests that HPA-axis genetic variation moderates the association between stress and depression, but has historically focused on individual variants with small effects. Recent studies, however, have tested an additive genetic score of biologically-plausible variants (multilocus genetic profile score; MGPS) in the HPA-axis (e.g., Pagliaccio et al., 2014). Among adolescents, an HPA-MGPS moderated the effects of stress on depressive symptoms; higher HPA-MGPS predicted heightened depressive symptoms when stress was high, but reduced symptoms when stress was low (Starr & Huang, 2019), consistent with differential susceptibility theory (Belsky & Pluess, 2009). Whether this same effect extends to emerging adults, however, is untested. Thus, the current study will test whether an HPA-MGPS interacts with chronic and episodic stress to predict depression onset in emerging adults. We hypothesize that an HPA-MGPS will interact with episodic (total, interpersonal), and chronic (interpersonal, non-interpersonal) stress, to predict depression onset, such that a higher HPA-MGPS will predict depression when stress is high, but reduced risk when stress is low. Participants (n=387) from the Youth Emotion Project, a longitudinal study of risk for emotional disorders that oversampled high school juniors for high levels of neuroticism, gave DNA and completed annual diagnostic and life stress interviews. Five years of data will be used. DNA was genotyped for 14 HPA-axis variants for inclusion in an HPA-MGPS. Hypotheses will be tested using Cox regression; results will be available by the time of the conference. Results will be discussed considering implications for future MGPS research and differential susceptibility theory.

Linking individual variability in functional brain connectivity to polygenic risk in major depressive disorder

BackgroundMajor depressive disorder (MDD) is a highly heterogeneous disease, which brings great difficulties to clinical diagnosis and therapy. Its mechanism is still unknown. Prior neuroimaging studies mainly focused on mean differences between patients and healthy controls (HC), largely ignoring individual differences between patients. MethodsThis study included 112 MDD patients and 93 HC subjects. Resting-state functional MRI data were obtained to examine the patterns of individual variability of brain functional connectivity (IVFC). The genetic risk of pathways including dopamine, 5-hydroxytryptamine (5-HT), norepinephrine (NE), hypothalamic-pituitary-adrenal (HPA) axis, and synaptic plasticity was assessed by multilocus genetic profile scores (MGPS), respectively. ResultsThe IVFC pattern of the MDD group was similar but higher than that in HCs. The inter-network functional connectivity in the default mode network contributed to altered IVFC in MDD. 5-HT, NE, and HPA pathway genes affected IVFC in MDD patients. The age of onset, duration, severity, and treatment response, were correlated with IVFC. IVFC in the left ventromedial prefrontal cortex had a mediating effect between MGPS of the 5-HT pathway and baseline depression severity. LimitationsEnvironmental factors and differences in locations of functional areas across individuals were not taken into account. ConclusionsThis study found MDD patients had significantly different inter-individual functional connectivity variations than healthy people, and genetic risk might affect clinical manifestations through brain function heterogeneity.

Genetic variation in the dopamine system is associated with mixed-strategy decision-making in patients with Parkinson's disease.

Decision-making during mixed-strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed-strategy decision-making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty-six PD patients (ages 49-85, Hoehn and Yahr Stages 1-3) and 22 healthy controls (ages 54-75) competed in a mixed-strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed-strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within-subject, multi-centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val158 Met), rs6277 (C957T) and rs907094 (encoding DARPP-32). PD and control participants displayed comparable mixed-strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow-up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD.

Enhanced endogenous oxytocin signaling in the brain modulates neural responses to social misalignment and promotes conformity in humans: A multi-locus genetic profile approach

The neuropeptide oxytocin (OT) is known to promote social conformity. However, the specific neurocognitive mechanisms underlying OT-induced conformity remain unclear. We aimed to address this gap by examining how genetic variation in the oxytocin receptor gene (OXTR) is linked with behavioral conformity and its underlying neural systems. Specifically, we utilized the genotype-tissue expression database (GTEx) to create a novel multi-locus genetic profile score (MPS) that reflects the level of OXTR expression in the human brain. A total of 194 participants (Neuroimaging N = 50, Behavioral N = 144) performed a novel conformity task in which they viewed a series of word pairs depicting various moral values and virtues widely recognized in the United States. In each trial, participants indicated the relative importance of these words and subsequently learned about the majority opinion. Participants later rated the same word pairs a second time. Changes in participants’ ratings between the first and second sessions were measured and analyzed with respect to social feedback, blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals, and OXTR MPS. We found that participants adjusted their ratings in accordance with the majority opinions. Social misalignment between self and others activated brain areas such as the striatum and the posterior medial frontal cortex (pMFC). However, unlike most findings from previous studies, activation in the pMFC during the inconsistent social feedback negatively, rather than positively, predicted behavioral conformity. Notably, those with higher OXTR MPS had reduced pMFC activation in the face of social misalignment, which led to greater conformity. Our findings suggest that OT may promote conformity by dampening the conflict-related signals in the pMFC. They also show that OXTR MPS may be useful for studying the effect of genes on highly complex human social traits, such as conformity.

A multilocus genetic study evidences the association of autoimmune-related genes with Psoriatic Arthritis in Italian patients

Psoriatic Arthritis (PsA) is an immune-mediated rheumatic disease caused by the interaction between environmental factors and genetic predisposition. Many of the risk loci associated with PsA susceptibility are shared with other autoimmune diseases, suggesting an involvement of the same pathways in these diseases. We investigated the association between nine selected polymorphisms and PsA susceptibility and their possible role in the modulation of the disease activity. We analysed 163 patients with PsA and 298 age and sex-matched healthy subjects. Our results showed the associations of five polymorphisms with the disease development: rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3), rs27524 (ERAP1), rs7574865 (STAT4) and rs1800872 (IL10). Patients carrying the variant allele of TRAF3IP2 polymorphism had a higher number of tender/swollen joints and a higher Disease Activity Index for PsA score. The multilocus genetic risk profile showed a higher probability to develop the disease in subjects with at least four risk alleles.

Hypothalamic-pituitary-adrenal Axis Multilocus Genetic Variation, Childhood Parenting and Adolescent Anxiety Symptoms: Evidence of Cumulative Polygenic Plasticity.

Research suggests that genetic variants that regulate the hypothalamic-pituitary-adrenal (HPA) axis function moderate the association between parenting and anxiety symptoms, but these studies have primarily focused on (i) individual genes with very small and unreliable effect and (ii) the role of mothers as opposed to fathers. Using a multilocus genetic profile score approach, the current study is the first to examine the moderation effect of HPA-axis multilocus genetic variants on the associations of both maternal and paternal parenting with adolescent anxiety symptoms. In a sample of Chinese Han adolescents (N = 772; 50.1% girls; Mage = 16.48 ± 1.40 years, range: 15-20 years), a theory-driven multilocus genetic profile score was computed by counting the numbers of alleles that were previously linked to heightened stress reactivity in six HPA-axis related genes. This HPA-axis related multilocus genetic profile score equivalently interacted with both maternal and paternal parenting in the prediction of adolescent anxiety symptoms. Consistent with cumulative polygenic plasticity hypothesis of differential susceptibility model, adolescents with more versus low alleles linked to heightened stress reactivity not only suffered more from poor maternal or paternal parenting quality, but also benefited more from high maternal or paternal parenting quality. However, none of the individual HPA-axis genes within this multilocus genetic profile score yielded a significant gene-by-environment (G × E) interaction when examined in isolation. The findings survived after internal replication analysis and a novel, valid influence statistic DFBETAS analysis, demonstrating the robustness of the results. The current study highlights the potential value of using a multilocus approach to understand G × E effects underlying anxiety symptoms and emphasizes the role of both mothers and fathers in such gene-parenting interactions, especially in Chinese families.

Additive serotonergic genetic sensitivity and cortisol reactivity to lab-based social evaluative stress: Influence of severity across two samples

Prior work demonstrates that an additive serotonergic multilocus genetic profile score (MGPS) predicts amplified risk for depression following significant life stress, and that it interacts with elevations in the cortisol awakening response to predict depression. The serotonin system and HPA-axis have bidirectional influence, but whether this MGPS predicts acute cortisol reactivity, which might then serve as a mechanism for depression, is unknown. Our prior work suggests that depression risk factors predict blunted cortisol reactivity to explicit negative evaluative lab-based stress. Thus, we hypothesized that a 4-variant serotonergic MGPS (three SNPs from the original 5-variant version plus 5HTTLPR) would predict blunted cortisol reactivity to explicit negative evaluative stress versus a control. In Sample 1, growth curve modeling showed that the MGPS predicted heightened cortisol reactivity (p = 0.0001) in an explicitly negative evaluative Trier Social Stress Test variant (TSST) versus a control condition among non-depressed emerging adults (N = 152; 57% female). In Sample 2, 125 males completed the Socially Evaluative Cold Pressor Test (SECPT), an ambiguously negative evaluative manipulation; findings displayed a similar pattern but did not reach statistical significance (ps.075–.091). A participant-level meta-analysis of the two samples demonstrated a significant effect of negative evaluation severity, such that the MGPS effect size on reactivity increased linearly from control to SECPT to an explicitly negative evaluative TSST. Findings indicate that this MGPS contributes to sensitivity to social threat and that cortisol dysregulation in the context of social stress may be one mechanism by which this MGPS contributes to depression.

Childhood parenting and adolescent internalizing and externalizing symptoms: Moderation by multilocus hypothalamic-pituitary-adrenal axis-related genetic variation.

Genetic variants that regulate hypothalamic-pituitary-adrenal (HPA) axis function have been demonstrated to moderate the association between parenting and mental health. However, extant research has focused primarily on (i) effects of individual genes or (ii) maternal as opposed to paternal parenting. Using a multilocus genetic profile score (MGPS) approach, the current study is the first to examine the moderation effect of multilocus HPA-axis related genetic variants on the association of both maternal and paternal parenting with adolescent internalizing and externalizing symptoms. In a sample of 772 Chinese Han adolescents (Mage = 16.48 ± 1.40 years; 50.1% girls), a theory-driven MGPS was calculated using six polymorphisms within HPA-axis related genes (CRHR1, NR3C1, NR3C2, FKBP5, COMT, and HT1RA). Results showed that the MGPS interacted with both maternal and paternal parenting in the association with adolescent internalizing symptoms, but not externalizing symptoms. Consistent with the differential susceptibility model, adolescents with high versus low MGPS exhibited not only more internalizing symptoms when exposed to low quality of parenting but also less internalizing symptoms when exposed to high quality of parenting. The current findings highlight the potential value of using a multilocus approach to understanding gene-by-environment interaction (G×E) effects underlying mental health. Within such G×E effects, not only maternal but also paternal parenting should be addressed.

An Investigation into the Association Between Dopamine Receptor D1 Multilocus Genetic Variation, Multiparametric Magnetic Resonance Imaging, and Antidepressant Treatment.

Combining genetic variants with neuroimaging phenotypes may facilitate understanding of the biological mechanisms for the etiology and pharmacology of antidepressant treatment of major depressive disorder (MDD). To explore the latent pathway of dopamine gene-hierarchical brain network-antidepressant treatment. Retrospective. One hundred and sixty-eight MDD inpatients divided into responders (N=98) or nonresponders (N=70) based on the treatment outcome of antidepressant. Diffusion tensors imaging and resting-state functional magnetic resonance imaging at 3.0T using echo-planar sequence. Four genetic variations of the dopamine receptor D1 (DRD1) were genotyped. Strengths of rich-club, feeder, and local connections were calculated based on the rich-club organizations of structural and functional brain networks at baseline and following 4 weeks of selective serotonin reuptake inhibitor (SSRI) therapy. Logistic and linear regressions were used to analyze the impact of DRD1 multilocus genetic profile score on the treatment response of SSRI, and their associations with strengths of rich-club, feeder, and local connections. Mediation models were developed to explore the mediation role of rich-club organizations on the relationship between DRD1 and SSRI therapy response. A P value <0.05 was considered to be statistically significant. Multiple genetic variations of DRD1 were significantly related to the strengths of feeder connections both in structural and functional networks, and to the treatment response of SSRI. Furthermore, the strength of the structural feeder connection significantly modulated the effect of DRD1 variants on SSRI treatment outcome. DRD1 displayed close connections both with SSRI treatment outcome and rich-club organizations of structural and functional data. Moreover, structural feeder connection played a mediating role in the relationship between DRD1 and antidepressant therapy. 3 TECHNICAL EFFICACY STAGE: 4.

Monoaminergic Multilocus Genetic Variants Interact with Stressful Life Events in Predicting Changes in Adolescent Anxiety Symptoms: A One-year Longitudinal Study

Research suggests that genetic variants linked to monoaminergic neurotransmitter function moderate the association between stress and anxiety symptoms, but examining gene-environment (G × E) interactions with individual genes limits power. As one of polygenetic approaches, the multilocus genetic profile score is derived theoretically from combining the effects of multiple candidate genes based on the "biological plausibility". Using this approach, the current study examined the interaction between monoaminergic multilocus genetic variants and stressful life events on the changes in adolescent anxiety symptoms across a one-year timespan. In a Chinese Han adolescent sample which was derived from three vocational high schools (N = 587; T1: Mage = 16.47 ± 1.53 years; 50.8%, girls), the monoaminergic multilocus genetic profile score was calculated using 5-HTR2C rs6318, TPH2 rs4570625 and DRD2 rs1800497 polymorphisms. Results showed that this monoaminergic multilocus genetic profile score interacted with stressful life events in predicting changes in anxiety symptoms. Consistent with the G×E hypothesis of differential susceptibility, adolescents with more monoaminergic plasticity alleles not only suffered more from high levels of stressful life events, which increased the risk for anxiety symptoms, but also benefited more from low levels of stressful life events, which decreased the risk for anxiety symptoms. There were no significant G × E interactions when individual polymorphisms were examined in isolation. The results highlight the importance of examining aggregated influences of multiple genes in G × E interactions underlying the longitudinal development of adolescent anxiety symptoms.

Dopaminergic Genetic Variation in Young Adolescents: Associations with Sensation-Seeking.

Deficient reward functioning, including reward-related personality, is implicated in depression's etiology. A dopaminergic genetic multilocus genetic profile score (MGPS) has previously been associated with neural reward responsivity but, despite theoretical basis, has not been studied with reward-related personality. Such research is needed to elucidate associations between genetic variation and reward-related personality in a developmentally sensitive population.In the present study, we examined associations between dopaminergic MGPS's and self-report reward-related personality in two young adolescent samples aged 10-15years old (Sample 1: N = 100 girls, 82% White, 18% Other; Sample 2: N = 141, 65 girls, 76 boys, 89.36% White, 10.64% Other) using an established MGPS and an augmented MGPS. A "mini" meta-analysis synthesized results across samples. In Sample 1, an exploratory mediation analysis intended to gauge effect size for future work tested a path between the MGPS and depression through significant reward traits.In each independent sample, both MGPS's showed significant associations with sensation-seeking but not social drive, a pattern that persisted following correction. Effect sizes of novel variants were at least as robust as established variants, suggesting their added utility. Additionally, the exploratory mediation analysis suggested no noteworthy indirect effect, but a small (R2 = 0.022), statistically non-significant direct effect of the MGPS predicting prospective depressive symptoms.Results suggest that dopaminergic genetic variation is associated with the reward-related personality trait of sensation seeking but not social drive. Additional work is needed to probe whether sensation seeking may be a path through which this genetic variation confers depression risk.

Dopamine Multilocus Genetic Profile, Spontaneous Activity of Left Superior Temporal Gyrus, and Early Therapeutic Effect in Major Depressive Disorder.

Objectives: This study aimed to examine the interactive effects of dopamine (DA) pathway gene and disease on spontaneous brain activity and further to explore the relationship between spontaneous brain activity and the early antidepressant therapeutic effect in patients with major depressive disorder (MDD).Methods: A total of 104 patients with MDD and 64 healthy controls (HCs) were recruited. The Hamilton Depression Scale-24 (HAMD-24) was used to measure the depression severity. Both groups were given resting-state functional magnetic resonance imaging (rs-fMRI) scan. The amplitude of low-frequency fluctuation (ALFF) was calculated to reflect the spontaneous brain activity based on the rs-fMRI data. After treatment for 2 weeks, depression severity was evaluated again, and HAMD-24 reductive rate was used to measure the therapeutic effect of antidepressants. Multilocus genetic profile scores (MGPS) were used to assess the multi-site cumulative effect of DA pathway gene. The interactive effects of MDD and DA pathway gene on the ALFF of regional brain areas were measured by the multivariate linear regression analysis. Finally, partial correlation analysis (age, sex, education, and illness durations as covariates) was performed to identify the relationship between regional ALFF and therapeutic effect.Results: MDD and DA-MGPS had interactive effects on the left fusiform gyrus (FG_L), right calcarine sulcus (CS_R), left superior temporal gyrus (STG_L), bilateral cerebellum posterior lobe (CPL), bilateral inferior frontal gyrus (IFG), and bilateral superior frontal gyrus (SFG). Partial correlation analysis revealed that the ALFF of STG_L had a significant negative correlation with 2-week HAMD-24 reductive rate (r = −0.211, P = 0.035).Conclusions: The spontaneous activity of STG_L may be a potential biomarker of antidepressant-related early therapeutic effect underlying the influence of DA pathway genes in MDD.

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

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.