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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 85-91

The role of brain-derived neurotrophic factor and serotonin polymorphisms in stress-related personality and psychiatric symptoms: Implications for cardiovascular health

Department of Psychology, University of Massachusetts Boston, Boston, MA, USA

Date of Submission23-Jun-2020
Date of Acceptance28-Aug-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Prof. Paul G Nestor
Department of Psychology University of Massachusetts Boston, 100 William Morrissey Blvd. Boston, MA 02125
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/hm.hm_26_20

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Background: Diathesis-stress perspectives of cardiovascular (CV) health and disease have long identified the important role of a host of mental health risk and protective factors in both illness course and recovery. Few studies, however, have investigated these factors within the same sample of healthy people. Aims and Objectives: Accordingly, we focused on the inter-relationships among well-established CV mental health risk factors, specifically childhood adversity, stress-related adult personality traits and psychiatric symptoms, and naturally occurring genetic polymorphisms. Materials and Methods: Here 100 college students completed the NEO Five Factor Model of personality in conjunction with measures of childhood adversity, psychiatric symptoms as well as genetic variables derived from assays of the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF).
Results: Single gene comparisons pointed to lower CV risk, as reflected in personality and psychiatric symptom measures for BDNF Met versus Val/Val carriers. In addition, polygenic comparisons revealed a significant BDNF x 5-HTTLPR interactional effect, suggesting that this particular allelic combination may moderate the phenotypic expression of key personality traits, namely neuroticism and extraversion, as well as psychiatric symptoms, all linked to cardiovascular health. In fact, the data showed across personality and symptom measures, evidence of stress-resistance, resilience and protection for carriers of the allelic pair, BDNF Met and 5-HTTLPR-S. Conclusions: The findings suggested the Met variant of the BDNF gene had a risk-reducing and health-promoting effect when paired with the short serotonin allele, arguably reversing the commonly reported 5-HTTLPR-S association with stress vulnerability.

Keywords: Genes, neurotrophic, personality, psychiatric symptoms, stress

How to cite this article:
Nestor PG, Lapp HE, Boodai SB, O'Donovan K, Hasler VC, Hunter R. The role of brain-derived neurotrophic factor and serotonin polymorphisms in stress-related personality and psychiatric symptoms: Implications for cardiovascular health. Heart Mind 2020;4:85-91

How to cite this URL:
Nestor PG, Lapp HE, Boodai SB, O'Donovan K, Hasler VC, Hunter R. The role of brain-derived neurotrophic factor and serotonin polymorphisms in stress-related personality and psychiatric symptoms: Implications for cardiovascular health. Heart Mind [serial online] 2020 [cited 2023 Mar 29];4:85-91. Available from: http://www.heartmindjournal.org/text.asp?2020/4/3/85/296564

  Introduction Top

Stress experienced during sensitive periods of hypothalamic–pituitary–adrenal axis development in early life is an established risk factor for poor adult cardiovascular (CV) outcomes.[1] This association is partly driven by the physiological effects of glucocorticoids across CV, metabolic, and central nervous systems with dysregulated HPA activity resulting from early childhood stress, predictive of ill health and CV disease later in adult life.[2] However, whether such early life adversity will ultimately affect later adult CV health depends on a combination of environmental, genetic, and temperamental factors. Indeed from a diathesis-stress perspective of CV health and disease, studies have identified individual differences in personality and genotype that may act as either risk or protective factors in both illness course and recovery.[3] Here, such research begs the intriguing question of the single, joint, and interactive influences of environmental stress with specific personality, psychiatric, and genetic diatheses on CV illness and health.[4],[5],[6],[7]

Of particular relevance are two genes, one that encodes the brain-derived neurotrophic factor (BDNF) and the other, the serotonin transporter (5-HTT), each implicated in both stress-related personality traits and CV health.[8],[9],[10],[11] First, consider the BDNF gene, which is located on human chromosome 11p13, contains a guanine-to-adenine single-nucleotide polymorphism (SNP) at nucleotide 196 (rs6265), which results in an amino acid substitution of valine (Val) to methionine (Met) at codon 66. Evidence from CV studies suggests that BDNF alterations promote endothelial cell survival and neoangiogenesis as well as regulate blood flow in ischemic tissue and contribute to recovery.[12],[13] In addition, BDNF genotype studies have also compared Val/Val homozygote carriers versus Met carriers in relationship to both CV functioning and personality traits. For example, Kim et al. recently reported evidence of a personality × BDFN val66met interaction in acute coronary syndrome (ACS) patients, as reflected by significantly poor outcome only for Met allele carriers with a psychometrically defined vulnerable personality type, marked by heightened neuroticism and reduced extraversion, agreeableness, and conscientiousness.[14] In a related study, Kang et al. examined poststroke anxiety and BDNF genotype and found higher levels of distress on a symptom measure, Hospital Anxiety and Depression Scale, in Met versus Val/Val homozygotes.[15] In contrast, other studies, although not including measures of stress-related personality traits and related symptoms, have associated Met rather than Val/Val carriers with better CV function and outcomes.[16],[17] Similarly, in a sample of controls and general anxiety disorder patients, Chang et al. examined the relationship of the BDNF genotype and parasympathetic activity, as measured by heart rate variability.[18] Their results indicated that in comparison to Met carriers, Val/Val homozygotes of their healthy participant control group showed significantly blunted vagal reactivity to both stress and relaxation, which may reflect the heightened risk for CV abnormalities.[19]

Studies have also examined the relationship of CV health and function with the 5-HTT protein, which is encoded by a single gene, SLC6A4, whose transcriptional activity is modulated by a variable number of tandem repeats in the 5' promoter region (5-HTTLPR). This repetitive sequence leads to systematic allelic variation of 5-HTT expression and function that has been directly linked to phenotype differences in negative emotions with carriers of the low-expressing short allele having elevated risk for depression, particularly in the context of social adversity.[20],[21],[22] More recently, Kim et al. examined the relationship of depression and two different classes of environmental stressors – recent adverse life events and social support deficits – in a longitudinal 1-year follow-up study of ACS patients, genotype for 5-HTTLPR.[23] These researchers reported that gene–environment interactional effects on depression differed as a function of acute and chronic phases, post-ACS. That is, for carriers of the short allele, increased incidence of depression occurred in the acute phase for those with high exposure to recent adversity, but at the 1-year follow-up, social support deficits emerged as the significant contributor to persistent depression in these individuals. In a related study, Kim et al. results pointed to a moderating effect of 5-HTT on anxiety in ACS patients who were followed for 5–12 years.[11] However, their results showed that the interactional effects of 5-HTT on anxiety in these ACS patients held not for the long versus short biallelic comparison but for the triallelic (9-, 10-, 12-) polymorphism assay in STin2 variable number tandem repeat.[24]

The foregoing studies have identified important contributors to CV health ranging from environmental stressors, personality traits, and psychiatric symptoms to genetic diatheses. Few studies, however, have investigated joint and interacting roles of these psychological and genetic influences within the same sample of healthy participants. Indeed, while polygenic studies have demonstrated a functional interconnection between serotonin and BDNF pathways in regulating synaptic plasticity and neurogenesis, how these signaling systems may interact with psychological variables and social adversity in mental health functioning has yet to be elucidated.[25] Such a multifactorial research design adopting a comprehensive framework focusing on individual differences across key psychological, environmental, psychiatric, and genetic variables may have direct application for not only CV function and treatment response but also public health, in general.[26],[27],[28] Accordingly, in the current study, we examined within the same sample of healthy participants' single and epistatic effects of BDND and HTTLPR in relation to specific personality traits, psychiatric symptoms, and exposure to adverse childhood experiences (ACEs), each of which has been linked to CV health and disease.

  Materials and Methods Top

Sample and procedures

One hundred participants were recruited from the greater Boston area, primarily at the University of Massachusetts, Boston (UMB). Participants were between the ages of 18 and 25 (M = 21.22 years, standard deviation [SD] = 1.99) and identified as English speaking for at least 5 years prior to study enrollment. Seventy percent of the participants identified as biologically female, 24% racially identified as White, 72% reported the United States of America as their country of origin, and 63% endorsed 1–3 years of college as their level of education. The Institutional Review Board at UMB approved all research study procedures. All participants were presumed to be physically healthy without any reported active or acute symptoms of mental illness. Consenting participants first completed self-report measures and were then asked to provide a DNA sample via a cheek swab for the assaying of genotypes. All self-report measures used in this study have strong evidence for both reliability and validity. All enrolled participants completed the study. Participants were compensated $25 for their time or received extra credit in psychology courses.


Brief Symptom Inventory

The Brief Symptom Inventory (BSI) is a 53-item scale that measures psychiatric symptom status across nine distinct domains: somatization, obsessive-compulsive, interpersonal sensitivity, anxiety, hostility, depression, paranoid ideation, psychoticism, and phobic anxiety.[29] The BSI also includes measures of the overall Global Severity Index and Positive Symptom Distress Index. BSI scores reflect current psychiatric status on a Likert scale ranging from 0 (not at all) to 4 (extremely), where zero indicated the absence of current distress related to psychiatric symptoms. The BSI has demonstrated good internal consistency among nonpsychiatric populations (0.71–0.85 across scales) and moderate-to-high test–retest reliability (0.68–0.91 across scales) and convergent and discriminant validity with the MMPI.[29],[30] For the purpose of this study, standardized T scores were used, derived from age-matched normative data, for BSI subscales.

Adverse childhood experiences

This scale is a 10-item measure that assesses eight categories of adverse experiences in childhood, including emotional, physical and sexual abuse, and household dysfunction (i.e., substance abuse, mental illness, mother treated violently, and incarcerated household member). Participants are asked to provide “Yes” or “No” responses to each of the 10 items. Total ACE scores are the sum of affirmative responses to questions such as: “Were your parents ever separated or divorced?” “Did a parent/adult in your household often or very often push, grab, slap, or throw something at you?” “Did a member of your household go to prison?” Each question falls under an initial prompt, specifying the timeframe as the first 18 years of the participants' life. Scores range from 0 to 10, with higher scores indicative of greater number of adverse events in childhood.[31] The ACE has demonstrated good-to-excellent reliability for each ACE item, as well as the total ACE score (e.g., range of Cohen's kappa: 0.46–0.86).[32] The detailed statistical characteristics and validity of the ACE have been published in previous studies.[33],[34],[35]

Revised NEO Personality Test (NEO-PI-R)

The NEO-PI-R is an objective, self-report measure of five distinct and presumably universal personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness.[36] DeYoung et al. reported alpha reliabilities of internal consistency for the five NEO trait scales as 0.92 for neuroticism, 0.87 for extraversion, 0.89 for openness, 0.91 for agreeableness, and 0.91 for conscientiousness.[37]

DNA collection and extraction

Cytobrush swabs (Coopersurgical Inc.) were used to collect buccal cells. Participants were instructed to brush the swab 30 times against the inside of their cheek while slowly rotating the swab. Swabs were immediately placed on ice and stored at −80°C until DNA extraction. Buccal samples were extracted using a Zymo Quick-DNA Universal Kit per the manufacturer's instructions (Zymo Research). DNA yield from buccal samples ranged from 0.48 μg to 14.4 μg of DNA. Extracted DNA was stored in molecular biology-grade water at −80°C until genotyping analysis.

5-HTTLPR genotyping

Genotyping for 5-HTTLPR polymorphisms was performed using polymerase chain reaction and resolution using gel electrophoresis.[38] 25 μL PCR reactions were set up to contain 1X Green GoTaq Flexi Buffer, 1.5 mM MgCl2, 0.25 mM PCR Nucleotide Mix, 2.5 ng of DNA sample, and 0.15 μM of both forward and reverse primers (FW: 5' TGA ATG CCA GCA CCT AAC CC 3' and RV: 5'TTC TGG TGC CAC CTA GAC GC 3'). DNA amplification was achieved used the following thermocycler programming: initial denaturation was run for 11 min at 95°C, followed by 40 cycles of 45 s at 95°C, 45 s at60°C, 45 s at 72°C, and a final elongation step of 72°C for 10 min. The two amplicon products varied by 44 base pairs (515 base pairs for the long allele and 471 base pairs for the short allele) and were visualized by running the DNA samples on a 1.5% agarose gel stained with 1.5% ethidium bromide. Length of amplicon was determined by comparing sample bands to a reference DNA ladder (Promega, USA; ref: G695A) using Molecular Imaging ChemiDoc XRS+. Heterozygous 5-HTTLPR genotype was visibly detected by the presence of two bands in the lane approximately 44 base pairs apart.

BDNF genotyping

TaqMan SNP genotyping was used to determine BDNF val66met genotype (rs6265). 25 μL PCR reactions were performed using a predesigned 1X TaqMan allelic discrimination assay (Applied Biosystems, USA; assay number: C__11592758_10), containing forward and reverse primers and allele-specific probe with 5 ng of sample DNA. Genotypic amplification was achieved using the StepOnePlus Real-Time (Applied Biosystems) PCR System with programming as follows: 95°C for 10 m, followed by 42 cycles of 95°C for 15 s and 60°C for 1 m. Genotype was determined from the resulting allelic discrimination plot.

For the BDNF gene, there were 72 Val/Val, 21 Met/Met, and 7 Val/Met carriers. We grouped Met/Mets (n = 21) with Val/Mets (n = 7) to form a “Met” carrier group (n = 28), with the remaining participants categorized as “Val/Val” (n = 72) genotype. For the 5-HTTLPR transporter gene, there were 41 Long/Long, 38 Short/Long, and 21 Short/Short carriers. The distribution of genotypes followed the Hardy–Weinberg equilibrium for 5-HTTLPR and BDNF alleles. In addition, we assigned the 41 Long/Long alleles to a 5-HTTLPR transporter-long (“5-HTTLPR-L,” n = 41) group, and the remaining 38 Short/Long and 21 Short/Short carriers to a 5-HTTLPR transporter short (“5-HTTLPR-S,” n = 59) group. Following previous research, we further divided the 100 participants into four allelic groups: (1) 34 5-HTTLPR-L, BDNF Val/Val carriers; (2) 7 HTTLPR-L, BDNF Met carriers; (3) 38 5-HTTLPR-S, BDNF Val/Val carriers; and (4) 21 5HTTLPR-S, BDNF Met carriers.[39]

Statistical analysis

We first present descriptive statistics for the entire sample. For each criterion measure (i.e., BSI and NEO), we used a series of 2 × 2 analyses of variance (ANOVAs) with two between-subjects factors of 5-HTTLPR (long, short) and BDNF (Val/Val, Met). These ANOVAs tested for the main effects of BDNF and 5-HTTLPR as well as for the interaction of BDNF × 5-HTTLPR on selected BSI scales and NEO personality measures. For multivariate group comparisons, BSI and NEO scores were submitted to a multiple analysis of variance (MANOVA) with two between-subjects factors of BDNF (Val/Val, Met) and 5-HTTLPR serotonin transporter gene (long, short).

  Results Top

[Table 1] presents descriptive statistics for the sample. As shown in [Table 1], participants reported on average 2.17 (SD = 2.31) exposures to ACE, and 51% reported less than two and 49% with two or more stressful events. NEO T-scores (M = 50, SD = 10) fell in within normal limits for neuroticism (M = 53.19, SD = 12.19), extraversion (M = 50.33, SD = 12.20), openness (M = 57.05, SD = 10.25), agreeableness (M = 49.93, 11.41), and conscientiousness (M = 48.88, SD = 12.26) as well as BSI ratings for anxiety (M = 56.43, SD = 13.16) and depression (M = 60.45, SD = 11.12).
Table 1: Adverse childhood experiences, Brief Symptom Inventory, and NEO scores for genotypes

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Single gene comparisons revealed for the BDNF genotype, in relation to Val/Val homozygotes, Met carriers had significantly lower BSI ratings for depression, t(98) = 2.11, P=.04 and anxiety t(98) = 2.17, P=.03 as well as reduced neuroticism, t(95)=2.62, P=.01 and elevated extraversion, t(95)=-2.87, P=.005. For the 5-HTTLPR genotype, group comparisons for BSI and personality traits revealed no significant differences between short and long allelic carriers. [Table 2] presents the ANOVA results of the polygenic comparisons of the two genotypes for symptom and personality trait measures. ANOVA results yielded a significant BDNF × 5-HTTLPR interaction for depression, F(1,96) = 12.39, P < 0.001 partial eta squared = 0.114; anxiety, F(1,96) = 5.30, P = 0.024, partial eta squared = 0.052; and for neuroticism, F(1,93) = 5.03, P = 0.027, partial eta squared = 0.051. Similarly, multivariate comparison (MANOVA) of the four allelic groups across BSI ratings of depression and anxiety as well as NEO personality traits of neuroticism and extraversion yielded a significant main effect for group, F(12, 276) = 2.13, P = 0.015, partial eta squared = 0.085. In relation to each of the three other allelic groups, BDNF-Met, 5-HTTLRP-S (n = 19) carriers had significantly lowest levels of stress (depression, anxiety, and neuroticism) and highest extraversion in relation to BDNF-Val/Val, 5-HTTLPR-L (n = 33) carriers, F(4, 47) = 3.24, P = 0.02, partial eta squared = 0.216; BDNF-Val/Val, 5HTTLPR-S (n = 38) carriers, F(4,52) = 4.24, P = 0.005, partial eta squared = 0.246; and BDNF-Met, 5-HTTLPR-L (n = 7) carriers, F(4,21) = 4.40, P = 0.009, partial eta squared = 0.458.
Table 2: ANOVA results using symptom and personality traits as criterion measures

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Finally, we computed a CV stress vulnerability variable averaging across T-scores for neuroticism, anxiety, and depression. A univariate ANOVA again revealed a significant interaction of 5-HTTLPR × BDNF, F(1,93) = 9.76, P = 0.002, partial eta squared = 0.095. As shown in [Figure 1], the lowest CV risk or stress vulnerability (lowest levels of anxiety, depression, and neuroticism) occurred for BDNF Met, 5-HTTLPR-S (M = 48.84, SD = 8.52), followed by BDNF Val/Val, 5-HTTLPR-L (M = 56.53, SD = 8.65), then by BDNF Val/Val, 5-HTTLPR-S (M = 59.98, SD = 11.90), and last by BDNF Met, 5-HTTLPR-L (M = 61.05, SD = 7.43).
Figure 1: Stress resistance (t-scores) for the four allelic groups. *Significant at the 0.05 level (two-tailed). **Significant at the 0.01 level (two-tailed)

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  Discussion Top

We examined in a healthy college student sample the relationship among well-established CV risk and protective factors – childhood adversity, stress-related adult personality traits and psychiatric symptoms, and naturally occurring genetic polymorphisms. The results demonstrated strong evidence linking particular allelic variation in BDNF and 5-HTTLPR genes with individual differences in psychiatric symptoms of depression and anxiety as well as in the personality dyad of neuroticism and extraversion. In particular, single-gene comparisons pointed to lower CV risk, as reflected in personality and psychiatric symptom measures for BDNF Met versus Val/Val carriers. Indeed, Met carriers had significantly lower levels of stress-related personality traits and psychiatric symptoms than their Val/Val counterparts. As such, these BDNF genotype differences suggested that the Met allele but not the Val allele may offer protection against depression and anxiety, which comports with other studies showing that the Met allele may be protective for bipolar disorder as well as for general anxiety disorder.[18],[40],[41] Perhaps most striking, though, polygenic comparisons revealed a significant BDNF × 5-HTTLPR interactional effect, suggesting that particular allelic combinations may moderate the phenotypic expression of these key personality traits and psychiatric symptoms linked to CV health. In fact, the data showed across personality and symptom measures, evidence of stress-resistance, resilience and protection for carriers of the allelic pair, BDNF Met, and 5-HHTLPR-S in comparison to the other three allelic groups. Thus, in line with the single-gene findings, the Met variant of the BDNF gene had a risk-reducing and health-promoting effect when paired with the short serotonin allele, arguably reversing the commonly reported 5-HTTLPR-S association with stress vulnerability.[27],[39] On the other hand, however, pairing of Met with the long serotonin allele had the lowest stress resistance and, by proxy highest CV risk, as reflected in both personality traits and psychiatric symptoms.

The current study thus revealed a consistent BDNF × 5-HTTLPR interaction that moderated particular personality traits and psychiatric symptoms that have long been linked to CV health.[42],[43] The epistatic interaction of these neurotrophic and neurotransmitter signaling systems suggested that CV risk may differ significantly depending on the exact pairing of BDNF and serotonin alleles, with the lowest vulnerability for carriers of Met, 5-HTTLPR-S, followed by Val/Val, 5-HTTLPR-L, and then by Val/Val, 5-HTTLPR-S, with the highest level of personality- and psychiatric-related CV illness susceptibility for the Met, 5-HTTLPR-L carriers. These findings align well with mounting evidence pointing to a functional interconnection between BDNF and serotonin pathways in regulating synaptic plasticity and HPA-mediated psychobiological stress that may act as key factors in the emergent homeostasis of the brain and CV development and function.[4],[6] However, future studies with larger samples and independent measures of CV risk and function are needed to elucidate these psychobiological pathways that may mediate the HPA stress response in heart diseases and recovery. Indeed, the current findings are limited by reliance on a relatively small sample of healthy college students of a restricted age range that did not allow for important subgroup analyses in relation to age, gender, and ethnicity.

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Conflicts of interest

There are no conflicts of interest.

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