The role of neuroticism and pain in dental anxiety: A twin study.

OBJECTIVES: Accumulating evidence has revealed that dental anxiety is robustly associated with dental care-related pain and discomfort, but also with the personality trait of neuroticism (i.e. the relatively stable disposition to experience the world as distressing, threatening and unsafe). However, there is a near absence of research on these risk factors in samples for which genetic information is available. With the aim of arriving at a more refined understanding of dental anxiety, this twin cohort study assessed genetic and environmental influences on neuroticism, dental care-related pain and dental anxiety, and the relation between these phenotypes. METHODS: Participants were recruited from the Norwegian Twin Registry, and data collections were carried out in 1992-98 (Time 1) and 2011 (Time 2). Well-validated questionnaires were used to assess the study variables, including Corah's Dental Anxiety Scale, the Numerical Pain Rating Scale, the NEO Personality Inventory Revised (Time 2) and Eysenck's Personality Questionnaire (Time 1). Pearson correlation analysis and generalized estimating equations (GEE) were used to investigate phenotypic associations. Analyses of genetic and environmental influences were performed using Cholesky modelling. RESULTS: A total of 746 monozygotic (MZ) and 770 dizygotic (DZ) twins in the age group of 50-65 participated in the study. Moderate estimates of heritability for dental anxiety (0.29), treatment-related pain (0.24) and neuroticism (0.45-0.54) were found. Cholesky modelling showed furthermore that neuroticism assessed at Time 1 and Time 2 was related to dental anxiety and pain via both genetic and individual-specific environmental pathways, albeit not very strongly. The particularly high phenotypic correlation observed between dental care-related pain and anxiety (r = .68) was explained by both overlapping genetic and individual-specific environmental influences (the genetic and environmental correlations were .84 and .63 respectively). CONCLUSIONS: The findings provide deeper insight into the aetiology of dental anxiety and confirm that while it is strongly linked to treatment-related pain experiences, this relation is to a considerable degree independent of general negative affectivity/neuroticism.

Genome-wide Scan of Dental Fear and Anxiety Nominates Novel Genes.

Dental care-related fear and anxiety (DFA) is prevalent, affects oral health care utilization, and is related to poor oral health and decreased quality of life. In addition to learned and cultural factors, genetics is hypothesized to contribute to DFA. Therefore, we performed a genome-wide association study to identify genetic variants contributing to DFA. Adult and adolescent participants were from 4 cohorts (3 from the US-based Center for Oral Health Research in Appalachia, n = 1,144, 1,164, and 535, and the UK-based Avon Longitudinal Study of Parents and Children [ALSPAC], n = 2,078). Two self-report instruments were used to assess DFA: the Dental Fear Survey (US cohorts) and Corah's Dental Anxiety Scale (ALSPAC). Genome-wide scans were performed for the DFA total scores and subscale scores (avoidance, physiological arousal, fear of dental treatment-specific stimuli), adjusting for age, sex, educational attainment, recruitment site, and genetic ancestry. Results across cohorts were combined using meta-analysis. Heritability estimates for DFA total and subscale scores were similar across cohorts and ranged from 23% to 59%. The meta-analysis revealed 3 significant (P < 5E-8) associations between genetic loci and 2 DFA subscales: physiological arousal and avoidance. Nearby genes included NTSR1 (P = 3.05E-8), DMRTA1 (P = 4.40E-8), and FAM84A (P = 7.72E-9). Of these, NTSR1, which was associated with the avoidance subscale, mediates neurotensin function, and its deficiency may lead to altered fear memory in mice. Gene enrichment analyses indicated that loci associated with the DFA total score and physiological arousal subscale score were enriched for genes associated with severe and persistent mental health (e.g., schizophrenia) and neurocognitive (e.g., autism) disorders. Heritability analysis indicated that DFA is partly explained by genetic factors, and our association results suggested shared genetic underpinnings with other psychological conditions.

Genes in treatment: Polygenic risk scores for different psychopathologies, neuroticism, educational attainment and IQ and the outcome of two different exposure-based fear treatments.

OBJECTIVES: Evidence for a genetic influence on psychological treatment outcome so far has been inconsistent, likely due to the focus on candidate genes and the heterogeneity of the disorders treated. Using polygenic risk scores (PRS) in homogenous patient samples may increase the chance of detecting genetic influences. METHODS: A sample of 342 phobic patients treated either for clinically relevant dental fear (n = 189) or other (mixed) phobic fears (n = 153) underwent highly standardised exposure-based CBT. A brief five-session format was used to treat dental fear, whereas longer multi-session treatments were used with the mixed-fear cohort. PRS were calculated based on large genetic studies of Neuroticism, Educational Attainment (EA), Intelligence, and four psychopathology domains. We compared PRS of post-treatment and follow-up remitters and non-remitters and regressed PRS on fear reduction percentages. RESULTS: In the dental fear cohort, EA PRS were associated with treatment outcomes, i.e. drop-out, short- and long-term remission state, fear reduction, and attendance of subsequent dental appointments. In the mixed fear treatment cohort, no gene effects were observable. CONCLUSIONS: Results indicate the importance of EA-related traits for outcomes following brief, but not long, standardised exposure-based CBT. Such use of PRS may help inform selection and tailoring of treatments.

Interaction between FKBP5 variability and recent life events in the anxiety spectrum: Evidence for the differential susceptibility model.

BACKGROUND: Gene-environment interaction (GxE) research has highlighted the importance of investigating the FK506 binding protein 51 (FKBP5) gene as a sensitivity gene. However, previous GxE studies with FKBP5 have not measured the full environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs) on FKBP5 gene moderate the association of positive and negative recent life events (LEs) with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits. METHODS: A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five FKBP5 SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916). RESULTS: Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences. DISCUSSION: Findings underscore the importance of testing the differential-susceptibility model in relation to FKBP5 to adequately characterize its role in healthy and pathological developmental processes.

INFLUENCE OF THE SEROTONERGIC SYSTEM POLYMORPHISM ON THE EXPRESSION OF DENTAL ANXIETY.

- The aim of the study was to test the correlation between 5-HTTLPR polymorphism and dental anxiety. Research hypothesis was that positive relation between the expression of dental anxiety and the S allele exists in the population of healthy Caucasians. We conducted a prospective study on 159 subjects, volunteers made up of medical and non-medical staff of the Sestre milosrdnice University Hospital Centre. Both genders were included, age range 19 to 59, mentally and physically healthy (according to DSM-5 classification of mental disorders). For the purpose of this research, we used a sociodemographic questionnaire containing the following information: age, gender, education level, work status, marital status and residence. Corah's Dental Anxiety Scale-Revised (DAS-R) was used to measure dental anxiety. Data distribution was tested by Kolmogorov-Smirnov test, difference between the groups by ?χ2-test and one-way analysis of variance, and correlation of variables by logistic regression. In the study population, we found positive correlation between S-allele and total result in DAS-R questionnaire. The presence of S allele suggests that the person will have a higher result in DAS-R questionnaire, i.e. higher expression of dental anxiety.

Fear of Pain Mediates the Association between MC1R Genotype and Dental Fear.

Fear of pain is experienced in acute and chronic pain populations, as well as in the general population, and it affects numerous aspects of the orofacial pain experience, including pain intensity, pain-related disability, and pain behavior (e.g., avoidance). A related but separate construct-dental fear-is also experienced in the general population, and it influences dental treatment-seeking behavior and oral and systemic health. Minimal work has addressed the role of genetics in the etiologies of fear of pain and dental fear. Limited available data suggest that variants of the melanocortin 1 receptor (MC1R) gene may predict greater levels of dental fear. The MC1R gene also may be etiologically important for fear of pain. This study aimed to replicate the finding that MC1R variant status predicts dental fear and to determine, for the first time, whether MC1R variant status predicts fear of pain. Participants were 817 Caucasian participants (62.5% female; mean ± SD age: 34.7 ± 8.7 y) taking part in a cross-sectional project that identified determinants of oral diseases at the community, family, and individual levels. Participants were genotyped for single-nucleotide polymorphisms on MC1R and completed self-report measures of fear of pain and dental fear. Presence of MC1R variant alleles predicted higher levels of dental fear and fear of pain. Importantly, fear of pain mediated the relation between MC1R variant status and dental fear (B = 1.60, 95% confidence interval: 0.281 to 3.056). MC1R variants may influence orofacial pain perception and, in turn, predispose individuals to develop fears about pain. Such fears influence the pain experience and associated pain behaviors, as well as fears about dental treatment. This study provides support for genetic contributions to the development/maintenance of fear of pain and dental fear, and it offers directions for future research to identify potential targets for intervention in the treatment of fear of pain and dental fear.

Dental anxiety in relation to neuroticism and pain sensitivity. A twin study.

Predisposing personality traits as well as heightened pain sensitivity and fear of pain have been hypothesized as central factors in the development of dental anxiety. The aim of the study was to estimate the heritability of dental anxiety, and to investigate the genetic and environmental sources of covariance between dental anxiety on one hand, and pain sensitivity and the neuroticism trait on the other. A sample comprising 188 twins, aged 23-35 years (53 monozygotic and 39 dizygotic twin pairs, and 4 single twins whose co-twin did not participate), was included in the study. Measures of dental anxiety and personality were obtained using Corah's Dental Anxiety Scale and the NEO Personality Inventory Revised, respectively. Heat pain and cold pressor pain sensitivity were assessed using standard pain testing procedures. Bivariate Cholesky models were employed to decompose the correlations between phenotypes into genetic and environmental factors. Using models with common additive genetic (A) and individual-specific environmental (E) factors, moderate heritability (i.e., .41) for dental anxiety was demonstrated. Virtually all of the phenotypic correlation between neuroticism and dental anxiety could be accounted for by A. Furthermore, a substantial part of the variance in dental anxiety was due to specific genetic and individual environmental influences unrelated to neuroticism. The phenotypic correlations between dental anxiety and the pain sensitivity indices were close to zero. Thus, while neuroticism and dental anxiety share a sizeable proportion of genetic (but not environmental) risk factors, the results also suggest that these two attributes are distinct entities with overlapping, but not identical, etiologies.

Heritability of dental fear.

The objective was to test a hypothesized genetic component (i.e., monozygotic being more similar compared with dizygotic twins) in dental fear/anxiety by comparing the probandwise concordance. We analyzed data based on a dichotomous measure of Dental Fear/Anxiety and a continuous measure of Dental Fear Intensity from over 2000 twins, collected when participants were 13-14 years old and once again three years later. The hypothesis was confirmed, but heritability of Dental Fear/Anxiety was estimated to be higher for girls (0.77 at time 1 and 0.55 at time 2) than for boys (0.14 and 0.0 at times 1 and 2, respectively). Heritability of Dental Fear Intensity, however, was similar for girls (0.30 and 0.40 at times 1 and 2, respectively) and boys (0.47, 0.44). Studies of the etiology of dental fear/anxiety should take genetic vulnerability into account and include molecular biology measures. Possible heritability differences between girls and boys need attention.

Genetic variations associated with red hair color and fear of dental pain, anxiety regarding dental care and avoidance of dental care.

BACKGROUND: Red hair color is caused by variants of the melanocortin-1 receptor (MC1R) gene. People with naturally red hair are resistant to subcutaneous local anesthetics and, therefore, may experience increased anxiety regarding dental care. The authors tested the hypothesis that having natural red hair color, a MC1R gene variant or both could predict a patient's experiencing dental care-related anxiety and dental care avoidance. METHODS: The authors enrolled 144 participants (67 natural red-haired and 77 dark-haired) aged 18 to 41 years in a cross-sectional observational study. Participants completed validated survey instruments designed to measure general and dental care-specific anxiety, fear of dental pain and previous dental care avoidance. The authors genotyped participants' blood samples to detect variants associated with natural red hair color. RESULTS: Eighty-five participants had MC1R gene variants (65 of the 67 red-haired participants and 20 of the 77 dark-haired participants) (P < .001). Participants with MC1R gene variants reported significantly more dental care-related anxiety and fear of dental pain than did participants with no MC1R gene variants. They were more than twice as likely to avoid dental care as were the participants with no MC1R gene variants, even after the authors controlled for general trait anxiety and sex. CONCLUSION: Dental care-related anxiety, fear of dental pain and avoidance of dental care may be influenced by genetic variations. CLINICAL IMPLICATIONS: Dentists should evaluate all patients, but especially those with naturally red hair, for dental care-related anxiety and use appropriate modalities to manage the patients' anxiety.