Other entities represented in this entry:
SNOMEDCT: 48694002; ICD10CM: F41.1; DO: 2030;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q11.2 | {Anxiety-related personality traits} | 607834 | 3 | SLC6A4 | 182138 |
A number sign (#) is used with this entry because of evidence that susceptibility to anxiety-related traits can be conferred by variation in the serotonin transmitter (SLC6A4; 182138) on chromosome 17q11.
Human personality is shaped by genetic and environmental factors, and evidence suggests that the genetic component is highly complex, polygenic, and epistatic. Genetic factors are thought to contribute to 40 to 60% of trait variance. Molecular genetics has tried to identify specific genes for quantitative traits, called quantitative trait loci (QTLs). The QTL concept suggests that complex personality traits or dimensions are not attributable to single genes, but to multiple interacting genes (Reif and Lesch, 2003).
Fullerton et al. (2003) stated that psychologists were in agreement that the wide variation in human personalities can be explained by a small number of personality factors, including neuroticism (a measure of emotional stability), which manifests at one extreme as anxiety, depression, moodiness, low self-esteem, and diffidence. They cited a number of studies that had described a relationship between high scores on measures of neuroticism and major depressive disorder. They also noted that theoretical studies had suggested that large samples of randomly ascertained sibs could be used to ascertain phenotypically extreme individuals and thereby increase power to detect genetic linkage in complex traits.
See also panic disorder (PAND1; 167870), which is a subtype of anxiety disorder.
Fullerton et al. (2003) reported a genetic linkage scan using 182 extremely discordant and 379 extremely concordant sib pairs selected from 34,580 sib pairs in the southwest of England who completed a personality questionnaire. They performed a genomewide scan for QTLs influencing variation in neuroticism and found 5 loci that met or exceeded the 5% genomewide significance threshold of 3.8 (negative logarithm of the P value) on chromosomes 1q, 4q, 7p, 12q, and 13q. QTLs on chromosomes 1, 12, and 13 were thought to be female-specific. The locus on chromosome 1 was syntenic with a rat QTL influencing emotionality, a model of neuroticism, suggesting that some animal and human QTLs influencing emotional stability may be homologous.
Cloninger et al. (1998) performed a genomewide scan in 758 sib pairs in 177 nuclear families of alcoholics. Personality traits were assessed using the Tridimensional Personality Questionnaire (TPQ). Significant linkage between a measure of anxiety proneness called harm avoidance and a locus on chromosome 8p23-p21 explained 38% of the trait variance. There was also significant evidence of epistasis between the locus on 8p and others on chromosomes 18p, 20p, and 21q, and these interactions explained most of the variance in harm avoidance.
In 384 sib pairs recruited from the general population, Zohar et al. (2003) found linkage between harm avoidance, as assessed by the TPQ, and a locus on 8p23-p21, with a maximum multipoint lod score of 2.34. The lod score increased to 2.9 when female gender was considered.
Nash et al. (2004) explored genetic variants for the liability to depression (608516) and anxiety in a large community-based sample of 34,371 individuals. A composite index of liability (G) was constructed and used to select a smaller but statistically powerful sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. Linkage analysis revealed 2 potential quantitative trait loci (QTL): 1 on chromosome 1p (lod = 2.2) around 64 cM near D1S2892 and another on chromosome 6p (lod = 2.7) around 47 cM near D6S1610. The authors further noted that these QTLs might have sex-limited effects.
Neale et al. (2005) analyzed a genome scan for neuroticism on a sample of 129 sib-pair families (113 with a single sib pair, 18 with multiple sib pairs) containing a total of 201 possible sib pairs, ascertained for concordance on nicotine dependence. The study replicated peaks for neuroticism described by prior studies on chromosomes 1q (137 cM) and 11 (132 cM) with lod scores of 2.52 and 1.97 (p = 0.003 and 0.0108), respectively, as well as evidence for a novel finding on chromosome 12 (45.5 cM) with a lod of 2.85 (p = 0.0014).
In a study of 2,287 Australian and 1,185 Dutch twins and sibs, Middeldorp et al. (2005) found a correlation of 0.20 for generalized anxiety disorder, yielding an upper heritability estimate of 40%.
To characterize the neural circuitry associated with anxious temperament and the extent to which the function of this circuit is heritable, Oler et al. (2010) studied a large sample of rhesus monkeys phenotyped for anxious temperament. Using 238 young monkeys from a multigenerational single-family pedigree, Oler et al. (2010) simultaneously assessed brain metabolic activity and anxious temperament while monkeys were exposed to the relevant ethologic condition that elicits the phenotype. High-resolution (18)F-labeled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semiquantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behavior and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Oler et al. (2010) demonstrated that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of anxious temperament. They also showed significant heritability of the anxious temperament phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, Oler et al. (2010) revealed significant heritability of metabolic activity in anxious temperament-associated hippocampal regions. However, activity in the amygdala region predictive of anxious temperament was not observed to be significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differed from each other. Oler et al. (2010) concluded that even though these structures are closely linked, the results suggested differential influences of genes and environment on how these brain regions mediate anxious temperament and the ongoing risk of developing anxiety and depression.
Serotonin Transporter
Transporter-facilitated uptake of serotonin has been implicated in anxiety in humans and in animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Lesch et al. (1996) found that transcription of the gene for serotonin transporter (SERT, or SLC6A4; 182138) is modulated by a common polymorphism in its upstream regulatory region. They found that the short variant of the polymorphism (182138.0001), designated 5-HTTLPR, reduces the transcriptional efficiency of the SLC6A4 gene promoter, resulting in decreased serotonin transporter expression and serotonin uptake in lymphoblasts. In family studies of 2 independently collected groups (505 total subjects), Lesch et al. (1996) found that neuroticism, the NEO personality inventory factor which is composed of anxiety and depression-related subfactors, was significantly associated with the SLC6A4 promoter polymorphism. The polymorphism was also associated with anxiety-related traits including 'tension,' 'suspiciousness,' and 'harm avoidance,' in 2 other personality assessment models. Lesch et al. (1996) determined that the polymorphism accounted for 3 to 4% of total variation and 7 to 9% of inherited variance of anxiety-related personality traits. The authors noted that if other genes were hypothesized to contribute similar gene dosage effects to anxiety, 10 to 15 genes might be predicted to be involved.
Mazzanti et al. (1998) found a relationship between the SLC6A4 promoter polymorphism and 2 anxiety-related subdimensions of harm avoidance in sib pairs, but found no association between the polymorphism and harm avoidance in others. Among 759 individuals, Jorm et al. (1998) found no association between the polymorphism and personality traits, including neuroticism, anxiety, depression, and alcoholism. In 74 same-sex sib pairs, Osher et al. (2000) found an association between 5-HTTLPR and harm avoidance and neuroticism. Sib-pair linkage analysis further supported a role of the polymorphism in anxiety-related personality traits.
To provide statistical measures of the strength of the relationship between long/short promoter polymorphisms of the serotonin transporter gene and trait anxiety, Schinka et al. (2004) conducted a metaanalysis of 26 studies of various ethnic groups. The results provided no support for a relationship between anxiety and the presence of the short form of the promoter polymorphism; however, there was strong evidence for the presence of moderating variables, and subsequent analysis revealed that choice of the measure of trait anxiety was significant. Studies using a neuroticism scale based on the 5-factor model of personality were found to produce a small positive effect.
Savitz and Ramesar (2004) reviewed the evidence that alleles of the serotonin transporter and the DRD4 (126452) genes impact variations in personality. They argued for the existence of a genuine effect: a gene-personality relationship rendered periodically latent through genetic epistasis, gene-environment interactions, variation in genetic background, and the presence of other variables.
Sen et al. (2004) noted that at least 26 studies had investigated a putative association between the functional serotonin transporter promoter polymorphism 5-HTTLPR and anxiety-related personality traits, with inconsistent results. They conducted a metaanalysis of these studies, which included 5,629 individuals, and found suggestive evidence for an association between the short allele (S) and increased anxiety-related personality trait scores (p = 0.087). Analysis of heterogeneity revealed that substantial variation was introduced by the inventories used; when analyses were stratified by inventory type, there was a significant association between 5-HTTLPR and neuroticism as measured by the NEO personality inventory (p = 0.000016) but not by other rating scales. Sen et al. (2004) concluded that there is a strong association between the serotonin transporter promoter variant and neuroticism, and that nonreplications are largely due to small sample size and use of different inventories.
Associations Pending Confirmation
Nash et al. (2005) noted that genetic susceptibility to depression and anxiety is both overlapping and dimensional. To index this common genetic susceptibility, they created a quantitative phenotype from several depression and anxiety-related measures. They studied 119 sibships comprising 312 individuals from a community-based sample of 34,371 individuals, selected for extreme scores on this measure. A pathway-based candidate gene study examined 5 microsatellite markers located within or close to 5 serotonin system genes, i.e., HTR2C (312861), HTR1D (182133), HTR1B (182131), TPH1 (191060), and MAOB (309860). Statistical analysis using the quantitative TDT gave significant association with a microsatellite downstream of TPH1. When further analysis included a life-events composite as a covariable, a stronger association with TPH1 was observed.
In a study of 67 college-aged students, Roe et al. (2009) found a significant association between harm avoidance and the rs4603829 and rs4522666 SNPs in the CHRNA4 gene (118504) on chromosome 20q13 (p = 0.029 and p = 0.042, respectively, after false discovery rate (FDR) correction). Both SNPs are located in the 3-prime region of the CHRNA4 gene and showed partial linkage disequilibrium. Harm avoidance was assessed as a psychologic risk attitude measurement. Roe et al. (2009) postulated that the association may be related to dopamine modulation in the mesolimbic region, and may reflect changes in inhibitory responses.
Pituitary adenylate cyclase-activating polypeptide (PACAP), encoded by the ADCYAP1 gene (102980), and its receptor PAC1 (ADCYAP1R1; 102981) play an integral role in the regulation of cellular and behavioral stress responses. Ressler et al. (2011) hypothesized that PACAPergic systems may be important mediators of abnormal stress responses following psychological trauma contributing to posttraumatic stress disorder (PTSD), an extreme maladaptive and debilitating psychiatric disorder affecting up to 40% of individuals over lifetime exposure to traumatic events. To investigate this hypothesis, Ressler et al. (2011) analyzed blood levels of PACAP and genetic variation and methylation of PACAP and PAC1 genes in more than 1,200 heavily traumatized subjects with and without PTSD. They found a sex-specific association of PACAP blood levels with fear physiology, PTSD, and symptoms in females. Ressler et al. (2011) examined 44 SNPs spanning the PACAP and PAC1 genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative estrogen response element with ADCYAP1R1, rs2267735, predicted PTSD diagnosis and symptoms in females only. This SNP also associated with fear discrimination and with ADCYAP1R1 mRNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood was also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA was induced with fear conditioning or estrogen replacement in rodent models. The data of Ressler et al. (2011) suggested that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via estrogen regulation of ADCYAP1R1. Ressler et al. (2011) suggested that PACAP levels and ADCYAP1RA SNPs may serve as useful biomarkers to further the mechanistic understanding of PTSD.
For discussion of a possible association between variation in expression of the NTRK3 gene and panic disorder related to agoraphobia, see 191316.
For discussion of a possible association between variation in the SIRT1 gene and anxiety disorders, see 604479.
Using a combination of behavioral analysis of 6 inbred mouse strains with quantitative gene expression profiling of several brain regions, Hovatta et al. (2005) identified 17 genes with expression patterns that correlated with anxiety-like behavioral phenotypes. Using lentivirus-mediated gene transfer, they found that local overexpression of glyoxalase-1 (138750) and glutathione reductase-1 (138300) in the mouse brain resulted in increased anxiety-like behavior, while local inhibition of glyoxalase-1 expression by RNA interference decreased the anxiety-like behavior. Hovatta et al. (2005) concluded that both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behavior.
Johnson et al. (2010) showed that orexin (HCRT; 602358) may be involved in panic disorder and anxiety, both of which are disorders associated with increased arousal, hypervigilance, and stimulation of the autonomic nervous system. A rat model of panic disorder showed increased activation of Hcrt-positive cells in the dorsomedial-perifornical hypothalamus after sodium lactate administration that correlated with anxious behavior compared to nonpanic rats. This response was attenuated with siRNA against the Hcrt gene, as well as by antagonists to the Hcrt receptor (HCRTR1; 602392) injected directly into the stria terminalis. These attenuating effects mimicked treatment with benzodiazepines, which result in increased GABAergic activity. Finally, cerebrospinal fluid levels of orexin were increased among 53 individuals with panic anxiety compared to controls, suggesting that the orexin system may be involved in the pathophysiology of panic anxiety.
Mervis et al. (2012) found that transgenic mice with 3 or 4 copies of the Gtf2i gene (601679) on chromosome 7q11 showed significantly increased maternal separation-induced anxiety compared to mice with 1 or 2 copies of the Gtf2i gene, as measured by ultrasonic vocalizations. The authors studied this gene specifically after observing that patients with Williams-Beuren (WBS) duplication syndrome (609757) had significantly higher levels of separation anxiety compared to patients with WBS (194050) and to the general population. The GTF2I gene lies within the WBS critical region.
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