anxiety disorder genetics


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(Updated 7/10/05)

Jiang X, Xu K, Hoberman J, Tian F, Marko AJ, Waheed JF, Harris CR, Marini AM, Enoch MA, Lipsky RH
BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects.
Neuropsychopharmacology. 2005 Jul;30(7):1353-61.
The brain-derived neurotrophic factor (BDNF) gene is critical for neuronal function and survival, and is likely to be important in psychiatric disorders. In this study, we used single-nucleotide polymorphism (SNP) discovery, functional analyses, and genetic association studies to better understand the potential role of BDNF sequence variation in behavior. Screening 480 unrelated individuals for SNPs and genotyping was performed in US Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) was administered to measure anxious temperament (harm avoidance (HA)) and novelty seeking (NS). A novel SNP (-281 C>A) in promoter 1 was discovered that had decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281 A allele was 0.03 in a Caucasian sample, but was virtually absent in other populations. Association analyses in a community-based sample showed that individuals with the -281 A allele (13 heterozygotes) had lower TPQ HA (F=4.8, p<0.05). In contrast, the Met 66 allele was associated with increased HA (F=4.1, p=0.02) and was most abundant in individuals with both anxiety disorders and major depression (p<0.05). Among the Val66Val homozygotes, individuals who were -281 CA heterozygotes had significantly lower HA than the -281 CC homozygotes (p<0.01). Our results suggest that in this population, the low activity -281 A allele may be protective against anxiety and psychiatric morbidity, whereas Met 66 may be a risk allele. [Abstract]

Tiemeier H, Schuit SC, den Heijer T, van Meurs JB, van Tuijl HR, Hofman A, Breteler MM, Pols HA, Uitterlinden AG
Estrogen receptor alpha gene polymorphisms and anxiety disorder in an elderly population.
Mol Psychiatry. 2005 Jun 7; [Abstract]

Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Moller HJ, Dahmen N.
Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression.
Am J Med Genet 2003 Feb 15;117B(1):1-6
"This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over-represented in patients suffering from GAD (chi(2) = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior." [Abstract]

Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepie? G, Grzywacz A, Kucharska-Mazur J
Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum.
Psychiatry Res. 2004 Aug 30;128(1):21-6.
Recent studies provide evidence that anxiety disorders may be linked to malfunction of serotonin neurotransmission or impaired activity of enzymes metabolising the catecholamines. Functional polymorphisms in the MAO-A uVNTR promoter gene, the COMT gene (Val158Met) exon 4, and the 5-HTT promoter gene (44 bp ins/del) were investigated in 101 patients with phobic disorders of the anxiety spectrum and 202 controls matched to the patients for sex, age and ethnicity. There were no significant differences between controls and patients in the allele and genotype frequencies of the 5-HTT and COMT gene polymorphisms. The frequency of >3 repeat alleles of the MAO-A gene polymorphism was significantly higher in female patients suffering from anxiety disorders, specifically panic attacks and generalized anxiety disorder. There was also a trend for the more frequent presence of >3 repeat alleles in female patients with agoraphobia and specific phobia, in contrast to female patients with social phobia, who did not differ from controls. The results support a possible role of the MAO-A gene in anxiety disorders. [Abstract]

Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H, Lindal E, Gagunashvili N, Frigge ML, Kong A, Stefansson K, Gulcher JR.
Anxiety with panic disorder linked to chromosome 9q in iceland.
Am J Hum Genet 2003 May;72(5):1221-30
"The results of a genomewide scan for genes conferring susceptibility to anxiety disorders in the Icelandic population are described. The aim of the study was to locate genes that predispose to anxiety by utilizing the extensive genealogical records and the relative homogeneity of the Icelandic population. Participants were recruited in two stages: (1) Initial case-identification by a population screening for anxiety disorders, using the Stamm Screening Questionnaire, was followed by aggregation into extended families, with the help of our genealogy database; and (2) those who fulfilled the diagnostic and family aggregation criteria underwent a more detailed diagnostic workup based on the Composite International Diagnostic Interview. Screening for anxiety in close relatives also identified additional affected members within the families. After genotyping was performed with 976 microsatellite markers, affected-only linkage analysis was done, and allele-sharing LOD scores were calculated using the program Allegro. Linkage analysis of 25 extended families, in each of which at least one affected individual had panic disorder (PD), resulted in a LOD score of 4.18 at D9S271, on chromosome 9q31. The intermarker distance was 4.4 cM on average, whereas it was 1.5 cM in the linked region as additional markers were added to increase the information content. The linkage results may be relevant not only to PD but also to anxiety in general, since our linkage study included patients with other forms of anxiety." [Abstract]

Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA, Chadwick LH, White C, Bulzacchelli M, Slaugenhaupt SA.
Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.
Am J Med Genet 2001 Mar 8;105(2):195-206
"Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder." [Abstract]

Manfro GG, Pollack MH, Otto MW, Worthington JJ, Rosenbaum JF, Scott EL, Kradin RL.
Cell-surface expression of L-selectin (CD62L) by blood lymphocytes: correlates with affective parameters and severity of panic disorder.
Depress Anxiety 2000;11(1):31-7
"The surface immune phenotype of peripheral blood lymphocytes (PBL) was examined in 30 patients meeting DSM-III-R criteria for panic disorder and in 10 normal controls by immunostaining and cytofluorimetry. Patients with panic disorder and controls showed comparable numbers of PBL and no differences in the percentages of blood T-cells, B-cells, or NK-cells. The PBL in panic disorder patients showed a trend toward enrichment for "naive" CD45RA+ T-lymphocytes (35.0 +/- 7.6 vs. 28.7 +/- 9.8, P = 0.09) and significant enrichment for cells expressing CD62L (L-selectin, 22.9 +/- 5.9 vs. 14.6 +/- 6.3, P = 0.002), a lymphocyte homing receptor that mediates binding to lymph node endothelium. Increased expression of CD62L correlated directly with the global severity of illness, Hamilton Anxiety (HAM-A) and Hamilton Depression (HAM-D) scores. Although in the normal range, plasma cortisol levels were significantly increased in patients with panic disorder (P = 0.003) with respect to controls and correlated with the expression of CD62L by PBL. We conclude that the peripheral blood in panic disorder shows phenotypic changes that may reflect diminished cell activation in vivo." [Abstract]

OMIM - Online Mendelian Inheritance in Man: Lymphocyte adhesion molecule-1 (CD62L)

Fehr C, Schleicher A, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N.
Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy.
Prog Neuropsychopharmacol Biol Psychiatry 2001 Jul;25(5):965-82
"1. Alterations in the serotonergic neurotransmission have been frequently described for patients suffering from alcoholism, anxiety disorders and narcolepsy. 2. The authors tested for association of the 5-HT2A receptor polymorphism (T102C) and the intron 7 tryptophan hydroxylase (TPH) polymorphism (A218C) among 176 alcohol dependent patients, 35 patients with panic disorder, 50 patients with generalized anxiety disorder, 55 patients with narcolepsy and 87 healthy controls. 3. Allele and genotype frequencies of the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH polymorphism (A218C) were almost similar between the patients suffering from alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy. 4. There was no association between the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH (A218C) polymorphisms and alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy in our subsets of German patients." [Abstract]

Fehr C, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N.
Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study.
Psychiatr Genet 2000 Jun;10(2):59-65
"Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide 68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5-HT2C receptors and an increased production of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and normal healthy volunteers for the 5-HT2C Cys23Ser polymorphism. 5-HT2C Cys23Ser allele frequencies and genotypes did not differ among patients with alcohol dependence, panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers. In an overall analysis, female subjects (n = 173) displayed a higher frequency of 5-HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential mechanisms of the observed gender difference in allele frequencies, including transmission ratio distortion, are discussed." [Abstract]

Fehr C, Grintschuk N, Szegedi A, Anghelescu I, Klawe C, Singer P, Hiemke C, Dahmen N.
The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy.
Psychiatry Res 2000 Dec 4;97(1):1-10
"The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al. , Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (chi(2)=4.02, d.f.=2, P=0.04). However, the association resulted from higher frequencies of the opposite alleles (HTR1B 861G), as originally reported by Lappalainen et al. (1998). Although the association in our study might be due to a type I error, the higher degree of HTR1B allele sharing within both populations could also argue for another alcoholism-relevant gene within the proximity of the HTR1B gene on human chromosome 6." [Abstract]

Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal S.
Association of a functional polymorphism of the monoamine oxidase A gene promoter with personality and psychiatric symptoms.
Psychiatr Genet 2000 Jun;10(2):87-90
"A functional polymorphism in the promoter of the monoamine oxidase gene has recently been described by Sabol et al. This polymorphism is a strong candidate for associations with personality traits and psychiatric symptoms. We report relevant data from a general population sample of 850 Caucasian Australians. We found no associations with anxiety and depression symptoms, with personality traits that predispose to anxiety (neuroticism, behavioral inhibition, negative affect) or to a personality trait related to antisocial behavior (psychoticism)." [Abstract]

Enoch MA, Xu K, Ferro E, Harris CR, Goldman D.
Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism.
Psychiatr Genet. 2003 Mar;13(1):33-41.
"OBJECTIVE Women are more prone to anxiety than men. The catechol- -methyltransferase functional polymorphism, Val158Met, is likely to be implicated in anxiety vulnerability. We hypothesized that, particularly in women, the low-activity Met158 allele would be associated with higher anxiety scores and a biological trait, low-voltage alpha resting electroencephalogram (EEG), previously associated with alcoholism and anxiety disorders.METHODS DNA was obtained from two independent groups of participants ascertained as community samples: 149 predominantly Caucasian individuals (92 women, 57 men), and 252 Plains American Indians (149 women, 103 men). Dimensional measures of anxiety (Tridimensional Personality Questionnaire harm avoidance subscales HA1 and HA2) were obtained and DSM-III-R lifetime psychiatric diagnoses were determined. EEGs were recorded and EEG phenotypes assigned.RESULT In both populations, women showed significant associations between catechol- -methyltransferase genotype and elevated harm avoidance scores, and the Met158/Met158 genotype was most strongly associated: predominantly Caucasian participants: HA1, =0.03, HA2, =0.03; and Plains American Indians: HA2, =0.01. This was also the case with low-voltage alpha resting EEG: predominantly Caucasian participants: =0.01, odds ratio=5.0 (95% confidence interval, 1.3-18.7); Plains American Indians: =0.03, odds ratio=3.7 (95% confidence interval, 1.1-12.7).CONCLUSIONS The results of the present study suggest that an inherited difference in catecholamine metabolism is important in the pathogenesis of anxiety in women." [Abstract]

Gelernter J, Page GP, Stein MB, Woods SW
Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus.
Am J Psychiatry. 2004 Jan;161(1):59-66.
OBJECTIVE: Social phobia is a common, sometimes disabling, fear of situations that might entail scrutiny by others. Several anxiety disorders, including social phobia, are genetically influenced. Genetic linkage analysis can provide the means to identify genomic locations harboring susceptibility loci for genetically influenced disorders. Identifying loci for social phobia was the goal of this study. METHOD: The authors conducted a genome-wide linkage scan, i.e., tested enough genetic markers to query the entire genome, in 17 American pedigrees (163 subjects) ascertained through probands with panic disorder. Several anxiety disorders segregate in these families; diagnoses were based on structured interviews. A total of 422 markers (404 autosomal, 18 on the X chromosome) with an average spacing of less than 10 centimorgans were genotyped. Multipoint lod score and nonparametric (Zlr score) linkage analyses for social phobia were completed with Allegro and Genehunter X software. RESULTS: Evidence for linkage to social phobia for chromosome 16 markers was identified. A Zlr score of 3.41 was observed for chromosome 16 near marker D16S415. The maximum observed lod score was 2.22, also for chromosome 16, between D16S415 and D16S503 (under a model of recessive inheritance). Additional areas of interest were identified on chromosomes 9, 14, and 18. CONCLUSIONS: These findings meet conservative criteria for "suggestive" linkage. The gene encoding the norepinephrine transporter protein (SLC6A2) maps to this broad region, making SLC6A2 both a positional and physiological candidate for influencing social phobia risk. To the authors' knowledge, this is the first complete linkage genome scan for this disorder. [Abstract]

Peroutka SJ, Price SC, Wilhoit TL, Jones KW.
Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles.
Mol Med 1998 Jan;4(1):14-21
"BACKGROUND: Unrelated individuals (n = 242) were interviewed directly for the presence of migraine, anxiety disorders, and major depression. MATERIALS AND METHODS: The data described in this study are derived from a clinical genetic relational database that was developed initially for the genetic analysis of migraine. Genotyping of the DRD2 NcoI C to T polymorphism located in exon 6 (His313His) was performed using previously described primers. RESULTS: A significantly increased incidence of migraine with aura (MWA), major depression, generalized anxiety disorder (GAD), panic attacks, and phobia was observed in individuals with the DRD2 NcoI C/C genotype compared with individuals with an DRD2 NcoI T allele. Specifically, 69% (91/131) of DRD2 NcoI C/C individuals in the present study met criteria for at least one of these neuropsychiatric disorders versus only 22% (4/18) of the DRD2 NcoI T/T individuals (Chi-square = 15.29; p < 0.00005). The DRD2 NcoI C allele frequency is significantly higher (Chi-square = 17.13; p < 0.00002) in individuals with MWA, anxiety disorders, and/or major depression (C allele frequency = 0.80) than in individuals who have none of these disorders (C allele frequency = 0.67). CONCLUSIONS: These data indicate that MWA, anxiety disorders, and major depression can be components of a distinct clinical syndrome associated with allelic variations within the DRD2 gene. Clinical recognition of this genetically based syndrome has significant diagnostic and therapeutic implications." [Abstract]

Henrichsen CN, Delorme R, Boucherie M, Marelli D, Baud P, Bellivier F, Courtet P, Chabane N, Henry C, Leboyer M, Malafosse A, Antonarakis SE, Dahoun S
No association between DUP25 and anxiety disorders.
Am J Med Genet B Neuropsychiatr Genet. 2004 Jul 1;128(1):80-3.
Gratacos et al. [2001: Cell 106:367-379] described an interstitial duplication dup(15)q24q26 (DUP25) in patients with anxiety disorders; this duplication was found in approximately 90% of patients and in 7% of controls. In order to determine if DUP25 is present in additional individuals susceptible to panic attacks, we tested 44 patients with anxiety disorders, using probes 251c23 and 216c14 mapping in the 15q24 and 15q26 region. We have not detected any DUP25. Our results suggest that DUP25 is not common in people with anxiety disorders in the population tested here. [Abstract]

Schumacher J, Otte AC, Becker T, Sun Y, Wienker TF, Wirth B, Franke P, Abou Jamra R, Propping P, Deckert J, Nöthen MM, Cichon S
No evidence for DUP25 in patients with panic disorder using a quantitative real-time PCR approach.
Hum Genet. 2003 Dec;114(1):115-7.
A duplication of chromosome 15q24-q26 (DUP25) has been reported to be associated with anxiety disorders. We tested for the presence of DUP25 in a sample of 50 patients with panic disorder and 50 controls using a quantitative real-time PCR approach. Contrary to the original finding, our results were compatible with the absence of DUP25, and no significant difference could be detected between patients and controls ( P=1.0). Thus, our study does not support the hypothesis of an involvement of DUP25 in panic disorder. [Abstract]

Hettema JM, Neale MC, Kendler KS.
A review and meta-analysis of the genetic epidemiology of anxiety disorders.
Am J Psychiatry 2001 Oct;158(10):1568-78
"OBJECTIVE: The authors conducted meta-analyses of data from family and twin studies of panic disorder, generalized anxiety disorder, phobias, and obsessive-compulsive disorder (OCD) to explore the roles of genetic and environmental factors in their etiology. METHOD: MEDLINE searches were performed to identify potential primary studies of these disorders. Data from studies that met inclusion criteria were incorporated into meta-analyses that estimated summary statistics of aggregate familial risk and heritability for each disorder. RESULTS: For family studies, odds ratios predicting association of illness in first-degree relatives with affection status of the proband (disorder present or absent) were homogeneous across studies for all disorders. The calculated summary odds ratios ranged from 4 to 6, depending on the disorder. Only for panic disorder and generalized anxiety disorder could the authors identify more than one large-scale twin study for meta-analysis. These yielded heritabilities of 0.43 for panic disorder and 0.32 for generalized anxiety disorder. For panic disorder, the remaining variance in liability could be attributed primarily to nonshared environment. For generalized anxiety disorder, this was true for men, but for women, a potentially significant role for common familial environment was also seen. CONCLUSIONS: Panic disorder, generalized anxiety disorder, phobias, and OCD all have significant familial aggregation. For panic disorder, generalized anxiety disorder, and probably phobias, genes largely explain this familial aggregation; the role of family environment in generalized anxiety disorder is uncertain. The role of nonshared environmental experience is significant, underscoring the importance of identifying putative environmental risk factors that predispose individuals to anxiety." [Abstract]

Hettema JM, Prescott CA, Kendler KS.
A population-based twin study of generalized anxiety disorder in men and women.
J Nerv Ment Dis 2001 Jul;189(7):413-20
"This study aimed to a) assess whether genetic or environmental effects are of similar magnitude in the etiology of GAD in men and women, and b) investigate whether familial (genetic or common environmental) risk factors are the same in men and women, or whether there are gender-specific effects. We obtained a lifetime history of DSM-IIII-R GAD, via face-to-face and telephone interviews, from 3100 complete male-male, female-female, and male-female twin pairs, ascertained through a population-based registry. Biometrical twin modeling was utilized to estimate the relative contributions of genetic and environmental factors to liability for GAD, allowing for gender-specific effects. The familial aggregation of GAD in this sample was only modest. In the best-fitting models, the heritability of GAD was the same in men and women, estimated at about 15% to 20%, with no effects of gender-specific genes detected." [Abstract]

Middeldorp CM, Cath DC, Van Dyck R, Boomsma DI
The co-morbidity of anxiety and depression in the perspective of genetic epidemiology. A review of twin and family studies.
Psychol Med. 2005 May;35(5):611-24.
BACKGROUND: Co-morbidity within anxiety disorders, and between anxiety disorders and depression, is common. According to the theory of Gray and McNaughton, this co-morbidity is caused by recursive interconnections linking the brain regions involved in fear, anxiety and panic and by heritable personality traits such as neuroticism. In other words, co-morbidity can be explained by one disorder being an epiphenomenon of the other and by a partly shared genetic etiology. The aim of this paper is to evaluate the theory of Gray and McNaughton using the results of genetic epidemiological studies. METHOD: Twenty-three twin studies and 12 family studies on co-morbidity are reviewed. To compare the outcomes systematically, genetic and environmental correlations between disorders are calculated for the twin studies and the results from the family studies are summarized according to the method of Klein and Riso. RESULTS: Twin studies show that co-morbidity within anxiety disorders and between anxiety disorders and depression is explained by a shared genetic vulnerability for both disorders. Some family studies support this conclusion, but others suggest that co-morbidity is due to one disorder being an epiphenomenon of the other. CONCLUSIONS: Discrepancies between the twin and family studies seem partly due to differences in used methodology. The theory of Gray and McNaughton that neuroticism is a shared risk factor for anxiety and depression is supported. Further research should reveal the role of recursive interconnections linking brain regions. A model is proposed to simultaneously investigate the influence of neuroticism and recursive interconnections on co-morbidity. [Abstract]

Gordon JA, Hen R
Genetic approaches to the study of anxiety.
Annu Rev Neurosci. 2004;27193-222.
Anxiety and its disorders have long been known to be familial. Recently, genetic approaches have been used to clarify the role of heredity in the development of anxiety and to probe its neurobiological underpinnings. Twin studies have shown that a significant proportion of the liability to develop any given anxiety disorder is due to genetic factors. Ongoing efforts to map anxiety-related loci in both animals and humans are underway with limited success to date. Animal models have played a large role in furthering our understanding of the genetic basis of anxiety, demonstrating that the genetic factors underlying anxiety are complex and varied. Recent advances in molecular genetic techniques have allowed increasing specificity in the manipulation of gene expression within the central nervous system of the mouse. With this increasing specificity has come the ability to ask and answer precise questions about the mechanisms of anxiety and its treatment. [Abstract]

Schoevers RA, Deeg DJ, van Tilburg W, Beekman AT
Depression and generalized anxiety disorder: co-occurrence and longitudinal patterns in elderly patients.
Am J Geriatr Psychiatry. 2005 Jan;13(1):31-9.
OBJECTIVE: The authors sought to establish the natural course and risk-profile of depression, generalized anxiety disorder (GAD), and depression with co-existing GAD in later life. METHODS: A total of 2,173 community-living elderly persons were interviewed at baseline, and at a 3-year follow-up. The course of "pure" depression, "pure" GAD, and depression with coexisting GAD was studied in 258 subjects with baseline psychopathology. Authors assessed bivariate and multivariate relationships between risk factors and course types. The risk-profile for onset of pure depression, pure GAD, and the mixed condition at follow-up was studied in 1,915 subjects without baseline psychopathology. RESULTS: Remission rate at follow-up was 41% for subjects with depression-only, 48% for pure GAD, and significantly lower (27%) for depression with coexisting GAD. A pattern of temporal sequencing was established, with anxiety often progressing to depression or depression with GAD. Onset of pure depression and depression with co-existing GAD was predicted by loss events, ill health, and functional disability. Onset of pure GAD, and, more strongly, that of depression with coexisting GAD, was associated with longstanding, possibly genetic vulnerability. CONCLUSIONS: In comparison with either depression-only or anxiety-only, the co-occurrence of these represents more severe and more chronic psychopathology, associated with longstanding vulnerability. In elderly persons, GAD often progresses to depression or to the mixed condition. These findings mostly favor a dimensional, rather than a categorical, classification of anxiety and depression. [Abstract]

Kendler KS.
Major depression and generalised anxiety disorder. Same genes, (partly)different environments--revisited.
Br J Psychiatry Suppl 1996 Jun;(30):68-75
"In both clinical and epidemiological samples, major depression (MD) and generalised anxiety disorder (GAD) display substantial comorbidity. In a prior analysis of lifetime MD and GAD in female twins, the same genetic factors were shown to influence the liability to MD and to GAD. A follow-up interview in the same twin cohort examined one-year prevalence for MD and GAD (diagnosed using a one-month minimum duration of illness). Bivariate twin models were fitted using the program Mx. High levels of comorbidity were observed between MD and GAD. The best-fitting twin models, when GAD was diagnosed with or without a diagnostic hierarchy, found a genetic correlation of unity between the two disorders. The correlation in environmental risk factors was +0.70 when GAD was diagnosed non-hierarchically, but zero when hierarchical diagnoses were used. Our findings provide further support for the hypothesis that in women, MD and GAD are the result of the same genetic factors. Environmental risk factors that predispose to 'pure' GAD episodes may be relatively distinct from those that increase risk for MD."

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.
Major depression and generalized anxiety disorder. Same genes, (partly) different environments?
Arch Gen Psychiatry 1992 Sep;49(9):716-22 [Abstract]

Camp NJ, Lowry MR, Richards RL, Plenk AM, Carter C, Hensel CH, Abkevich V, Skolnick MH, Shattuck D, Rowe KG, Hughes DC, Cannon-Albright LA
Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders.
Am J Med Genet B Neuropsychiatr Genet. 2005 May 5;135(1):85-93.
Major depressive disorder (MDD) is a common, clinically heterogeneous disorder often found comorbid with other disorders. We studied recurrent, early-onset MDD (MDD-RE) and anxiety disorders in combination to define powerful phenotypes for genetic study. We used 87 large, extended Utah pedigrees to investigate linkage to 3 phenotypes: "MDD-RE;" "MDD-RE or anxiety;" and "MDD-RE and anxiety;" where in the latter definition the disorders must appear comorbid within an individual. Pedigrees ranged in size from 2 to 6 generations and contained 3 to 42 individuals affected with MDD or anxiety (718 total). In primary analyses, we identified three regions with at least suggestive genome-wide evidence for linkage on chromosomes 3centr, 7p, and 18q. Both 7p and 18q are replication findings for related phenotypes. The best linkage evidence was for a novel locus at 3p12.3-q12.3 (LOD = 3.88, "MDD-RE or anxiety") and 18q21.33-q22.2 (LOD = 3.75, "MDD-RE and anxiety"), a well-established susceptibility locus for bipolar disorder. In our secondary sex-specific analyses, we identified two further regions of interest on chromosomes 4q and 15q. Using linked pedigrees, we localized 3centr and 18q to 9.8 and 12.2 cM, respectively, with potential for further localization with the addition of markers in specific pedigrees. Our success in replication and novel locus identification illustrates the utility of large extended pedigrees for common disorders, such as MDD. Further, it supports the hypothesis that MDD and anxiety disorders have over-lapping genetic etiologies and suggests that comorbid diagnoses may be useful in defining more genetically homogeneous forms of MDD for linkage mapping. [Abstract]

Nash MW, Sugden K, Huezo-Diaz P, Williamson R, Sterne A, Purcell S, Sham PC, Craig IW
Association analysis of monoamine genes with measures of depression and anxiety in a selected community sample of siblings.
Am J Med Genet B Neuropsychiatr Genet. 2005 May 5;135(1):33-7.
Evidence indicates the genetic susceptibility to depression and anxiety is both overlapping and dimensional. In the current study, a quantitative phenotype had been created from several depression and anxiety-related measures in order to index this common genetic susceptibility (G). This has been studied in 119 sibships comprising 312 individuals, selected for extreme scores on G, from a community-based sample of 34,371 individuals. In a pathway based candidate gene study, we examined five microsatellite markers located within or nearby to five serotonin system genes (5HT2C, 5HT1D, 5HT1B, TPH1, and MAOB). Statistical analysis, carried out using QTDT, gave a significant association with a microsatellite downstream of TPH1. Further analysis included a life-events composite as a co-variable, this lead to a stronger association of TPH1. To our knowledge, this is the first study to report an association of the 3' end of TPH1 with continuous measures of depression and anxiety. [Abstract]

You JS, Hu SY, Chen B, Zhang HG
Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder.
Psychiatr Genet. 2005 Mar;15(1):7-11.
BACKGROUND: The serotonin transporter (5-HTT) and tryptophan hydroxylase (TPH) gene are important candidate genes for the psychiatric disorders. Many studies of patients with anxiety disorders have found abnormalities of serotonin metabolism and dysfunction of regulation in the transporter itself. In this study, we hypothesize that genetic variation in the 5-HTT and TPH gene may have an effect on the etiology of generalized anxiety disorder (GAD). METHODS: Using a polymerase chain reaction-based technique, the allele and genotype frequencies of three polymorphisms in the serotonin transporter gene (a deletion/insertion polymorphism in the transcriptional control region and a variable number of tandem repeats in intron 2) and TPH gene (A218C in intron 7) were analyzed in 138 patients with GAD and 90 healthy controls. These two groups were matched for ethnic and geographic origin. RESULTS: The frequencies of 5-HTT gene-linked functional polymorphic region (5-HTTLPR) SS (short/short) genotype were significantly higher in GAD patients than in control subjects (68% versus 49%, chi = 12.274, df = 2, P = 0.002), and the frequencies of S (short) allele observed in the GAD patients were higher than those in healthy subjects (79 versus 71%, chi = 4.063, df = 1, P = 0.044). The odds ratio for the SS genotype versus the other two genotypes was 2.33 (95% confidence interval, 1.29-3.86). Similarly, the odds ratio for the S allele versus L allele was 1.56 (95% confidence interval, 1.01-2.41). The genotypic and allelic distribution of 5-HTT VNTR and TPH A218C polymorphisms did not show statistically significant differences between patients and controls. CONCLUSION: Our findings support that the presence of 5-HTTLPR-SS genotype may increase the risk of GAD. [Abstract]

Sun HS, Tsai HW, Ko HC, Chang FM, Yeh TL
Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population-based sample of postpartum Taiwanese women.
Genes Brain Behav. 2004 Dec;3(6):328-36.
Depression and anxiety disorders often coexist clinically and both are known to have a genetic basis, but the mode of inheritance is too complicated to be determined so far. Serotonin is the biogenic amine neurotransmitter most commonly associated with depression and anxiety. Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied. In this study, we examined whether polymorphism of the TPH1 gene is related to the etiology of major depression, anxiety and comorbid depression and anxiety. Five single nucleoside polymorphisms of the TPH1 gene were studied in a population-based sample of postpartum Taiwanese women consisting of 120 subjects with depression or/and anxiety and 86 matched normal controls. A significant difference (P = 0.0107) in genotype frequency for the T27224C polymorphism was found between the comorbid and normal groups, and risk analysis showed that the C allele conferred a strong protective effect (odds ratio = 0.27; 95% confident interval = 0.11-0.7). Three-allele haplotypes involving T27224C polymorphism were constructed and haplotype associations between particular haplotype combinations and various diseases identified. However, the associations were weak and the overall haplotype frequency profiles in all groups were similar. The results suggest that depression, anxiety, and comorbid depression and anxiety disorders may have related etiologies. In addition, this study suggests that the TPH1 gene might play a role in the pathogenesis of these closely related disorders. [Abstract]

Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal S.
An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms.
Mol Psychiatry 1998 Sep;3(5):449-51
"A functional polymorphism in the regulatory region of the serotonin transporter gene has been reported to be associated with anxiety-related personality traits. We attempted to replicate this finding in an association study involving 759 Caucasians selected from the general Australian population. We found no associations with personality traits (including neuroticism, negative affect and behavioral inhibition), anxiety and depressive symptoms, or alcohol misuse." [Abstract]

Ohara K, Suzuki Y, Ochiai M, Tsukamoto T, Tani K, Ohara K.
A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders.
Prog Neuropsychopharmacol Biol Psychiatry 1999 Jan;23(1):55-65
"1. A polymorphism of the variable-number-tandem-repeat (VNTR) in the second intron of the serotonin transporter (ST) gene, which has been reported to be associated with major depression, was studied in anxiety disorders. 2. The VNTR of the human ST gene was compared between 103 patients with anxiety and 106 controls. 3. The frequency of the allele containing 12 copies of the VNTR element (STin2.12) was significantly higher in the combined patient group (p = 0.027), and among patients with OCD (p = 0.0326), and GAD (p = 0.0123), in comparison with in controls. 4. The presence of the STin2.12 allele was significantly associated with the risk of combined anxiety disorders (odds ratio = 2.06, 95% CI 1.09-3.90), OCD (10.2, 1.34-77.4), and GAD (3.61, 1.23-10.6)." [Abstract]

Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS
The structure of genetic and environmental risk factors for anxiety disorders in men and women.
Arch Gen Psychiatry. 2005 Feb;62(2):182-9.
BACKGROUND: The anxiety disorders exhibit high levels of lifetime comorbidity with one another. Understanding the underlying causes of this comorbidity can provide insight into the etiology of the disorders and inform classification and treatment. OBJECTIVE: To explain anxiety disorder comorbidity by examining the structure of the underlying genetic and environmental risk factors. DESIGN: Lifetime diagnoses for 6 anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, and situational phobia) were obtained during personal interviews from a population-based twin registry. Multivariate structural equation modeling that allowed for sex differences was performed. SETTING: General community sample. PARTICIPANTS: More than 5000 members of male-male and female-female twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURES: Parameter estimates for best-fitting model. RESULTS: The full model, which contained 2 common genetic, shared environmental, and unique environmental factors plus disorder-specific factors, could be constrained to equality across male and female study participants. In the best-fitting model, the genetic influences on anxiety were best explained by 2 additive genetic factors common across the disorders. The first loaded most strongly in generalized anxiety disorder, panic disorder, and agoraphobia, whereas the second loaded primarily in the 2 specific phobias. Social phobia was intermediate in that it was influenced by both genetic factors. A small role for shared environmental influences was observed owing to a single common factor that accounted for less than 12% of the total variance for any disorder. Unique environmental influences could be explained by a single common factor plus disorder-specific effects. CONCLUSIONS: The underlying structure of the genetic and environmental risk factors for the anxiety disorders is similar between men and women. Genes predispose to 2 broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety vs the specific phobias. The remaining associations between the disorders are largely explained by a unique environmental factor shared across the disorders and, to a lesser extent, a common shared environmental factor. [Abstract]

Gorwood PH.
[Is anxiety hereditary?]
Encephale 1998 May-Jun;24(3):252-5
"The role of genetic factors in anxiety disorders is yet unknown, although their is a clear familial aggregation, and although twin studies found genetic factors to be at least as important as familial factors for some anxiety disorders such as panic disorder or phobias. In this review, the complexity of genetic studies on anxiety disorders are presented. The problem of incomplete penetrance (only a fraction of cases carrying a given gene manifest a specified phenotype) is illustrated by familial studies on some stress disorder, such as post-traumatic stress disorder. The presence of a severe stress is necessary to be able to manifest the disorder, familial studies on PTSD should thus use analysis with censored data. Questions concerning phenotype specificities are also raised. For exemple, on the basis of twin samples, generalised anxiety disorder and separation anxiety disorder seem to share most of their genetic determinism. Furthermore, more major depressive disorders are found in families of probands with generalised anxiety disorder, suggesting commun vulnerability factors for some of anxiety and mood disorders. Lastly, as standardised diagnostic criteria are much more based on clinical evidence than on etiopathogenic validity, genetic factors may be involved in various bounderies of the phenotype, for example taking into account level of severity, age at onset, or comorbidity. Some of the association studies in humans, analysing the impact of genetic polymorphisms on the existence of anxiety disorders, were either negative or showed week evidence for commun traits such as nevroticism. For animal studies, quantitative trait loci technics may help to pinpoint some still unknown candidate genes. In conclusion, the genetics of anxiety disorders reflect all the difficulties proper to the genetics of complex disorders. Progress in molecular genetics will nevertheless probably change the diagnostic criteria, which are more based on clinical evidence rather than on etiological originality." [Abstract]

Ohara K, Suzuki Y, Ochiai M, Yoshida K, Ohara K.
Age of onset anticipation in anxiety disorders.
Psychiatry Res 1999 Dec 27;89(3):215-21
"Anticipation, an increase in severity or a decrease in the age of onset inherent in the transmission of a disease gene from an affected parent to a child, is being increasingly described in human diseases. In this study we searched for possible anticipation in anxiety disorders. Seventeen unilineal families who had anxiety disorders were compared across two successive generations as to age at the onset of anxiety disorders. Life table analyses revealed a significant decrease in the onset of anxiety disorders from older to younger generations. No evidence of a difference in the type of anxiety disorder was found. Anticipation was thus found in families with anxiety disorders and, if it is confirmed by other studies, trinucleotide repeat sequences may be considered to account for the familial aggregation of anxiety disorders." [Abstract]


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Recent Anxiety Disorder Genetic Research

1) Lau JY, Hilbert K, Goodman R, Gregory AM, Pine DS, Viding EM, Eley TC
Investigating the genetic and environmental bases of biases in threat recognition and avoidance in children with anxiety problems.
Biol Mood Anxiety Disord. 2012 Jul 12;2(1):12.
ABSTRACT: BACKGROUND: Adults with anxiety show biased categorization and avoidance of threats. Such biases mayemerge through complex interplay between genetics and environments, occurring early inlife. Research on threat biases in children has focuses on a restricted range of biases, withinsufficient focus on genetic and environmental origins. Here, we explore differencesbetween children with and without anxiety problems in under-studied areas of threat bias. We focused both on associations with anxious phenotype and the underlying gene-environmentalcorrelates for two specific processes: the categorisation of threat faces and avoidancelearning. METHOD: Two-hundred and fifty 10-year old MZ and DZ twin pairs (500 individuals) completed tasksassessing accuracy in the labelling of threatening facial expressions and in the acquisition ofavoidant responses to a card associated with a masked threatening face. To assess whetherparticipants met criteria for an anxiety disorder, parents of twins completed a self-guidedcomputerized version of the Development and Well-being Assessment (DAWBA).Comparison of MZ and DZ twin correlations using model-fitting were used to computeestimates of genetic, shared and non-shared environmental effects. RESULTS: Of the 500 twins assessed, 25 (5%) met diagnostic criteria for a current anxiety disorder.Children with anxiety disorders were more accurate in their ability to recognize disgust facesthan those without anxiety disorders, but were commensurate on identifying other threateningface emotions (angry, fearful, sad). Children with anxiety disorders but also more stronglyavoided selecting a conditioned stimulus than non-anxious children. While recognition ofsocially threatening faces was moderately heritable, avoidant responses were heavilyinfluenced by the non-shared environment. CONCLUSION: These data add to other findings on threat biases in anxious children. Specifically, we foundbiases in the labelling of some negative-valence faces and in the acquisition of avoidantresponses. While non-shared environmental effects explained all of the variance on threatavoidance, some of this may be due to measurement error. [PubMed Citation] [Order full text from Infotrieve]

2) Lenze EJ, Dixon D, Nowotny P, Lotrich FE, Doré PM, Pollock BG, Hinrichs AL, Butters MA
Escitalopram reduces attentional performance in anxious older adults with high-expression genetic variants at serotonin 2A and 1B receptors.
Int J Neuropsychopharmacol. 2012 Apr 17;:1-10.
Older adults are among the most vulnerable to adverse cognitive effects of psychotropic medications and, therefore, the personalization of psychotropic treatment based on adverse drug reactions in this demographic is of great importance. We examined changes on neuropsychological tests of attention attributable to selective serotonin reuptake inhibitor (SSRI) treatment in anxious older adults. We also examined whether variation in serotonin receptor genes was associated with reduced attentional performance with SSRIs. We examined change from pre- to post-treatment in two attention measures - digit span and coding - in 133 adults aged ?60 yr with generalized anxiety disorder in a 12-wk trial of escitalopram vs. placebo. We also examined attentional change in relation to genetic variability in four central serotonin receptors: the serotonin transporter and serotonin 1A, 2A and 1B receptors. Digit span scores were significantly lowered in patients receiving escitalopram relative to placebo, indicating reduced attentional performance attributable to the SSRI. Individuals with high-transcription variants in the receptors 5-HTR2A rs6311 and 5-HTR1B rs11568817 had greater reductions in attention with SSRI treatment compared to placebo. We conclude that SSRIs reduce attention in older adults, particularly in those with high-expression genetic variants at the serotonin 2A and 1B receptors. Analysing neuropsychological changes with SSRIs in relation to genetic variation in the serotonin system may be a useful strategy for detecting subgroups of older adults who are more susceptible to side-effects of SSRIs. These results, if confirmed, could lead to the personalization of SSRI use to reduce adverse neurocognitive effects. [PubMed Citation] [Order full text from Infotrieve]

3) Mervis CB, Dida J, Lam E, Crawford-Zelli NA, Young EJ, Henderson DR, Onay T, Morris CA, Woodruff-Borden J, Yeomans J, Osborne LR
Duplication of GTF2I Results in Separation Anxiety in Mice and Humans.
Am J Hum Genet. 2012 Jun 8;90(6):1064-70.
Duplication (dup7q11.23) and deletion (Williams syndrome) of chromosomal region 7q11.23 cause neurodevelopmental disorders with contrasting anxiety phenotypes. We found that 30% of 4- to 12-year-olds with dup7q11.23 but fewer than 5% of children with WS or in the general population met diagnostic criteria for a separation-anxiety disorder. To address the role of one commonly duplicated or deleted gene in separation anxiety, we compared mice that had varying numbers of Gtf2i copies. Relative to mouse pups with one or two Gtf2i copies, pups with additional Gtf2i copies showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. This study links the copy number of a single gene from 7q11.23 to separation anxiety in both mice and humans, highlighting the utility of mouse models in dissecting specific gene functions for genomic disorders that span many genes. This study also offers insight into molecular separation-anxiety pathways that might enable the development of targeted therapeutics. [PubMed Citation] [Order full text from Infotrieve]

4) Barbano RL, Hill DF, Snively BM, Light LS, Boggs N, McCall WV, Stacy M, Ozelius L, Sweadner KJ, Brashear A
New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism.
Parkinsonism Relat Disord. 2012 Jul;18(6):737-41.
[PubMed Citation] [Order full text from Infotrieve]

5) Brüne M
Does the oxytocin receptor polymorphism (rs2254298) confer 'vulnerability' for psychopathology or 'differential susceptibility'? insights from evolution.
BMC Med. 2012;10:38.
ABSTRACT: The diathesis-stress model of psychiatric conditions has recently been challenged by the view that it might be more accurate to speak of 'differential susceptibility' or 'plasticity' genes, rather than one-sidedly focusing on individual vulnerability. That is, the same allelic variation that predisposes to a psychiatric disorder if associated with (developmentally early) environmental adversity may lead to a better-than-average functional outcome in the same domain under thriving (or favourable) environmental conditions. Studies of polymorphic variations of the serotonin transporter gene, the monoamino-oxidase-inhibitor A coding gene or the dopamine D4 receptor gene indicate that the early environment plays a crucial role in the development of favourable versus unfavourable outcomes. Current evidence is limited, however, to establishing a link between genetic variation and behavioural phenotypes. In contrast, little is known about how plasticity may be expressed at the neuroanatomical level as a 'hard-wired' correlate of observable behaviour. The present review article seeks to further strengthen the argument in favour of the differential susceptibility theory by incorporating findings from behavioural and neuroanatomical studies in relation to genetic variation of the oxytocin receptor gene. It is suggested that polymorphic variation at the oxytocin receptor gene (rs2254298) is associated with sociability, amygdala volume and differential risk for psychiatric conditions including autism, depression and anxiety disorder, depending on the quality of early environmental experiences. Seeing genetic variation at the core of developmental plasticity can explain, in contrast to the diathesis-stress perspective, why evolution by natural selection has maintained such 'risk' alleles in the gene pool of a population.Please see related manuscript: [PubMed Citation] [Order full text from Infotrieve]

6) Narasimhan S, Aquino TD, Multani PK, Rickels K, Lohoff FW
Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder.
Psychiatry Res. 2012 Mar 12;
Antidepressant drugs are the preferred choice for the treatment of generalized anxiety disorder (GAD). However, the choice of pharmacotherapy is determined on a trial-and-error basis, as the underlying mechanisms of treatment response are unknown. We examined whether the COMT gene, which has been known to play a role in antidepressant treatment response in major depressive disorder (MDD), has a pharmacogenetic effect in antidepressant treatment response in GAD. In our study, 156 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes were obtained for the COMT functional variant rs4680 (Val158Met) for all patients; however, pharmacogenetic analysis was only conducted for the European American population (n=112). We found no significant association between our primary HAM-A outcome measure and rs4680. However, we did find a nominally significant allelic association (P=0.049, OR=1.98) between this variant and a secondary treatment outcome measure (CGI-I) in our European American population (n=112). Furthermore, we show a slight dominant effect of the A-allele with the CGI-I measure in the European American population (P=0.018, OR=3.26), indicating a possible pharmacogenetic role of rs4680 in antidepressant treatment outcome in GAD. Further studies in a larger population are needed to confirm this effect. [PubMed Citation] [Order full text from Infotrieve]

7) Wang CC, Lung FW
The role of PGC-1 and Apoε4 in insomnia.
Psychiatr Genet. 2012 Apr;22(2):82-7.
[PubMed Citation] [Order full text from Infotrieve]

8) Costa B, Pini S, Abelli M, Gabelloni P, Da Pozzo E, Chelli B, Calugi S, Lari L, Cardini A, Lucacchini A, Cassano GB, Martini C
Role of translocator protein (18 kDa) in adult separation anxiety and attachment style in patients with depression.
Curr Mol Med. 2012 May;12(4):483-7.
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9) Donner J, Sipilä T, Ripatti S, Kananen L, Chen X, Kendler KS, Lönnqvist J, Pirkola S, Hettema JM, Hovatta I
Support for involvement of glutamate decarboxylase 1 and neuropeptide y in anxiety susceptibility.
Am J Med Genet B Neuropsychiatr Genet. 2012 Apr;159B(3):316-27.
Genetic mapping efforts have identified putative susceptibility genes for human anxiety disorders. The most intensively studied genes are involved in neurotransmitter metabolism and signaling or stress response. In addition, neuropeptides and targets of anxiolytics have been examined. It has become apparent that gene?×?environment interactions may explain individual variation in stress resilience and predisposition to mental disorders. We aimed to replicate previous genetic findings in 16 putative anxiety susceptibility genes and further test whether they modulate the risk for developing an anxiety disorder in adulthood after childhood stress exposure. We tested 93 single-nucleotide polymorphisms (SNPs) for genetic association to anxiety disorders in the Finnish population-based Health 2000 sample (282 cases and 575 matched controls). In addition, we examined by logistic regression modeling whether the SNP genotypes modified the effect of the number of self-reported childhood adversities on anxiety disorder risk. The most significant evidence for association was observed in glutamate decarboxylase 1 (GAD1) with phobias (P?=?0.0005). A subsequent meta-analysis (N?=?1985) incorporating previously published findings supported involvement of a single GAD1 risk haplotype in determining susceptibility to a broad range of internalizing disorders (P?=?0.0009). We additionally found that SNPs and haplotypes in neuropeptide Y (NPY) modified the effect of childhood adversities on anxiety susceptibility (P?=?0.003). In conclusion, we provide further support for involvement of mainly GAD1, but also NPY in determining predisposition to anxiety disorders. [PubMed Citation] [Order full text from Infotrieve]

10) Hedman E, Andersson E, Ljótsson B, Andersson G, Andersson E, Schalling M, Lindefors N, Rück C
Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder.
Acta Psychiatr Scand. 2012 Aug;126(2):126-36.
Hedman E, Andersson E, Ljótsson B, Andersson G, Andersson E, Schalling M, Lindefors N, Rück C. Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder (SAD). Objective:? No study has investigated clinical or genetic predictors and moderators of Internet-based cognitive behavior therapy (ICBT) compared with cognitive behavioral group therapy for (CBGT) for SAD. Identification of predictors and moderators is essential to the clinician in deciding which treatment to recommend for whom. We aimed to identify clinical and genetic (5-HTTLPR, COMTval158met, and BDNFval66met) predictors and moderators of ICBT and CBGT. Method:? We performed three types of analyses on data from a sample comprising participants (N?=?126) who had undergone ICBT or CBGT in a randomized controlled trial. Outcomes were i) end state symptom severity, ii) SAD diagnosis, and iii) clinically significant improvement. Results:? The most stable predictors of better treatment response were working full time, having children, less depressive symptoms, higher expectancy of treatment effectiveness, and adhering to treatment. None of the tested gene polymorphisms were associated with treatment outcome. Comorbid general anxiety and depression were moderators meaning that lower levels were associated with a better treatment response in ICBT but not in CBGT. Conclusion:? We conclude that demographic factors, symptom burden, adherence, and expectations may play an important role as predictors of treatment outcome. The investigated gene polymorphisms do not appear to make a difference. [PubMed Citation] [Order full text from Infotrieve]

11) Logue MW, Bauver SR, Knowles JA, Gameroff MJ, Weissman MM, Crowe RR, Fyer AJ, Hamilton SP
Multivariate analysis of anxiety disorders yields further evidence of linkage to chromosomes 4q21 and 7p in panic disorder families.
Am J Med Genet B Neuropsychiatr Genet. 2012 Apr;159B(3):274-80.
Replication has been difficult to achieve in linkage studies of psychiatric disease. Linkage studies of panic disorder have indicated regions of interest on chromosomes 1q, 2p, 2q, 3, 7, 9, 11, 12q13, 12q23, and 15. Few regions have been implicated in more than one study. We examine two samples, the Iowa (IA) and the Columba panic disorder families. We use the fuzzy-clustering method presented by Kaabi et al. [Kaabi et al. (2006); Am J Hum Genet 78: 543-553] to summarize liability to panic disorder, agoraphobia, simple phobia, and social phobia. Kaabi et al. applied this method to the Yale panic disorder linkage families and found evidence of linkage to chromosomes 4q21, 4q32, 7p, and 8. When we apply the same method to the IA families, we obtain overlapping evidence of linkage to chromosomes 4q21 and 7p. Additionally, we find evidence of linkage on chromosomes 1, 5, 6, 16, and 22. The Columbia (CO) data does not indicate linkage to any of the Kaabi et al. peaks, instead implicating chromosomes 2 and 22q11 (2?Mb from COMT). There is some evidence of overlapping linkage between the IA and CO datasets on chromosomes 1 and 14. While use of fuzzy clustering has not produced complete concordance across datasets, it has produced more than previously seen in analyses of panic disorder proper. We conclude that chromosomes 4q21 and 7p should be considered strong candidate regions for panic and fear-associated anxiety disorder loci. More generally, this suggests that analyses including multiple aspects of psychopathology may lead to greater consistency across datasets. [PubMed Citation] [Order full text from Infotrieve]

12) Perlis RH, Fijal B, Dharia S, Houston JP
Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder.
Pharmacogenomics J. 2012 Jan 17;
We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60-120?mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P?0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression-Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin-releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response.The Pharmacogenomics Journal advance online publication, 17 January 2012; doi:10.1038/tpj.2011.62. [PubMed Citation] [Order full text from Infotrieve]

13) Zeitlin R, Patel S, Solomon R, Tran J, Weeber EJ, Echeverria V
Cotinine enhances the extinction of contextual fear memory and reduces anxiety after fear conditioning.
Behav Brain Res. 2012 Mar 17;228(2):284-93.
Posttraumatic stress disorder (PTSD) is an anxiety disorder triggered by traumatic events. Symptoms include anxiety, depression and deficits in fear memory extinction (FE). PTSD patients show a higher prevalence of cigarette smoking than the general population. The present study investigated the effects of cotinine, a tobacco-derived compound, over anxiety and contextual fear memory after fear conditioning (FC) in mice, a model for inducing PTSD-like symptoms. Two-month-old C57BL/6J mice were separated into three experimental groups. These groups were used to investigate the effect of pretreatment with cotinine on contextual fear memory and posttreatment on extinction and stability or retrievability of the fear memory. Also, changes induced by cotinine on the expression of extracellular signal-regulated kinase (ERK)1/2 were assessed after extinction in the hippocampus. An increase in anxiety and corticosterone levels were found after fear conditioning. Cotinine did not affect corticosterone levels but enhanced the extinction of contextual fear, decreased anxiety and the stability and/or retrievability of contextual fear memory. Cotinine-treated mice showed higher levels of the active forms of ERK1/2 than vehicle-treated mice after FC. This evidence suggests that cotinine is a potential new pharmacological treatment to reduce symptoms in individuals with PTSD. [PubMed Citation] [Order full text from Infotrieve]

14) Lohoff FW, Aquino TD, Narasimhan S, Multani PK, Etemad B, Rickels K
Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder.
Pharmacogenomics J. 2011 Oct 18;
Generalized anxiety disorder (GAD) is a chronic psychiatric disorder with significant morbidity and mortality. Antidepressant drugs are the preferred choice for treatment; however, treatment response is often variable. Several studies in major depression have implicated a role of the serotonin receptor gene (HTR2A) in treatment response to antidepressants. We tested the hypothesis that the genetic polymorphism rs7997012 in the HTR2A gene predicts treatment outcome in GAD patients treated with venlafaxine XR. Treatment response was assessed in 156 patients that participated in a 6-month open-label clinical trial of venlafaxine XR for GAD. Primary analysis included Hamilton Anxiety Scale (HAM-A) reduction at 6 months. Secondary outcome measure was the Clinical Global Impression of Improvement (CGI-I) score at 6 months. Genotype and allele frequencies were compared between groups using ?(2) contingency analysis. The frequency of the G-allele differed significantly between responders (70%) and nonresponders (56%) at 6 months (P=0.05) using the HAM-A scale as outcome measure. Similarly, using the CGI-I as outcome, the G-allele was significantly associated with improvement (P=0.01). Assuming a dominant effect of the G-allele, improvement differed significantly between groups (P=0.001, odds ratio=4.72). Similar trends were observed for remission although not statistically significant. We show for the first time a pharmacogenetic effect of the HTR2A rs7997012 variant in anxiety disorders, suggesting that pharmacogenetic effects cross diagnostic categories. Our data document that individuals with the HTR2A rs7997012 single nucleotide polymorphism G-allele have better treatment outcome over time. Future studies with larger sample sizes are necessary to further characterize this effect in treatment response to antidepressants in GAD.The Pharmacogenomics Journal advance online publication, 18 October 2011; doi:10.1038/tpj.2011.47. [PubMed Citation] [Order full text from Infotrieve]

15) Battaglia M, Zanoni A, Taddei M, Giorda R, Bertoletti E, Lampis V, Scaini S, Cappa S, Tettamanti M
Cerebral responses to emotional expressions and the development of social anxiety disorder: a preliminary longitudinal study.
Depress Anxiety. 2012 Jan;29(1):54-61.
[PubMed Citation] [Order full text from Infotrieve]

16) Narasimhan S, Aquino TD, Hodge R, Rickels K, Lohoff FW
Association analysis between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and treatment response to venlafaxine XR in generalized anxiety disorder.
Neurosci Lett. 2011 Oct 10;503(3):200-2.
While antidepressant drugs are used to treat generalized anxiety disorder (GAD), patients vary greatly in their treatment response. Evidence shows genetic factors may play a role in treatment response in GAD. We examined whether the BDNF gene, which has been shown to play a role in antidepressant treatment response in major depressive disorder (MDD), also has an effect in GAD. In our study, 155 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes were obtained for the BDNF functional variant rs6265 (Val66Met) for the entire sample (n=155); however, only the European American (EA) population was considered (n=111) for pharmacogenetic analysis. We did not find a significant association between rs6265 and antidepressant treatment response in our GAD population. Future studies in larger populations will need to be conducted to further elucidate the pharmacogenetic role of this variant in anxiety disorders. [PubMed Citation] [Order full text from Infotrieve]

17) Dissanayaka NN, O'Sullivan JD, Silburn PA, Mellick GD
Assessment methods and factors associated with depression in Parkinson's disease.
J Neurol Sci. 2011 Nov 15;310(1-2):208-10.
Depression is a common problem experienced by patients with Parkinson's disease (PD). Identifying depression in PD is difficult and the determinants of depression in PD are complex and debatable. Here we review our recent studies which have (i) examined the validity of current depression rating scales in PD, (ii) introduced a self-reported and validated strategy to identify a lifetime history of depression in PD, and (iii) investigated genetic and non-genetic factors associated with depression in the context of PD. Our research showed PD-specific cut-off values suitable to use for the Hamilton Depression Scales (HAMD and HDI) and the Geriatric Depression Scale (GDS-15) when dichotomising patients with and without a current depression. Using the GDS-15 specific cut-off scores and a number of self-reported questions that screen for a lifetime history of depression, we developed a novel method to dichotomise PD patients according to current depression or a past history of depression. This method was applied in a large-scale study examining the factors associated with depression in PD. We clarified that the severity of PD is positively related to depression. We also showed that a number of other clinical factors including a longer duration of PD, a younger PD onset age, frequent falls, a history of anxiety disorder and memory problems were associated with depression in PD. In addition to these clinical factors, we observed associations between depression, and lower education levels, a history of smoking and a regular use of non-aspirin bases NSAIDs or analgesics. No associations were found between depression in PD and common genetic variations examined across the serotonin and dopamine transporter genes. Our studies provide a focus for future intervention strategies. [PubMed Citation] [Order full text from Infotrieve]

18) Galvăo-de Almeida A, Quarantini LC, Sampaio AS, Lyra AC, Parise CL, Paraná R, de Oliveira IR, Koenen KC, Miranda-Scippa A, Guindalini C
Lack of association of indoleamine 2,3-dioxygenase polymorphisms with interferon-alpha-related depression in hepatitis C.
Brain Behav Immun. 2011 Oct;25(7):1491-7.
[PubMed Citation] [Order full text from Infotrieve]

19) Flandreau EI, Ressler KJ, Owens MJ, Nemeroff CB
Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus.
Psychoneuroendocrinology. 2012 Jan;37(1):27-38.
Environmental stress has been demonstrated to increase susceptibility for mood and anxiety disorders, and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, the primary endocrine response to stress, is often observed in these patients. HPA axis activation is initiated by corticotropin-releasing factor (CRF) from the hypothalamus, leading to the hypothesis that hypothalamic CRF overexpression contributes to HPA axis hyperactivity in psychiatric patients. In addition, elevated CRF in cerebrospinal fluid is observed in mood and anxiety disorder patients, suggesting that CRF is also being overproduced from extrahypothalamic sources such as the central amygdala (CeA) and overactivity of the amygdala in neuroimaging studies is a consistent finding in anxiety and depression patients. Due to the importance of CRF and the amygdala in the etiology of stress-sensitive psychiatric disorders, the present study sought to further dissect the impact of CRF overexpression (OE) in the amygdala on downstream behavioral, endocrine, and gene-expression changes typically associated with chronic stress. To test the hypothesis that elevated CRF output from the amygdala would reproduce HPA axis hyperactivity and behavioral symptoms of chronic stress, we developed a lentiviral vector in which 3.0kb of the CRF promoter drives overexpression of CRF (LVCRFp3.0CRF). In adult male rats, Experiment-1 examined behavioral consequences of chronic CRF overexpression from the amygdala; the dexamethasone (Dex)/CRF test was used to measure HPA axis reactivity. Experiment-2 focused on HPA axis disruptions; the dexamethasone-suppression and CRF-stimulation tests as well as the Dex/CRF test were used. In both experiments, expression of HPA-axis related transcripts were assessed. [PubMed Citation] [Order full text from Infotrieve]

20) Ryan J, Scali J, Carričre I, Scarabin PY, Ritchie K, Ancelin ML
Estrogen receptor gene variants are associated with anxiety disorders in older women.
Psychoneuroendocrinology. 2011 Nov;36(10):1582-6.
[PubMed Citation] [Order full text from Infotrieve]