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.
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]
TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H, Lindal E,
Gagunashvili N, Frigge ML, Kong A, Stefansson K, Gulcher JR.
with panic disorder linked to chromosome 9q in iceland.
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
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]
GG, Pollack MH, Otto MW, Worthington JJ, Rosenbaum JF, Scott EL, Kradin RL.
expression of L-selectin (CD62L) by blood lymphocytes: correlates with affective
parameters and severity of panic disorder.
"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.
in patients suffering from alcoholism, anxiety disorders and narcolepsy.
Neuropsychopharmacol Biol Psychiatry 2001 Jul;25(5):965-82
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]
C, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N.
in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients
and healthy volunteers: findings from an association study.
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]
C, Grintschuk N, Szegedi A, Anghelescu I, Klawe C, Singer P, Hiemke C, Dahmen
The HTR1B 861G>C receptor polymorphism among patients suffering
from alcoholism, major depression, anxiety disorders and narcolepsy.
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]
AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal
Association of a functional polymorphism of the monoamine oxidase
A gene promoter with personality and psychiatric symptoms.
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
MA, Xu K, Ferro E, Harris CR, Goldman D.
Genetic origins of anxiety
in women: a role for a functional catechol-O-methyltransferase polymorphism.
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.
review and meta-analysis of the genetic epidemiology of anxiety disorders.
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]
JM, Prescott CA, Kendler KS.
A population-based twin study of generalized
anxiety disorder in men and women.
J Nerv Ment Dis 2001
"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]
Major depression and generalised anxiety disorder. Same genes,
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."
KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.
Major depression and
generalized anxiety disorder. Same genes, (partly) different environments?
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]
AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal
An association study of a functional polymorphism of the serotonin
transporter gene with personality and psychiatric symptoms.
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,
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]
[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]