Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition.

BACKGROUND: Behavioral inhibition to the unfamiliar (BI), a heritable temperamental profile involving an avoidant response to novel situations, may be an intermediate phenotype in the development of anxiety disorders. Corticotropin-releasing hormone (CRH) is a key mediator of the stress response through its effects on the hypothalamic-pituitary-adrenal axis and limbic brain systems. Transgenic mice overexpressing CRH exhibit BI-like behaviors, implicating this gene in the development of the phenotype. METHODS: We genotyped a marker tightly linked to the CRH locus in 85 families of children who underwent laboratory-based behavioral assessments of BI and performed family-based association analyses. RESULTS: We observed an association between an allele of the CRH-linked locus and BI (p =.015). Among offspring of parents with panic disorder, this association was particularly marked (p =.0009). We further demonstrate linkage disequilibrium between this marker and single nucleotide polymorphisms encompassing the CRH gene. CONCLUSIONS: These results are consistent with the possibility that variants in the CRH gene are associated with anxiety proneness.     

No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder.     

Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22.

BACKGROUND: A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder. METHODS: Subjects from 70 panic disorder pedigrees, and 83 "triads", were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and approximately 339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage. RESULTS: Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p =.0001-.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p =.0001), as was the "global" p value for this combination (p =.005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder. CONCLUSIONS: Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22.     

Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer

OBJECTIVE: The aim of this study was to assess the frequency and impact of anxiety disorders on illness severity and response to mood stabilizers in bipolar disorders. METHOD: 318 bipolar patients consecutively admitted to the psychiatric wards of 2 centers as inpatients were recruited. Patients were interviewed with a French version of the Diagnostic Interview for Genetic Studies providing DSM-IV Axis I diagnoses and demographic and historical illness characteristics. Logistic and linear regressions to adjust for age and sex were performed. RESULTS: In a population with mostly bipolar type I patients (75%), 24% had at least 1 lifetime anxiety disorder (47% of these patients had more than 1 such disorder), 16% of patients had panic disorder (with and without agoraphobia, and panic attacks), 11% had phobia (agoraphobia without panic disorder, social phobia, and other specific phobias), and 3% had obsessive-compulsive disorder. Comorbidity with anxiety disorders was not correlated with severity of bipolar illness as assessed by the number of hospitalizations, psychotic characteristics, misuse of alcohol and drugs, and suicide attempts (violent and nonviolent). Bipolar patients with an early onset of illness had more comorbidity with panic disorder (p <.05). Anxiety disorders were detected more frequently in bipolar II patients than in other patients, but this difference was not significant (p =.09). Bipolar patients with anxiety responded less well to anticonvulsant drugs than did bipolar subjects without anxiety disorder (p <.05), whereas the efficacy of lithium was similar in the 2 groups. There was also a strong correlation between comorbid anxiety disorders and depressive temperament in bipolar patients (p =.004). CONCLUSION: Patients with bipolar disorders often have comorbid anxiety disorders, particularly patients with depressive temperament, and the level of comorbidity seems to decrease the response to anticonvulsant drugs.     

Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism

Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.     

Polymorphisms of the human homologue of the Drosophila white gene are associated with mood and panic disorders

The Drosophila white gene is a member of the ATP-binding cassette (ABC) transporter superfamily and is involved in the cellular uptake of tryptophan. Its human homologue gene (hW) has been mapped to chromosome 21q22.3. Tryptophan is the precursor for the neurotransmitter serotonin, which has been implicated in the regulation of mood and anxiety. The locus 21q22.3 has also been reported to be associated with mood disorders. The 3'-untranslated region (3'-UTR) in the hW gene has been shown to contain a polymorphic poly(T) region. We have identified a new polymorphism G2457A in the 3'-UTR in the present study. We examined the relationship between these polymorphisms and mood and panic disorders, and a significant association between the poly(T) polymorphisms and mood disorders was detected (P=0.039 (allele frequency)). Associations were found between the polymorphisms and mood (poly(T) polymorphism: P=0.047 (allele frequency), G2457A: P=0.040 (allele frequency), P=0.044 (genotype frequency)) and panic disorders (G2457A: P=0.026 (allele frequency), P=0.011 (genotype frequency)) in males, but not in females. These findings suggest that the hW gene may be an important gene in the control of mood and anxiety as well as one of the genetic factors related to mood disorders and panic disorder in males. The statistical significance of the association remains relatively low and larger materials facilitating further dissection of the clinical phenotype will be needed to confirm and independently validate this finding and to evaluate its significance.     

Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders.

BACKGROUND: The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of mood disorders. The GABRA1 gene encodes one of the subunits of GABA-A receptor and is located on human chromosome 5q34-q35, which is a region reportedly linked to mood disorders. We examined the GABRA1 gene as a candidate for mood disorders. METHODS: We performed mutation screening of GABRA1 in 24 Japanese bipolar patients and evaluated associations in Japanese case-control subjects consisting of 125 patients with bipolar disorder, 147 patients with depressive disorders, and 191 healthy control subjects. Associations were confirmed in the National Institute of Mental Health (NIMH) Initiative Bipolar Pedigrees, which consists of 88 multiplex pedigrees with 480 informative persons. RESULTS: We identified 13 polymorphisms in the GABRA1 gene. Nonsynonymous mutations were not found. Association of a specific haplotype with affective disorders was suggested in the Japanese case-control population (corrected p=.0008). This haplotype association was confirmed in the NIMH pedigrees (p=.007). CONCLUSIONS: These results indicate that the GABRA1 gene may play a role in the etiology of bipolar disorders.     

Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum

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.     

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p

Schizophrenia (SC) and bipolar disorder (BP) share many clinical features, among them psychosis. We previously identified a putative gene locus for psychosis on chromosome 18p in a sample from the Central Valley of Costa Rica (CVCR) population. The present study replicated the association to a specific allele of microsatellite marker D18S63 on 18p11.3, using a newly collected sample from the CVCR. A combined analysis of both samples, plus additional subjects, showed that this specific allele on D18S63, which lies within an intron on the TGFB-induced factor (TGIF) gene, is strongly associated (P-value=0.0005) with psychosis. Eleven additional SNP markers, spanning five genes in the region, were analyzed in the combined sample from the CVCR. Only the four SNPs within the TGIF gene were in strong linkage disequilibrium with D18S63 (D'=1.00). A specific haplotype for all five markers within the TGIF gene showed evidence of association (P-value=0.011) to psychosis. A second, distinct haplotype, containing a newly identified nonsynonymous polymorphism in exon 5 of the TGIF gene, showed a nonsignificant trend towards association to psychosis (P-value=0.077). TGIF is involved in neurodevelopment, neuron survival and controls the expression of dopamine receptors. Altogether, our results point to the possible involvement of TGIF in the pathophysiology of psychotic disorders in the CVCR population.     

Suggestive evidence for association between L‐type voltage‐gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family‐based association study

Objectives: Through recent genome‐wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage‐dependent, L‐type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European‐American cohorts. We performed a family‐based association study to determine whether CACNA1C is associated with BP in the Latino population. Methods: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single‐nucleotide polymorphisms (SNPs) that spanned a 602.9‐kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family‐Based Association Test (version 2.0.3) and Haploview (version 4.2) software. Results: An eight‐locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). Conclusions: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.     

A case-control and family-based association study of the 5-HTTLPR in pediatric-onset depressive disorders.

BACKGROUND: Pediatric depression can be particularly informative for clarification of the causes of mood disorders. The aim of this work was to explore the possible association between childhood- and early-adolescent-onset DSM-IV depressive disorders (DD; including major depression and dysthymia) and the serotonin transporter-linked promoter polymorphism (5-HTTLPR) locus. METHODS: The case-control sample consisted of 68 unrelated patients with DD, and 68 unrelated age- and gender-matched healthy control subjects. The same patients were included in the family-based study, which consisted of 41 triads and 11 dyads. RESULTS: An excess of the SS-genotype (p =.025) and of the S-allele (p =.021) was found among DD children (odds ratio = 1.81; 95% confidence interval = 1.12-2.94). The family-based results suggested that the S-allele was preferentially transmitted to depressed children (haplotype-based haplotype relative risk: chi(2) = 7.231 df = 1, p =.007; transmission disequilibrium test: chi(2) = 5.233, df = 1, p =.022). CONCLUSIONS: A role for the 5-HTTLPR locus that needs replication in larger samples is suggested in childhood DD.     

No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF)

The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.     

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.     

Association of GABRB3 polymorphisms with autism spectrum disorders in Korean trios

BACKGROUND/AIMS: Autism spectrum disorders (ASD) are complex neuropsychiatric disorders having a genetic risk factor. The association and linkage study for the gamma-aminobutyric acid type A receptor beta3 subunit gene (GABRB3), located within the chromosome 15q11-q13 autism candidate region, and ASD have been evaluated. The aim of this study was to investigate the association between GABRB3 and ASD in the Korean population. METHODS: The present study was conducted with the detection of four single-nucleotide polymorphisms (rs1426217, rs2081648, rs890317, rs981778) in GABRB3 and association analysis in 104 Korean ASD trios using the transmission disequilibrium test. RESULTS: The transmission disequilibrium test demonstrated that an allele at rs2081648 showed preferential transmission (p = 0.027). One haplotype, including all examined markers in GABRB3, demonstrated significant association (p = 0.043), but the global chi2 test for haplotype transmission did not reveal an association between GABRB3 and ASD (chi2 = 15.516, d.f. = 15). CONCLUSION: Our finding suggested that single-nucleotide polymorphisms in GABRB3 may play a significant role in the genetic predisposition to ASD in the Korean population.     

Temperament and hypothalamic-pituitary-adrenal axis function in healthy adults

BACKGROUND: Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults. METHODS AND MATERIALS: Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ). RESULTS: Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment. CONCLUSIONS: These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.     

Association of a Met88Val diazepam binding inhibitor (DBI) gene polymorphism and anxiety disorders with panic attacks

Several lines of evidence suggest that anxiety disorders have a strong genetic component, but so far only few susceptibility genes have been identified. There is preclinical and clinical evidence for a dysregulation of the central gamma-aminobutyric acid (GABA)-ergic tone in the pathophysiology of anxiety disorders. Diazepam binding inhibitor (DBI) has been suggested to play a pivotal role in anxiety disorders through direct and indirect, i.e. via synthesis of neuroactive steroids, modulation of GABA(A) receptor function. These findings suggest that the DBI gene can be postulated as a candidate for a genetic association study in this disorder. Thus, single nucleotide polymorphisms (SNPs) of the DBI gene were investigated for putative disease associations in a German sample of anxiety disorder patients suffering from panic attacks and matched controls. We were able to detect a significant association between a non-synonymous coding variant of DBI with anxiety disorders with panic attacks. The rare allele of this polymorphism was more frequent in controls than in patients (OR=0.43; 95% CI: 0.19-0.95). In conclusion, these results suggest a central role of DBI genetic variants in the susceptibility for the development of anxiety disorders that are characterized by the occurrence of panic attacks.     

Association study between the corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar disorder.

Family, adoption and twin studies show that genetics influences suicidal behavior, but does not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, that are common features in Bipolar Disorder (BD). CRH is a hypothalamic factor that stimulates the pituitary gland. Two CRH receptors are known, CRHR1 and CRHR2. To search for markers conferring genetic susceptibility to suicide, we typed three polymorphisms of the CRHR2 gene, CRHR2(CA), CRHR2(GT), and CRHR2(GAT), in 312 families where at least one subject had DSM-IV bipolar disorder. Family based association analyses in the suicide attempters using FBAT yielded no difference in the distribution of the alleles for all three markers. HBAT analysis for quantitative measures on suicide-related traits showed association between haplotype 5-2-3 and higher severity. The current results show that haplotype variation at the CRHR2 locus is associated with suicidal behaviour. This is to our knowledge the first investigation on suicidal behavior and genetic variation at the CRHR2 locus, an important regulator of the HPA axis.     

NOTCH4 gene haplotype is associated with schizophrenia in African Americans.

BACKGROUND: The goal of this study was to investigate the relationship between the NOTCH4 gene and schizophrenia in African American (AA) and European American (EA) subjects. METHODS: Two single nucleotide polymorphisms (SNPs) at the NOTCH4 locus were genotyped in 123 AA schizophrenia patients, 223 EA schizophrenia patients, 85 AA healthy control subjects, and 211 EA healthy control subjects. The specific markers studied were -1725T/G and -25T/C. Comparisons of allele and haplotype frequencies between patients and control subjects were performed with the chi-square test, the Fisher's Exact Test, and CLUMP software. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. RESULTS: The haplotype -1725G/-25T associates to schizophrenia in AA subjects (p =.0008), but not in EA subjects. Alleles -1725G and allele -25T are in positive LD both in AAs and EAs. Allele and haplotype frequencies differ significantly between AAs and EAs. CONCLUSIONS: The haplotype -1725G/-25T at the NOTCH4 locus, which results from SNPs of NOTCH4 that are in LD, may increase susceptibility to schizophrenia in AAs. Any effect of this locus on risk for schizophrenia is population-specific.     

No association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with panic disorder

Several lines of evidence suggest that genetic factors might contribute to susceptibility to panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common pathophysiology of depression and anxiety, we analyzed the association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C > T (formerly named C270T) in the noncoding region of exon V and 196G > A (val66met) in the coding region of exon XIIIA, with panic disorder. In this study, 109 patients with panic disorder diagnosed according to the DSM-IV criteria, and 178 control subjects were recruited. There were no significant differences in the frequency of the genotype or allele in these two SNPs between patients and controls [132C > T in exon V: genotype, p = 1.0, allele, p = 0.59; 196G > A (val66met) in exon XIIIA: genotype, p = 0.77, allele, p = 0.78]. Furthermore, no significant associations of agoraphobia with the two SNPs were detected. This study suggests that the BDNF gene polymorphisms are not associated with panic disorder in our Japanese population.     

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.