Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions

Smoller, Jordan W.; Acierno, James S.; Rosenbaum, Jerrold F.; Biederman, Joseph; Pollack, Mark H.; Meminger, Susan R.; Pava, Joel A.; Chadwick, Lisa H.; White, Candace N.; Bulzacchelli, Maria T.; Slaugenhaupt, Susan A.

doi:10.1002/ajmg.1209

Cited by 86 publications

(64 citation statements)

References 68 publications

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“…Linkage analyses of PD have implicated several chromosomal regions including 1q, 8 2q, 9 7p, 10,11 9q, 12 12q, 13 13q, 14,15 15q 9 and 22q. 15 In association analyses, candidate genes including HTR 1A, 16 2A, 17,18 CCK, 19 ADORA2A, 20 MAOA 21 and COMT 22,23 have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Replication of a genome-wide association study of panic disorder in a Japanese population

Otowa

Tanii

Sugaya³

et al. 2009

J Hum Genet

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Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Although a number of association and linkage studies have been conducted, no gene has been identified as a susceptibility locus. We previously conducted a genome-wide association analysis of PD in 200 Japanese patients and the same number of controls, using a 500 K single nucleotide polymorphisms (SNPs) chip. In this study, we report a replication analysis of PD using the DigTag2 assay. The second stage sample consisted of 558 Japanese patients and 566 controls. Thirty-two markers were tested in a replication sample. As a result, no significant association was found after correction for multiple testing. However, the difference was observed at the nominal allele P-value o0.05 for two SNPs (rs6733840 and rs132617). We also conducted haplotype analyses of SNPs in the APOL3 and CLU genes. Our results failed to show any significant association with PD in these genes. Further studies on these variants with a larger sample size may be worth testing to confirm the results. Keywords: genome-wide association study (GWAS); Japanese population; panic disorder; replication; single nucleotide polymorphism (SNP) INTRODUCTIONPanic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Life prevalence of PD is 1-3% and twice as many women as men suffer from the disorder. 1 The disorder frequently takes a chronic course, with many remissions and relapses. 2 Genetic epidemiological studies including family and twin studies have shown that genetic as well as environmental factors have an important role in the pathogeneses of PD. First-degree relatives of proband with PD have an approximately fivefold increased risk of PD. 3,4 Twin studies show that about 40% of the liability towards PD consists of heritable factors [5][6][7] However, the etiology of PD is currently unknown.

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Section: Introductionmentioning

confidence: 99%

Replication of a genome-wide association study of panic disorder in a Japanese population

Otowa

Tanii

Sugaya³

et al. 2009

J Hum Genet

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“…[3][4][5] Several genome-wide linkage studies have tried to identify genomic regions harboring quantitative trait loci (QTLs) that influence the vulnerability for anxiety disorders. All these studies [6][7][8][9][10][11][12][13][14][15] ascertained the pedigrees through probands with panic disorder, except for one study 16 that included pedigrees with at least one member having an anxiety disorder or somatoform pain. Panic disorder is the most frequently analyzed phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…Panic disorder is the most frequently analyzed phenotype. [6][7][8]13,14 Two studies focused on panic disorder with comorbid medical conditions, that is renal/ bladder conditions, thyroid irregularities, mitral valve prolapse and severe headaches. 11,15 Simple phobia and social phobia have each been investigated once.…”

Section: Introductionmentioning

confidence: 99%

“…11,15 Simple phobia and social phobia have each been investigated once. 9,10 Other anxiety phenotypes 12,14,16 have been based on findings from genetic epidemiological studies indicating a common genetic background for anxiety disorders, 4,17 Thorgeirsson et al 16 considered anxiety disorder or somatoform pain as indicators of affection status. Smoller et al 14 and Kaabi et al 12 constructed new phenotypes of anxiety proneness.…”

Section: Introductionmentioning

confidence: 99%

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Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

et al. 2007

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Several linkage studies on anxiety have been carried out in samples ascertained through probands with panic disorder. The results indicated that using a broad anxiety phenotype instead of a DSM-IV anxiety disorder diagnosis might enhance the chance of finding a linkage signal. In the current study, a genome-wide linkage analysis was performed on anxiety measured with a self-report questionnaire whose scores are highly correlated with DSM-IV anxiety disorders. The self-report questionnaire was included in five surveys of a longitudinal study of the Netherlands Twin Register. Genotype and phenotype data were available for 1602 twins and siblings. To estimate identity by descent , additional genotype data for 564 parents and 22 siblings were used. Linkage analyses were carried out using MERLIN-regress on the average anxiety scores across time. A linkage signal (logarithm of odds score 3.4, empirical P-value 0.07) was obtained at chromosome 14 for marker D14S65 at 105 cM (90% confidence interval, 99-115 cM bounded by markers D14S1434 and D14S985). This finding replicates a linkage finding for a broad anxiety phenotype in a clinically based sample, indicating that the region might harbor a quantitative trait locus associated with the whole spectrum of general anxiety, that is from the normal to the clinical range. Moreover, genome-wide linkage and association studies on emotionality in mice obtained significant results in a syntenic region on mouse chromosome 12. Two homolog genes lie in this region -Dlk1 (delta-like 1 homolog, Drosophila) and Rtl1 (retrotransposon-like 1). Future association studies of these genes are warranted.

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“…19 The region also overlaps a suggestive linkage from the Kaabi et al 22 PD study included herein as well as a locus identified in a targeted linkage scan performed in a single, large pedigree segregating PD and risk for early-onset ANX. 38 Surprisingly, there was no evidence in the 8p22, a region with replicated linkage to harm avoidance, another anxiety-related trait. 39 …”

Section: Neuroticismmentioning

confidence: 99%

Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes

et al. 2012

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Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n ¼ 8) or anxiety disorders (n ¼ 3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, P SR and P OR , were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant P SR P-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.

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Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions

Cited by 86 publications

References 68 publications

Replication of a genome-wide association study of panic disorder in a Japanese population

Replication of a genome-wide association study of panic disorder in a Japanese population

Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes

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