The Genetic Basis of Panic Disorder

Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.

[1]  J. Rosenbaum,et al.  Behavioral inhibition , 2021, Depression and anxiety.

[2]  R. Evershed,et al.  Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption , 2010, Neuropsychopharmacology.

[3]  J. Rehfeld,et al.  Gene variations in the cholecystokinin system in patients with panic disorder , 2010, Psychiatric genetics.

[4]  S. Hodge,et al.  Association of a Polyadenylation Polymorphism in the Serotonin Transporter and Panic Disorder , 2010, Biological Psychiatry.

[5]  S. Hodge,et al.  Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR) , 2010, Molecular Psychiatry.

[6]  K. Tokunaga,et al.  Replication of a genome-wide association study of panic disorder in a Japanese population , 2010, Journal of Human Genetics.

[7]  G. Andersson,et al.  The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  F. Collins,et al.  The HapMap and genome-wide association studies in diagnosis and therapy. , 2009, Annual review of medicine.

[9]  Yong-Ku Kim,et al.  A Tryptophan Hydroxylase 2 Gene Polymorphism is Associated with Panic Disorder , 2009, Behavior genetics.

[10]  Yong-Ku Kim,et al.  The association between serotonin-related gene polymorphisms and panic disorder. , 2008, Journal of anxiety disorders.

[11]  G. Salum,et al.  Harm avoidance and self-directedness as essential features of panic disorder patients. , 2008, Comprehensive psychiatry.

[12]  J. Badner,et al.  Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety , 2008, Neuropsychopharmacology.

[13]  Nikolaos Sakellaridis,et al.  Is 472G/A catechol-O-methyl-transferase gene polymorphism related to panic disorder? , 2007, Psychiatric genetics.

[14]  J. Smoller,et al.  Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study. , 2007, Archives of general psychiatry.

[15]  G. Salum,et al.  Lack of association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder: a systematic review and meta-analysis , 2007, Behavioral and Brain Functions.

[16]  Katharina Domschke,et al.  Meta‐analysis of COMT val158met in panic disorder: Ethnic heterogeneity and gender specificity , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[17]  E. Maron,et al.  Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder , 2007, Neuroscience Letters.

[18]  J. Woo,et al.  Tryptophan hydroxylase and serotonin transporter gene polymorphism does not affect the diagnosis, clinical features and treatment outcome of panic disorder in the Korean population , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[19]  Fabio Macciardi,et al.  Association of the Val158Met Catechol O-Methyltransferase Genetic Polymorphism with Panic Disorder , 2006, Neuropsychopharmacology.

[20]  S. Hodge,et al.  A Third-Pass Genome Scan in Panic Disorder: Evidence for Multiple Susceptibility Loci , 2006, Biological Psychiatry.

[21]  J. Bukszár,et al.  Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism , 2006, Molecular Psychiatry.

[22]  R. Elston,et al.  Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. , 2006, American journal of human genetics.

[23]  Ayelet Meron Ruscio,et al.  The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. , 2006, Archives of general psychiatry.

[24]  C. Freitag,et al.  Interaction of serotonergic and noradrenergic gene variants in panic disorder , 2006, Psychiatric genetics.

[25]  M. Rietschel,et al.  The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder , 2006, Journal of psychopharmacology.

[26]  K. E. Nichols,et al.  Evidence for a Gene-Environment Interaction in Predicting Behavioral Inhibition in Middle Childhood , 2005, Psychological science.

[27]  Jerome Kagan,et al.  The Corticotropin-Releasing Hormone Gene and Behavioral Inhibition in Children at Risk for Panic Disorder , 2005, Biological Psychiatry.

[28]  E. Maron,et al.  Associations between serotonin-related gene polymorphisms and panic disorder. , 2005, The international journal of neuropsychopharmacology.

[29]  Olga V. Demler,et al.  Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[30]  C. Zeni,et al.  Behaviorial inhibition and history of childhood anxiety disorders in Brazilian adult patients with panic disorder and social anxiety disorder , 2005 .

[31]  Michael C Neale,et al.  The structure of genetic and environmental risk factors for anxiety disorders in men and women. , 2005, Archives of general psychiatry.

[32]  J. Haavik,et al.  Different properties of the central and peripheral forms of human tryptophan hydroxylase , 2005, Journal of neurochemistry.

[33]  Jerzy Samochowiec,et al.  Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum , 2004, Psychiatry Research.

[34]  Young-Hee Choi,et al.  The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. , 2004, Journal of psychiatric research.

[35]  Katharina Domschke,et al.  Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. , 2004, The international journal of neuropsychopharmacology.

[36]  P. Sand,et al.  Association Between A2a Receptor Gene Polymorphisms and Caffeine-Induced Anxiety , 2003, Neuropsychopharmacology.

[37]  S. Rauch,et al.  Inhibited and Uninhibited Infants "Grown Up": Adult Amygdalar Response to Novelty , 2003, Science.

[38]  T. Thorgeirsson,et al.  Anxiety with panic disorder linked to chromosome 9q in Iceland. , 2003, American journal of human genetics.

[39]  N. Norton,et al.  Association between a promoter variant in the monoamine oxidase A gene and schizophrenia , 2003, Schizophrenia Research.

[40]  J. Akiyoshi,et al.  Association between the CCK‐A receptor gene and panic disorder , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[41]  S. Higuchi,et al.  Association of cholecystokinin-a receptor gene polymorphisms and panic disorder in japanese , 2003 .

[42]  S. Hodge,et al.  Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  B. Yu,et al.  Catechol O-methyltransferase genetic polymorphism in panic disorder. , 2002, The American journal of psychiatry.

[44]  M C Neale,et al.  A review and meta-analysis of the genetic epidemiology of anxiety disorders. , 2001, The American journal of psychiatry.

[45]  S. Woods,et al.  Linkage genome scan for loci predisposing to panic disorder or agoraphobia. , 2001, American journal of medical genetics.

[46]  E. Hattori,et al.  Identification of a compound short tandem repeat stretch in the 5′-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia , 2001, Molecular Psychiatry.

[47]  J. Rosenbaum,et al.  Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. , 2001, American journal of medical genetics.

[48]  P. Costa,et al.  Phobic, panic, and major depressive disorders and the five-factor model of personality. , 2001, The Journal of nervous and mental disease.

[49]  R. Wilson,et al.  Genomewide survey of panic disorder. , 2001, American journal of medical genetics.

[50]  J. Kagan,et al.  A controlled study of behavioral inhibition in children of parents with panic disorder and depression. , 2000, The American journal of psychiatry.

[51]  S. Hodge,et al.  No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder , 2000, Molecular Psychiatry.

[52]  Steven P. Hamilton,et al.  Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22 , 2000, Biological Psychiatry.

[53]  S. Hodge,et al.  Potential panic disorder syndrome: clinical and genetic linkage evidence. , 2000, American journal of medical genetics.

[54]  Kenneth K Kidd,et al.  Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles , 1999, Biological Psychiatry.

[55]  R. Kessler,et al.  The economic burden of anxiety disorders in the 1990s. , 1999, The Journal of clinical psychiatry.

[56]  J. Vincent,et al.  Investigation of cholecystokinin system genes in panic disorder , 1999, Molecular Psychiatry.

[57]  M. Nöthen,et al.  Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. , 1999, Human molecular genetics.

[58]  K. Ohara,et al.  No association between anxiety disorders and catechol-O-methyltransferase polymorphism , 1998, Psychiatry Research.

[59]  R. Noyes,et al.  Possible association of a cholecystokinin promotor polymorphism (CCK-36CT) with panic disorder. , 1998, American journal of medical genetics.

[60]  S E Hodge,et al.  Results of a genome-wide genetic screen for panic disorder. , 1998, American journal of medical genetics.

[61]  H. Mönnikes,et al.  Peripheral administration of cholecystokinin activates c-fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rat , 1997, Brain Research.

[62]  T. Arinami,et al.  An association study between a transcriptional polymorphism in the serotonin transporter gene and panic disorder in a Japanese population , 1997, Psychiatry and clinical neurosciences.

[63]  M. Weissman,et al.  Familial aggregation and phenomenology of 'early'-onset (at or before age 20 years) panic disorder. , 1997, Archives of general psychiatry.

[64]  R. Crowe,et al.  Missense mutation of the cholecystokinin B receptor gene: lack of association with panic disorder. , 1996, American journal of medical genetics.

[65]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[66]  Streichenwein Sm,et al.  Am J Psychiatry , 1996 .

[67]  M. Weissman,et al.  Is the comorbidity between social phobia and panic disorder due to familial cotransmission or other factors? , 1995, Archives of general psychiatry.

[68]  S. Wank,et al.  Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse. , 1995, Genomics.

[69]  M. Weissman,et al.  Psychiatric disorders in relatives of probands with panic disorder and/or major depression. , 1994, Archives of general psychiatry.

[70]  T. Yamada,et al.  The human gastrin/cholecystokinin type B receptor gene: alternative splice donor site in exon 4 generates two variant mRNAs. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[71]  J. Kagan,et al.  Behavioral Inhibition in Childhood: A Risk Factor for Anxiety Disorders , 1993 .

[72]  J. Rosenbaum,et al.  Behavioral inhibition in children: a possible precursor to panic disorder or social phobia. , 1991, The Journal of clinical psychiatry.

[73]  J. Kagan,et al.  Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study. , 1988, Archives of general psychiatry.

[74]  E. Harris,et al.  Relationship between panic disorder and agoraphobia. A family study. , 1986, Archives of general psychiatry.

[75]  J. Vanderhaeghen,et al.  New peptide in the vertebrate CNS reacting with antigastrin antibodies , 1975, Nature.

[76]  H. S. Davis,et al.  A Controlled Study , 1966 .

[77]  E. Donaldson,et al.  A Family Study. , 1962 .

[78]  A. Mack Childhood history of behavioral inhibition and comorbidity status in 256 adults with social phobia , 2012 .

[79]  P. Sullivan,et al.  Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype , 2008, Molecular Psychiatry.

[80]  N. Schork,et al.  Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders , 2008, Neuropsychopharmacology.

[81]  N. Wray,et al.  Association study of candidate variants of COMT with neuroticism, anxiety and depression , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[82]  K. E. Nichols,et al.  Behavioral inhibition: linking biology and behavior within a developmental framework. , 2005, Annual review of psychology.

[83]  C. Zeni,et al.  Behavioral inhibition and history of childhood anxiety disorders in Brazilian adult patients with panic disorder and social anxiety disorder. , 2005, Revista brasileira de psiquiatria.

[84]  M. Rietschel,et al.  Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder. , 2004, Journal of neural transmission. Supplementum.

[85]  P. Sullivan,et al.  Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. , 2002, The American journal of psychiatry.

[86]  E. Hattori,et al.  Association studies of the cholecystokinin B receptor and A2a adenosine receptor genes in panic disorder , 2001, Journal of Neural Transmission.

[87]  S. Hodge,et al.  No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder , 2001, Molecular Psychiatry.

[88]  A. Fyer,et al.  The DSM-IV panic disorder field trial: panic attack frequency and functional disability. , 1996, Anxiety.

[89]  D. Lichtermann,et al.  A controlled family study in panic disorder. , 1993, Journal of psychiatric research.

[90]  J. Mendlewicz,et al.  Minireview: Molecular genetics in affective illness. , 1993, Life sciences.