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Panic disorder is unlikely to be a homogeneous autosomal dominant disorder: Results of a genome-wide genetic screen
Abstracts
binding. Theantisense treatment withCRH.-R AS-DON when :Jpplicll to clonal mouse pituitary cells reduced CRH·clicitcd ACTH release. Moreover, chronic infusion of CRH1"R AS·DON into the central nucleus of the amygdala reduced anxiety-related behavior. This effect. however. was not associated with reductions of CRH1·R mRNA and CRH binding in this particular bruin area, Similar Investigations using AS-OON targeted against theCRH 2"R mRNA failed to induceanxiolytic effects in rats thal were rendered anxious by exposure to social defeat. These findings support the idea that the CRH, receptor plays it key role in mcdlating CRH·etici{ed anxiety and thus is II prime target for anxiolytlc drugs.
232. STRESS - RESTRESS: AN ANIMAL MODEL OF HPA ABNORMALITIES IN PTSD I. Liberzon, M, Krstov, & E.A. Young MHRI, University of Michigan. Ann Arbor, MI 48104 While ACTH andcorticosterone responses have been extensively studied in normal or chronically stressed animals, little is known regarding the longer lasting effects of a single severe stressor on this system. This is pilrticularly important since II single stressful event can result in post traumatic stress disorder in humans. Specific HPA axis abnorrnalltiesr low 24h glucocorticoid secretion and hypersensitive negative feedback were reported in this disorder. In the current study we examined the effects of delayed stress on corticosterone and ACTH responses to restrcss and on ghicocerticold negative feedback sensitivity in rats, Sprague-Dawley male rots (250 g) were studied in II stress - restress paradigm in two experiments. with and without pretreatment with cortisol. After single severe stress (2 hours restrain + swim + ether), anima/<; were lefL untouched for 7 days then restressed, Plasma ACTH and corticosterone levels were measured (It 0, 5. 15 and 30 minutes. There W
233. PANIC DISORDER IS UNLIKELY TO BE A HOMOGENEOUS AUTOSOMAL DOMINANT DISORDER: RESULTS OF A GENOME-WIDE GENETIC SCREEN J.A. Knowles', V.J. Vleland'', M.M. Weissman',
a. Heiman', G. de Jesus', A. Judenberg', J. Cunjak l , S. Mick', P, Adams', S.E. Hodge', D.P. Klein', AJ. Fyer', & T'C, aiJIiam l
'New York State Psychiatric Institute/Columbia University, NY. NY 10032: 2Universily of lowa, IowaCity. IA
Panic disorder is characterized by spontaneous and recurrent panic attacks, often accompanied by agoraphobia, Increased familial loading,
mOL PSYCIIIATRY 1996;39;500-666
567
concordance natcs in twins, and transmission patterns in famllles suggest a genetic role in the etiology of the illness. Early segregation analyses suggested thedisorder wastransmitted in an autosomal dominant pauem. We have genotyped up to 23 families with a high density of panic disorder with over 625 DNA markers. The thirteen best families (clod >6.0 under the dominant genetic model) have been genotyped with an ordered set of markers encompassing ::111 {he autosomes at an average marker density of 14 eM. Over 110.000 genotypes have been generated on the whole set of families (as of November 1995) and the data have been analyzed under both dominant and a recessive models. No 100 scores exceed 2.0 foreithermodel. Two markers give lod scoresover 1.0 under dominant model, and live under the recessive model. Under the homogeneous dominant genetic model we have 100 scoresbelow-2.0 for greaterthan 85% of the genetic length of the autosomes, This collection of pedigrees is lessinformative under therecessive model. Consequently, less than 50% of 'he genetic length of the autosomes have lod scores below -2.0 with the homogeneous recessive model. Given the lack of significant positive lad scores and the presence of lod scores below ·2.0 for almost all of the autosomes, we conclude' that panic disorder is unlikely to be caused by a single dominant genetic locus. A single recessive locus. dominant or recessi ve loci with genetic heterogeneity, ami multiple additive genetic loci can not be excluded from our results.
234. A TRAIT MARKER FOR PANIC DISORDER W.H. Coryell University of Iowa Hospitals and Clinics. Psychiatric Research Department There is now substantial evidence lhat an abnormal threshold for suffocation alarm undcrlles panic disorder. Because this disorder is highly familial. evidence of an abnormal suffocation threshold may be apparent in high-risk individuals before they'develop clinical illness. To explore this possiblllty, we evaluated II subjects who hall at least one first-degree relative with DSM·IIr·R panic disorder (HR·PD). 13 who had lit least two rctatlves treated for mania or for depression (UR·AD), and 15 low-risk controls who had no family history of panic disorder, affective disorderor alcoholism (Lk-control), All were aged 18- 35 and had nopersonal history of any RDCdisorder as determined by theSADS. Nonehave everexperienced panic attacks, Subjects completed ratings of the 14 possible panic disorder symptoms after a full breath of room air and aftern full breath of a 35%CO;l6S% OJ mixture. A threshold of four or more symptoms ruled at n "moderate level" dl!signaled n panic Quack. Five (45.5%) of the subjecLs lit hlgh-risk for panic disorder. but none of the LR·control subjects (p = 0.007), nor any of the HR-AD subjects (p = O.DlI). developed a panic auack following inhalation of the CO2 mixture. None in any group developed panicattacks following inhalation of room air. These findings. if replicated with larger samples, have Implications for linkage studies, foi' efforts to clarify the relationship between panic disorder and major depressive disorder and for the development of prophylactic treatment for panic disorder.
binding. Theantisense treatment withCRH.-R AS-DON when :Jpplicll to clonal mouse pituitary cells reduced CRH·clicitcd ACTH release. Moreover, chronic infusion of CRH1"R AS·DON into the central nucleus of the amygdala reduced anxiety-related behavior. This effect. however. was not associated with reductions of CRH1·R mRNA and CRH binding in this particular bruin area, Similar Investigations using AS-OON targeted against theCRH 2"R mRNA failed to induceanxiolytic effects in rats thal were rendered anxious by exposure to social defeat. These findings support the idea that the CRH, receptor plays it key role in mcdlating CRH·etici{ed anxiety and thus is II prime target for anxiolytlc drugs.
232. STRESS - RESTRESS: AN ANIMAL MODEL OF HPA ABNORMALITIES IN PTSD I. Liberzon, M, Krstov, & E.A. Young MHRI, University of Michigan. Ann Arbor, MI 48104 While ACTH andcorticosterone responses have been extensively studied in normal or chronically stressed animals, little is known regarding the longer lasting effects of a single severe stressor on this system. This is pilrticularly important since II single stressful event can result in post traumatic stress disorder in humans. Specific HPA axis abnorrnalltiesr low 24h glucocorticoid secretion and hypersensitive negative feedback were reported in this disorder. In the current study we examined the effects of delayed stress on corticosterone and ACTH responses to restrcss and on ghicocerticold negative feedback sensitivity in rats, Sprague-Dawley male rots (250 g) were studied in II stress - restress paradigm in two experiments. with and without pretreatment with cortisol. After single severe stress (2 hours restrain + swim + ether), anima/<; were lefL untouched for 7 days then restressed, Plasma ACTH and corticosterone levels were measured (It 0, 5. 15 and 30 minutes. There W
233. PANIC DISORDER IS UNLIKELY TO BE A HOMOGENEOUS AUTOSOMAL DOMINANT DISORDER: RESULTS OF A GENOME-WIDE GENETIC SCREEN J.A. Knowles', V.J. Vleland'', M.M. Weissman',
a. Heiman', G. de Jesus', A. Judenberg', J. Cunjak l , S. Mick', P, Adams', S.E. Hodge', D.P. Klein', AJ. Fyer', & T'C, aiJIiam l
'New York State Psychiatric Institute/Columbia University, NY. NY 10032: 2Universily of lowa, IowaCity. IA
Panic disorder is characterized by spontaneous and recurrent panic attacks, often accompanied by agoraphobia, Increased familial loading,
mOL PSYCIIIATRY 1996;39;500-666
567
concordance natcs in twins, and transmission patterns in famllles suggest a genetic role in the etiology of the illness. Early segregation analyses suggested thedisorder wastransmitted in an autosomal dominant pauem. We have genotyped up to 23 families with a high density of panic disorder with over 625 DNA markers. The thirteen best families (clod >6.0 under the dominant genetic model) have been genotyped with an ordered set of markers encompassing ::111 {he autosomes at an average marker density of 14 eM. Over 110.000 genotypes have been generated on the whole set of families (as of November 1995) and the data have been analyzed under both dominant and a recessive models. No 100 scores exceed 2.0 foreithermodel. Two markers give lod scoresover 1.0 under dominant model, and live under the recessive model. Under the homogeneous dominant genetic model we have 100 scoresbelow-2.0 for greaterthan 85% of the genetic length of the autosomes, This collection of pedigrees is lessinformative under therecessive model. Consequently, less than 50% of 'he genetic length of the autosomes have lod scores below -2.0 with the homogeneous recessive model. Given the lack of significant positive lad scores and the presence of lod scores below ·2.0 for almost all of the autosomes, we conclude' that panic disorder is unlikely to be caused by a single dominant genetic locus. A single recessive locus. dominant or recessi ve loci with genetic heterogeneity, ami multiple additive genetic loci can not be excluded from our results.
234. A TRAIT MARKER FOR PANIC DISORDER W.H. Coryell University of Iowa Hospitals and Clinics. Psychiatric Research Department There is now substantial evidence lhat an abnormal threshold for suffocation alarm undcrlles panic disorder. Because this disorder is highly familial. evidence of an abnormal suffocation threshold may be apparent in high-risk individuals before they'develop clinical illness. To explore this possiblllty, we evaluated II subjects who hall at least one first-degree relative with DSM·IIr·R panic disorder (HR·PD). 13 who had lit least two rctatlves treated for mania or for depression (UR·AD), and 15 low-risk controls who had no family history of panic disorder, affective disorderor alcoholism (Lk-control), All were aged 18- 35 and had nopersonal history of any RDCdisorder as determined by theSADS. Nonehave everexperienced panic attacks, Subjects completed ratings of the 14 possible panic disorder symptoms after a full breath of room air and aftern full breath of a 35%CO;l6S% OJ mixture. A threshold of four or more symptoms ruled at n "moderate level" dl!signaled n panic Quack. Five (45.5%) of the subjecLs lit hlgh-risk for panic disorder. but none of the LR·control subjects (p = 0.007), nor any of the HR-AD subjects (p = O.DlI). developed a panic auack following inhalation of the CO2 mixture. None in any group developed panicattacks following inhalation of room air. These findings. if replicated with larger samples, have Implications for linkage studies, foi' efforts to clarify the relationship between panic disorder and major depressive disorder and for the development of prophylactic treatment for panic disorder.