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P.1.a.003 A possible association between panic disorder and the ghrelin gene
S238
P.1.a. Basic and clinical neuroscience − Genetics and genomics
gene or by providing a permissive genetic environment for mutations elsewhere in the genom. As there is no specific biological or clinical finding for autism, also there is not a specific gene responsible for it. Data from whole-genome screens in multiplex families suggest interactions of at least 15 genes in the causation of autism. Since it has been recently shown that de novo deletions and duplications play a significant role in the etiology of autism, we aimed to scan this disease with the most sensitive molecular cytogenetic approaches. Methods: Array comparative genomic hybridization (arrayCGH) is a technique capable of detecting DNA copy number variations that cause human genetic disorders; and it has recently lead to the characterization of many novel microdeletion and microduplication syndromes. This method has proven to be a specific, sensitive, and fast technique which enables to analyse the whole genome in a single experiment. Thus array-CGH evaluation of 0−18 year-old 35 patients (29 male-6 female) with primary autism is presented in this study. Feature Axtraction programme is used to analyse the data. Numerical data is converted to image and. quality control analysis was performed (QC Metric). Appropiate patient data was chosen and analysed (Cytosure Analysis Software Version 2.2). Potential deletion and duplications were investigated. Results: Previously identified cytogenetic abnormalities at 16p13.11, 8p23.1 region in autistic individuals. was also detected in our study. In addition, our findings revealed 16p11.2 deletion in twelve patients, 1q21 deletion in ten patients, 2q21.1 deletion in eight patients, 2p21 deletion in seven patients, and 10q11.22 deletion in four patients. So far to our knowledge, these findings are the first data that we offer to the literature. Analysis of gene expression in patients with the same data support to analyse molecular pathogenesis of the disease and will lead to significant gains achieved. Conclusion: The results of our study suggest that 16p13.11 region and related genes might also represent a predisposition to autism. This study is one of the first “whole-genome” array CGH analysis in patients with autism; and since it will provide important clues for the underlying mechanisims and treatment and of the disease, more intensive research with further application of a CGH to wider groups of patients is needed. References [1] Harvard, C., Malenfant, P., Koochek, M., 2005 A variant Cri du Chat phenotype and autism spectrum disorder in a subject with de novo cryptic microdeletions involving 5p15.2 and 3p24.3−25 detected using whole genomic array CGH. Clin Genet 67, 341–351. [2] Shinawi, M., Cheung, S.W., 2008 The array CGH and its clinical applications. Drug Discovery Today 13, 760–770.
P.1.a.003 A possible association between panic disorder and the ghrelin gene
Gothenburg, Sweden; 7 Gothenburg university hospital, Institute of Neuroscience and Physiology, Gothenburg, Sweden Panic disorder is a severe anxiety disorder characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms such as heart palpitations, shortness of breath, and hyperventilation. Twin and adoption studies have shown the disorder to be in part hereditary, but the genes underlying the disease still remain to be elucidated. The general belief is that it is a combination of several polymorphism rather than a singel gene that is responsible [1]. The stomach-derived circulating hormone ghrelin plays an important role in hunger and motivated behaviour for food, but ghrelin in the central nervous system also appears to affect anxiety-like behaviour in animal studies [2,3]. Whether ghrelin also affects anxiety in humans has not been investigated. In the present study we genotyped six SNPs in the preproghrelin gene in Swedish patients suffering from panic disorder and controls. Three of the genotyped polymorphisms are missense mutations (rs4684677, rs34911341, and rs696217), and three of the polymorphisms are intronic (rs42451, rs35680, rs26802). The study was approved by the Ethics committee at the University of Gothenburg, and all participants provided written informed consent. The patient group consisted of 215 Swedish patients (63 men and 152 women, mean age 43 years) meeting the DSM-IV criteria for panic disorder, 83% also suffered from agoraphobia. Controls were 199 Swedish men born in 1944 and 252 Swedish women born in 1956. The control cohort was originally recruited for a study of cardiovascular risk factors. The polymorphisms were assessed using sequenom and, for samples for which the sequenom analysis failed, with pyrosequencing. Allele frequencies were analyzed using chi-square tests and an LD-plot was generated and haplotype blocks were analyzed using Haploview. The genotype frequencies in the control sample were in Hardy-Weinberg equilibrium and there were no differences between males and females regarding genotype distribution. The A allele of the rs4684677 polymorphism was significantly more common in patients than in controls (p = 0.02). No other significant associations were found for the other SNPs tested. The haplotype containing the SNPs rs4684677, rs42451, rs35680 and rs34911341 showed a strong significance for the block ACTC (p = 0.0042). The present study suggests that the A allele in the rs4684677 polymorphism may be more common in patients suffering from panic disorder than in controls. The polymorphism is a missense mutation located in exon 4 and is responsible for an amino acid exchange from Leu to Gln. To what extent this effects the function of the hormone is not known. Needless to say, the results of this study should be interpreted with caution as they need to be confirmed in other populations. However, taken together with the effects of ghrelin on anxiety-related behavior in animal studies, it makes an interesting finding and we suggest that the possible role for ghrelin in human anxiety disorders should be further investigated. References
K. Annerbrink1 ° , C. Hansson1 , C. Allgulander2 , S. Andersch3 , I. Sj¨odin4 , G. Holm5 , S. Dickson6 , E. Eriksson7 . 1 University of G¨ oteborg, Institute of Neuroscience and Physiology, G¨oteborg, Sweden; 2 Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; 3 Sahlgrenska university hospital, Department of Psychiatry, Gotehnburg, Sweden; 4 Link¨ oping university hospital, Department of Neuroscience and Locomotion, Link¨oping, Sweden; 5 Sahlgrenska university hospital, Department of medicine, Gothenburg, Sweden; 6 University of Gothenburg, Institute of Neuroscience and Physiology,
[1] Hettema, J.M., Neale, M.C., Kendler, K.S. 2001. A review and metaanalysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158(10), 1568−78. [2] Hansson, C., Haage, D., Taube, M., Egecioglu, E., Salom´e, N., Dickson, S.L. 2011. Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence. Neuroscience Feb 14. [3] Chuang, J.C., Zigman, J.M. 2010. Ghrelin’s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept. pii: 460549.
P.1.a. Basic and clinical neuroscience − Genetics and genomics
gene or by providing a permissive genetic environment for mutations elsewhere in the genom. As there is no specific biological or clinical finding for autism, also there is not a specific gene responsible for it. Data from whole-genome screens in multiplex families suggest interactions of at least 15 genes in the causation of autism. Since it has been recently shown that de novo deletions and duplications play a significant role in the etiology of autism, we aimed to scan this disease with the most sensitive molecular cytogenetic approaches. Methods: Array comparative genomic hybridization (arrayCGH) is a technique capable of detecting DNA copy number variations that cause human genetic disorders; and it has recently lead to the characterization of many novel microdeletion and microduplication syndromes. This method has proven to be a specific, sensitive, and fast technique which enables to analyse the whole genome in a single experiment. Thus array-CGH evaluation of 0−18 year-old 35 patients (29 male-6 female) with primary autism is presented in this study. Feature Axtraction programme is used to analyse the data. Numerical data is converted to image and. quality control analysis was performed (QC Metric). Appropiate patient data was chosen and analysed (Cytosure Analysis Software Version 2.2). Potential deletion and duplications were investigated. Results: Previously identified cytogenetic abnormalities at 16p13.11, 8p23.1 region in autistic individuals. was also detected in our study. In addition, our findings revealed 16p11.2 deletion in twelve patients, 1q21 deletion in ten patients, 2q21.1 deletion in eight patients, 2p21 deletion in seven patients, and 10q11.22 deletion in four patients. So far to our knowledge, these findings are the first data that we offer to the literature. Analysis of gene expression in patients with the same data support to analyse molecular pathogenesis of the disease and will lead to significant gains achieved. Conclusion: The results of our study suggest that 16p13.11 region and related genes might also represent a predisposition to autism. This study is one of the first “whole-genome” array CGH analysis in patients with autism; and since it will provide important clues for the underlying mechanisims and treatment and of the disease, more intensive research with further application of a CGH to wider groups of patients is needed. References [1] Harvard, C., Malenfant, P., Koochek, M., 2005 A variant Cri du Chat phenotype and autism spectrum disorder in a subject with de novo cryptic microdeletions involving 5p15.2 and 3p24.3−25 detected using whole genomic array CGH. Clin Genet 67, 341–351. [2] Shinawi, M., Cheung, S.W., 2008 The array CGH and its clinical applications. Drug Discovery Today 13, 760–770.
P.1.a.003 A possible association between panic disorder and the ghrelin gene
Gothenburg, Sweden; 7 Gothenburg university hospital, Institute of Neuroscience and Physiology, Gothenburg, Sweden Panic disorder is a severe anxiety disorder characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms such as heart palpitations, shortness of breath, and hyperventilation. Twin and adoption studies have shown the disorder to be in part hereditary, but the genes underlying the disease still remain to be elucidated. The general belief is that it is a combination of several polymorphism rather than a singel gene that is responsible [1]. The stomach-derived circulating hormone ghrelin plays an important role in hunger and motivated behaviour for food, but ghrelin in the central nervous system also appears to affect anxiety-like behaviour in animal studies [2,3]. Whether ghrelin also affects anxiety in humans has not been investigated. In the present study we genotyped six SNPs in the preproghrelin gene in Swedish patients suffering from panic disorder and controls. Three of the genotyped polymorphisms are missense mutations (rs4684677, rs34911341, and rs696217), and three of the polymorphisms are intronic (rs42451, rs35680, rs26802). The study was approved by the Ethics committee at the University of Gothenburg, and all participants provided written informed consent. The patient group consisted of 215 Swedish patients (63 men and 152 women, mean age 43 years) meeting the DSM-IV criteria for panic disorder, 83% also suffered from agoraphobia. Controls were 199 Swedish men born in 1944 and 252 Swedish women born in 1956. The control cohort was originally recruited for a study of cardiovascular risk factors. The polymorphisms were assessed using sequenom and, for samples for which the sequenom analysis failed, with pyrosequencing. Allele frequencies were analyzed using chi-square tests and an LD-plot was generated and haplotype blocks were analyzed using Haploview. The genotype frequencies in the control sample were in Hardy-Weinberg equilibrium and there were no differences between males and females regarding genotype distribution. The A allele of the rs4684677 polymorphism was significantly more common in patients than in controls (p = 0.02). No other significant associations were found for the other SNPs tested. The haplotype containing the SNPs rs4684677, rs42451, rs35680 and rs34911341 showed a strong significance for the block ACTC (p = 0.0042). The present study suggests that the A allele in the rs4684677 polymorphism may be more common in patients suffering from panic disorder than in controls. The polymorphism is a missense mutation located in exon 4 and is responsible for an amino acid exchange from Leu to Gln. To what extent this effects the function of the hormone is not known. Needless to say, the results of this study should be interpreted with caution as they need to be confirmed in other populations. However, taken together with the effects of ghrelin on anxiety-related behavior in animal studies, it makes an interesting finding and we suggest that the possible role for ghrelin in human anxiety disorders should be further investigated. References
K. Annerbrink1 ° , C. Hansson1 , C. Allgulander2 , S. Andersch3 , I. Sj¨odin4 , G. Holm5 , S. Dickson6 , E. Eriksson7 . 1 University of G¨ oteborg, Institute of Neuroscience and Physiology, G¨oteborg, Sweden; 2 Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; 3 Sahlgrenska university hospital, Department of Psychiatry, Gotehnburg, Sweden; 4 Link¨ oping university hospital, Department of Neuroscience and Locomotion, Link¨oping, Sweden; 5 Sahlgrenska university hospital, Department of medicine, Gothenburg, Sweden; 6 University of Gothenburg, Institute of Neuroscience and Physiology,
[1] Hettema, J.M., Neale, M.C., Kendler, K.S. 2001. A review and metaanalysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158(10), 1568−78. [2] Hansson, C., Haage, D., Taube, M., Egecioglu, E., Salom´e, N., Dickson, S.L. 2011. Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence. Neuroscience Feb 14. [3] Chuang, J.C., Zigman, J.M. 2010. Ghrelin’s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept. pii: 460549.