Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene

Annerbrink, Kristina; Westberg, Lars; Olsson, Marie; Andersch, Sven; Sjödin, Ingemar; Holm, Göran; Allgulander, Christer; Eriksson, Elias

doi:10.1097/ypg.0b013e328341a3db

Cited by 42 publications

(28 citation statements)

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“…Even though most of the research performed so far supports a prominent role for the OX1R in anxiety, an association between a OX2R polymorphism (Val308Iso) and panic disorder has been reported in female patients [69]. Therefore, further research will be needed to fully understand the specific involvement of the different components of the orexin system in the pathophysiological substrate of panic disorders.…”

Section: Reviewmentioning

confidence: 99%

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Orexins and fear: implications for the treatment of anxiety disorders

Flores

Saravia

Maldonado

et al. 2015

Trends in Neurosciences

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An understanding of the neurobiological mechanisms involved in the regulation of fear is essential for the development of new treatments for anxiety disorders, such as phobias, panic, and post-traumatic stress disorders (PTSD). Orexins, also known as hypocretins, are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system. Although this system was initially believed to be primarily involved in the regulation of feeding behavior, recent studies have shown that orexins also modulate neural circuits implicated in the expression and extinction of fear memories. Here, we discuss recent findings involving orexins in anxiety disorders and current clinical trials using orexin ligands that could be applied to identify new therapies for diseases characterized by pathological fear.

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Section: Reviewmentioning

confidence: 99%

“…Panic disorder has been associated with the Val308Iso polymorphism in the OX2R gene [69]. In addition, epigenetic mechanisms regulate the formation and extinction of fear memories [100].…”

Section: How Effective Is Oxr Antagonism In Humans?mentioning

confidence: 99%

Orexins and fear: implications for the treatment of anxiety disorders

Flores

Saravia

Maldonado

et al. 2015

Trends in Neurosciences

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“…OX 2 308 Ile variant has been associated with panic disorder in female patients (Annerbrink et al, 2011). In contrast, neither male nor female populations showed a risk associated with either variant (Val or Ile) of OX 1 408 (Annerbrink et al, 2011).…”

Section: Orexin Receptor Variants In Psychiatric Disordersmentioning

confidence: 99%

“…In contrast, neither male nor female populations showed a risk associated with either variant (Val or Ile) of OX 1 408 (Annerbrink et al, 2011). Functional analysis of variant orexin receptors may provide insight into these allele associations.…”

Section: Orexin Receptor Variants In Psychiatric Disordersmentioning

confidence: 99%

“…Gene variants for the orexin peptides and, especially, their G protein-coupled receptors, OX 1 and OX 2 , have been identified (Figures 1, 2), and investigated in many CNS disorders, including sleep and wakefulness (Lin et al, 1999), polydipsia in schizophrenia (Meerabux et al, 2005; Fukunaka et al, 2007), panic disorder (Annerbrink et al, 2011), mood disorders (Rainero et al, 2011a), migraine (Schürks et al, 2007b; Rainero et al, 2011b), and cluster headache (Rainero et al, 2004). The associations under investigation will ultimately benefit from the clarification, possible from genome-wide association studies (GWAS).…”

Section: Introductionmentioning

confidence: 99%

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OX1 and OX2 orexin/hypocretin receptor pharmacogenetics

et al. 2014

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Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts the involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are discussed. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated—with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency—leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics) is also discussed in the review.

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Genetics of Panic Disorder

Maron

Shlik

2013

Encyclopedia of Life Sciences

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The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. To date, several hundreds of candidate genes have been examined in association studies, but most of the results have been negative, inconsistent or awaiting replication. Perhaps most intriguing have been findings involving the genes of biological systems known to be pertinent to anxiety phenotypes, such as serotonin, cholecystokinin and adenosine. An array of other genes related to hormonal, neurotrophic and intracellular systems has also been implicated in disposition to PD. The recent advances in bioinformatics and genotyping technologies, including genome‐wide association and gene expression methods, promise more comprehensive discovery in PD. Preliminary findings point to a number of novel gene targets with still unknown pathogenetic relationship to PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current ambiguity to more definitive findings. Key Concepts: The linkage and candidate gene association studies have so far showed only weak success to identify reliable and replicated evidence for the genetic substrate of PD. The genetic research in PD to date has been mostly restricted to small phenotypically and ethnically diverse datasets with genotyping of limited numbers of SNPs. An improved understanding of neurobiological pathways of PD could contribute to a more effective identification of candidate genes. Novel conceptual and analytic approaches, such as pathways‐based analyses, may help to advance GWA studies in PD. Laboratory panic challenge models may provide clues to genetic predisposition to PD. The understanding of genetic underpinnings of PD will not be of full value without a conceptual integration of the clinical phenomena of PD with psychological models and neurobiological or molecular substrates underlying its development and course. The course of PD may depend on the balance between pathogenetic and compensatory or recovery processes, accompanied by activation or inhibition of relevant genes. PD might exist in many distinct genetic forms, each with a different set of genes, but also in one form with certain genes reflecting broader vulnerability to panicogenesis. The heterogeneity in PD phenotypes, age of onset, subtypes and severity of panic attacks, gender and familial aggregation were not sufficiently accounted for in most of published studies and should be more carefully addressed in further analyses. Other comprehensive genetic approaches, including GWA, the analysis of copy number variants and the study of regulatory small noncoding RNAs, may lead to uncovering new genomic mechanisms of PD.

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Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene

Cited by 42 publications

References 65 publications

Orexins and fear: implications for the treatment of anxiety disorders

Orexins and fear: implications for the treatment of anxiety disorders

OX1 and OX2 orexin/hypocretin receptor pharmacogenetics

Genetics of Panic Disorder

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