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Gene variations in the cholecystokinin system in patients with panic disorder

Koefoed, Pernillea b c; Woldbye, David P.a c; Hansen, Thomas O.b; Hansen, Elsebeth S.c e; Knudsen, Gitte M.d; Bolwig, Tom G.c; Rehfeld, Jens F.b

doi: 10.1097/YPG.0b013e32833511a8
Original Articles

Objectives: Panic disorder (PD) is a common psychiatric disease occurring more frequently in women than men. Multiple common and/or rare variants in the genome contribute to the complex etiology of the disorder. The neuropeptide cholecystokinin (CCK) and its receptors (the CCK system) have been suggested to be involved in the pathogenesis of PD.

Methods: We examined the promoter, exon, and exon–intron boundaries of the genes encoding CCK and its receptors (CCKAR and CCKBR) for variations in 187 patients with PD and 277 screened control individuals. Up to 1342 additional healthy population controls were examined for some of the variations. One CCK gene intron variation was analyzed for alternative splicing using an exon-trapping assay.

Results: The promoter variant (−36C > T; rs1799923) and an intron 1 polymorphism (IVS1-7C > G; rs754635) in the CCK gene were found to protect against PD (P<0.05). The intron 1 variation did not seem to alter the splicing of the gene. None of the other variations found were associated with PD, but a 2-marker haplotype (rs1800855/rs1800857) in the CCKAR gene protected women against PD (P=0.004). In addition, we found two novel rare missense variations in the CCKBR gene (Lys329Asn and Pro446Leu) in two and one patient, respectively.

Conclusion: The results suggest that the CCK system may play a role in the pathogenesis of PD, with susceptibility alleles both protecting and contributing to the disease. Both common and rare variants seem to be involved. The involvement of the CCK system may also contribute to the increased prevalence of PD in women.

aLaboratory for Neuropsychiatry, Department of Neuroscience and Pharmacology

bDepartment of Clinical Biochemistry

cCentre of Psychiatry

dCenter for Integrated Molecular Brain Imaging, Rigshospitalet, University of Copenhagen

eOringe, Psychiatry Vordingborg, Denmark

Correspondence to Pernille Koefoed, PhD, Laboratory for Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, O-6102, Blegdamsvej 9, Copenhagen 2100, Denmark

Tel: +45 3545 6115; fax: +45 3539 3546; e-mail: pkoefoed@sund.ku.dk

Received 21 April 2009 Revised 18 August 2009 Accepted 24 August 2009

© 2010 Lippincott Williams & Wilkins, Inc.