Abstract
Clinical and animal studies suggest a role for pathways regulated by cyclicβAMP in anxiety. Mouse gene deletion studies, our own linkage findings on chromosome 10, and a recently published genetic association study by Domschke et al. [2003: Am J Med Genet 117B:70β78] suggest that the cAMP responsive element modulator (CREM) may be involved in panic disorder. We have employed a familyβbased design to investigate the role of DNA sequence variations in the gene for CREM in panic disorder. We have genotyped 613 individuals in 70 panic disorder pedigrees, as well as 42 parent/offspring triads. Subjects were genotyped at two informative single nucleotide polymorphisms (SNPs) and three polymorphic microsatellites in the CREM genomic region; and the data were analyzed for genetic association and linkage. Linkage analysis employing several diagnostic/genetic models produced a maximum lod score of 0.63 for SNPβ1, located in the 5β² UTR of CREM, under a dominant model with a broad diagnostic definition of panic disorder. Nonβparametric analysis, using the NPL statistic or FBAT, also did not support any linkage or association between the markers and panic disorder. All five markers (spanning 77 kb) used in the study showed modest, but significant linkage disequilibrium. Analysis of 2β, 3β, 4β, or 5βmarker haplotypes using TRANSMIT failed to find any globally significant results; however, individual haplotypes containing a single allele of MSβ3 were nominally associated with panic disorder. These findings provide little additional evidence for a susceptibility locus for panic disorder either within the CREM gene or in a nearby region of chromosome 10p11 in our sample. Β© 2003 WileyβLiss, Inc.