This project will be a three year continuation of a linkage study of panic disorder. At this time 21 multiplex pedigrees of panic disorder consisting of 244 individuals, 40% affected, have been evaluated with SCID interviews by project psychiatrists, DSM-III diagnoses have been made, and cell lines have been cryopreserved. Five pedigrees collected in Iceland totaling 95 subjects, 37 of whom are affected, will be used to replicate any promising findings from the US pedigrees. Over 200 DNA markers have been typed on the pedigrees, approximately 150 of which have been sufficiently informative to provide linkage data. These markers have excluded 29% of the genome by virtue of lod scores less than -2 but no linkage has been detected. The pedigree sample is presently being reinterviewed with the SCID interview and the diagnoses are being upgraded from DSM-III to DSM-III-R. Over the next project period an additional five pedigrees per year averaging 15 relatives per pedigree will be added to the study. The goals of the next project period will be to type 300-450 short tandem repeat polymorphisms on the estimated 25 pedigrees that will be available when that project starts. Linkage analyses will be conducted using three genetic models: 1. lod score analysis of definite DSM-III-R panic disorder as the affected phenotype; 2. lod score analysis of definite plus subsyndromal cases; and 3. affected sib pair analysis of definite plus subsyndromal cases. Exclusion maps of the chromosomes will be constructed until the genome has been covered at a lod score level of -2.0 or less. Lod scores greater than 1.5 will be explored by saturating the region of interest with additional markers and creating a fine grained map. Provisional linkage findings will be tested in the Icelandic pedigree sample for replicability.
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