Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7

Abstract

This article presents a Bayesian re-analysis of a linkage study of panic disorder Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. In the initial analysis Crowe et al. failed to find compelling evidence for linkage based on either LOD scores or NPL scores anywhere in the genome. The maximum LOD score was 2.23 on chromosome 7 at marker D7S2846 (57.79 cM according to Marshfield). Over the past several years we have been developing a Bayesian alternative approach to linkage analysis, based on direct measurement of the posterior probability of linkage (PPL), and have shown elsewhere that this approach has several advantages over the available alternatives for mapping complex-disease genes Vieland [1998: Am J Med Genet 63:947-954]; Wang et al. [1999: Genet Epidemiol 17(Suppl 1):S749-S754]; Wang et al. [2000: Ann Hum Genet 64:533-553]; and Vieland et al. [2001: Hum Hered 51:199-208]. One limitation of this approach in previous applications has been that it required the investigator to specify a fixed genetic model for the trait. We employ a new implementation of the PPL that treats the unknown trait model as a vector of nuisance parameters, which is integrated out of the PPL equation. When we apply this new model-integrated version of the PPL to the data of Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109] we obtain much clearer evidence than previously reported for a locus on chromosome 7, with an 80% probability of linkage to marker D7S521. A second location is also identified on chromosome 16 near marker D16S749 (PPL = 24%). The results for the remainder of the genome are consistently low. The two loci identified here are also supported by independent evidence from other studies.