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Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families

Fyer, Abby J.a,c; Costa, Ramiroc; Haghighi, Fatemeha,c; Logue, Mark W.d; Knowles, James A.e; Weissman, Myrna M.a,c; Hodge, Susan E.b,c; Hamilton, Steven P.f

doi: 10.1097/YPG.0b013e328353956a
Original Articles

Background: The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin, and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We have previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., PD definition. Here, we extend this work by carrying out exploratory linkage analyses in this same pedigree set using ten additional literature-based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities.

Methods: Multiply affected families (>2 individuals with PD) were recruited from clinical and nonclinical sources, evaluated by a clinician-administered semistructured interview and a subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric two-point (homogeneity and heterogeneity), multipoint, and nonparametric methods. Empirically based permutations were used to estimate model-specific and global (across all phenotypes) P-values.

Results: The highest score was a two-point lod (4.27, global P<0.08) on chromosome 13 (D13S793, 76 cM) for the phenotype ‘specific or social phobia’ under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes.

Conclusion: Although the interpretation of findings is limited by the sample size and the large number of phenotypes and models analyzed, these data suggest a region on chromosome 13 as a potential site for further exploration in relation to the risk for specific and social phobias.

aDepartment of Psychiatry, College of Physicians and Surgeons

bDivision of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health, Columbia University

cNew York State Psychiatric Institute, New York, New York

dBiomedical Genetics, Boston University School of Medicine, Boston, Massachusetts

eKeck School of Medicine, University of Southern California, Los Angeles

fDepartment of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, USA

Correspondence to Abby Joy Fyer, MD, New York State Psychiatric Institute, Box 82, 1051 Riverside Drive, NY 10032, USA Tel: +1 212 543 5372; fax: +1 212 543 6609; e-mail:

Received May 5, 2011

Accepted October 10, 2011

© 2012 Lippincott Williams & Wilkins, Inc.