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Resemblance Among Relatives Across a Broad Spectrum of Phenotypic Characteristics

Thomas G. Schulze, MD; Donald Hedeker, PhD; Peter Zandi, PhD; Marcella Rietschel, MD; Francis J. McMahon, MD

Arch Gen Psychiatry. 2006;63:1368-1376.

Context  Current diagnostic criteria for bipolar affective disorder define a phenotype that is highly heritable, yet clinically variable. A more homogeneous definition might facilitate genetic and other studies, but the best approach is unclear. Familial features of bipolar disorder should help define more homogeneous subtypes, but there are few data indicating which clinical features of bipolar disorder are the most familial.

Objective  To study the familiality of phenotypic features in families ascertained through individuals with bipolar affective disorder.

Design  The study comprises 1246 individuals in 172 multiplex families ascertained for genetic linkage studies of bipolar disorder. The familiality of 40 diverse phenotypic features was studied using mixed-effects regression analysis.

Results  Substance abuse, alcoholism, psychosis, history of suicide attempt, and the level of social functioning were all strongly familial in this sample. Several other traits, including clinical subtype, earliest age at onset, and comorbid panic disorder, showed a suggestion of familiality that did not hold up to conservative correction for multiple testing.

Conclusions  This is the largest and most comprehensive study to assess the familiality of phenotypic features in bipolar disorder. Our results suggest that comorbid conditions and social functioning should be considered along with other familial clinical features in formulating subtypes of bipolar disorder suitable for further studies. Familial variables may help reduce diagnostic heterogeneity in genetic and other biological studies.

Author Affiliations: Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany (Drs Schulze and Rietschel); Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Md (Drs Schulze and McMahon); Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Ill (Dr Hedeker); and Department of Mental Health, The Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Md (Dr Zandi).

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