Research paperQuantitative genetic analysis of anxiety trait in bipolar disorder

•In summary, anxiety trait meets the criteria, for being an endophenotype of BPI as outlined by Gottesman and Gould (2003). The trait is associated with BPI, is state independent (Reichenberg and Harvey, 2007), is heritable and co-segregates with BPI within families.•The current report is a replication of the initial findings with a larger sample of extended and multigenerational families with one or more BPI from the CVCR.•We confirmed each of the criteria for an endophenotype before running the heritability analysis.We assessed subclinical anxiety in healthy relatives with high genetic risk for BPI and healthy unrelated controls.•The diagnosis of each subject was obtained through the best-estimate procedure, considered the gold standard in psychiatric genetic research, and fully tested by our research group (Contreras et al., 2009).•All participants were from the Central Valley of Costa Rica.

BackgroundBipolar disorder type I (BPI) affects approximately 1% of the world population. Although genetic influences on bipolar disorder are well established, identification of genes that predispose to the illness has been difficult. Most genetic studies are based on categorical diagnosis. One strategy to overcome this obstacle is the use of quantitative endophenotypes, as has been done for other medical disorders.MethodsWe studied 619 individuals, 568 participants from 61 extended families and 51 unrelated healthy controls. The sample was 55% female and had a mean age of 43.25 (SD 13.90; range 18-78).Heritability and genetic correlation of the trait scale from the Anxiety State and Trait Inventory (STAI) was computed by using the general linear model (SOLAR package software).Resultswe observed that anxiety trait meets the following criteria for an endophenotype of bipolar disorder type I (BPI): 1) association with BPI (individuals with BPI showed the highest trait score (F = 15.20 [5,24], p = 0.009), 2) state-independence confirmed after conducting a test-retest in 321 subjects, 3) co-segregation within families 4) heritability of 0.70 (SE: 0.060), p = 2.33 × 10-14 and 5) genetic correlation with BPI was 0.20, (SE = 0.17, p = 3.12 × 10−5).LimitationsConfounding factors such as comorbid disorders and pharmacological treatment could affect the clinical relationship between BPI and anxiety trait. Further research is needed to evaluate if anxiety traits are specially related to BPI in comparison with other traits such as anger, attention or response inhibition deficit, pathological impulsivity or low self-directedness.ConclusionsAnxiety trait is a heritable phenotype that follows a normal distribution when measured not only in subjects with BPI but also in unrelated healthy controls. It could be used as an endophenotype in BPI for the identification of genomic regions with susceptibility genes for this disorder.