Genome-Wide Association Study of Temperament in Bipolar Disorder Reveals Significant Associations with Three Novel Loci

Abstract

The many attempts to identify genes for bipolar disorder (BD) have met with limited success, which has generally been attributed to genetic heterogeneity and small gene effects. However, it is also possible that the categorical phenotypes used in genetic studies of BD are not the most informative or biologically relevant. Although quantitative phenotypes provide an alternative to categorical phenotypes based on diagnosis, they have not been fully exploited in BD genetics due to the lack of accessible biological measures. We have explored aspects of temperament as quantitative phenotypes that might define subtypes of BD with different clinical features and courses of illness. Temperament is a heritable personality factor that establishes the baseline level of reactivity, mood, and energy of a person. We have performed a genome-wide association study with genotype data from the Bipolar Genome Study and 1263 bipolar subjects that had completed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). The TEMPS-A is designed to assess lifelong, milder aspects of bipolar symptomatology and defines five temperaments: hyperthymic, dysthymic, cyclothymic, irritable, and anxious. The irritable temperament produced the most significant result with a genome-wide significant p value of 1.7 × 10(-8) on chromosome 1. The hyperthymic temperament produced additional genome-wide significant p values of 4.1 × 10(-8) and 2.1 × 10(-8) on chromosomes 12 and 22, respectively. These results suggest that aspects of temperament might define subtypes of BD that are more clinically and genetically homogenous, which might aid in the identification of predisposing genetic variants.