A Genome-Wide Association Study of Amygdala Activation in Youths With and Without Bipolar Disorder

Objective: Functional magnetic resonance imaging is commonly used to characterize brain activity underlying a variety of psychiatric disorders. A previous functional magnetic resonance imaging study found that amygdala activation during a face-processing task differed between pediatric patients with bipolar disorder (BD) and healthy controls. We undertook a genome-wide association study to explore the genetic architecture of this neuroimaging phenotype. Method: Thirty-nine patients with BD and 29 healthy controls who had previously undergone functional magnetic resonance imaging when viewing a neutral face were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array. After quality control, 104,043 SNPs were tested against normalized amygdala activation scores obtained from the right and left hemispheres. Genetic association was tested with covariates to control for race and ethnicity. Patients and controls were grouped together in the primary analyses. Results: Right amygdala activation under the hostility contrast was most strongly associated with an SNP in the gene DOK5 (rs2023454, p = 4.88 × 10 ^-7, false discovery rate = 0.05). DOK5 encodes a substrate of tropomyosin-related kinase B/C receptors involved in neurotrophin signaling. This SNP accounted for about 33% of the variance in youths with BD and 12% of the variance in healthy youths. Other results (false discovery rate <50%) were also observed at SNPs near several other genes. Conclusions: To our knowledge, this is the first genome-wide association study of amygdala activation in adolescents with BD. Although preliminary, these data suggest that DOK5 and perhaps several other genes influence the magnitude of amygdala activation during face processing, particularly in those with BD. Further studies are needed to replicate these findings and characterize the mechanisms involved.