Intracortical myelin in bipolar disorder type I and the impacts of neuregulin-1 variation and age

Abstract

Introduction: Bipolar disorder is associated with cortical abnormalities, including deficits in intracortical myelination. Intracortical myelin follows an inverted-U trajectory over the lifetime, but this trajectory is blunted in individuals with bipolar disorder. Little is understood about which genetic factors contribute to these deficits. Neuregulin-1, a cell-signalling protein, has been shown to contribute to cortical abnormalities and increase susceptibility to related disorders. Assessing the prevalence of neuregulin-1 polymorphisms, notably rs6994992, in bipolar disorder may elucidate the genetic contributors of intracortical myelin deficits and increase our understanding of factors causing susceptibility to bipolar disorder. Methods: 67 participants with bipolar disorder type I and 75 healthy control participants were included. T1-weighted MRI images were collected and processed to create R1 cortical maps, a proxy measure of intracortical myelin. Participant blood samples were genotyped at the rs6994992 locus. Linear models were used to test whether intracortical myelin can be predicted by age, bipolar diagnosis and NRG1 genotype. Results: Intracortical myelin is significantly predicted by age, diagnosis and genotype together in the motor cortex (left: R2 = 0.09, p < 0.01, right: R2 = 0.06, p < 0.05), the right premotor cortex (R2 = 0.095, p < 0.001), and the right inferior frontal cortex (R2 = 0.098, p < 0.001). Age is a significant individual predictor of intracortical myelin in the right dorsal anterior cingulate cortex, the bilateral motor cortex, the right premotor cortex, and the right inferior frontal cortex. Conclusions and Future Directions: Our study suggests that the right premotor, bilateral primary motor, and right inferior frontal cortices are regions of interest for understanding how intracortical myelin changes throughout the lifetime, especially in bipolar disorder. Future work should examine the impact of polygenic risk scores of bipolar disorder on intracortical myelin.