Altered Frontoparietal, Temporal and Sensorimotor Structure-Function Coupling and Its Genetic Underpinnings in Bipolar Disorder

BackgroundStructure-function coupling quantifies how strongly structural connectivity supports functional communication across brain regions. Investigating structure-function coupling in bipolar disorder, a condition marked by dysconnectivity, may elucidate underlying neural mechanisms. We examined regional structure-function coupling in bipolar disorder and its genetic underpinnings to characterize network-level disruptions. MethodsRegional structure-function coupling was estimated in UK Biobank participants using edge-wise regression between measures of structural connectivity and functional connectivity. Bipolar disorder (n=163) and controls (n=326) were age and sex-matched and compared using general linear models. To explore the genetic basis of these structure-function coupling alterations, genome-wide association studies (GWAS) were conducted in an independent UK Biobank sample (n=38,190) for regions showing significant group differences. ResultsStructure-function coupling demonstrated a unimodal-to-transmodal gradient with highest coupling evident in visual regions (R2=0.29) and lowest in the insula (R2=0.03). The Bipolar disorder group showed higher structure-function coupling in the temporal pole and superior frontal gyrus ({beta}=0.269; {beta}=0.211) and lower coupling in the supramarginal, precentral, and postcentral gyri and the frontal pole ({beta}=-0.206 to -0.275). GWAS identified seven significant loci, with mapped genes (e.g., KAT6B, INPP5A, PLCE1) involved in neuronal development and cellular signaling. ConclusionBipolar disorder showed altered structure-function coupling across regions implicating multiple networks. These alterations suggest stronger structure-function alignment in limbic and attention networks and weaker alignment in sensorimotor, executive, frontoparietal, and salience regions relative to controls, potentially disrupting flexible polysynaptic communication. Altered coupling may relate to genetic variation affecting neurodevelopment, neuronal signaling, and synaptic plasticity. Together, these findings offer novel insight into the architectural contributions to the pathophysiology underlying bipolar disorder.