B. Wan, Y. He, V. Warrier, A. John, M. Kirschner, S. B. Eickhoff, R. A. I. Bethlehem, S. L. Valk
The intrinsic functional organization of the human connectome can be captured along multiple spatial axes or gradients that differentiate sensory from association networks, visual from somatomotor networks, and control from default networks. These gradients demonstrate variability at the individual level, changing across the lifespan and varying across disorders. However, the biological basis of this variability is not fully understood. In this study, we integrated genetic, neuroimaging, and transcriptomic data using genome-wide association studies (GWAS) and twin-based heritability analysis of over 30,000 individuals to understand the contribution of genes to variability in functional organization gradients. Specifically, we identified five genetic loci involving 16 genes associated with the global organization of functional gradients that are enriched for lipid biosynthesis and energy metabolism. At the local regional level, we observe modest heritability scores across twin- and GWAS-based analyses of different samples, including adolescents, young adults, and middle-aged and older adults. Association areas are the most heritable. Importantly, the genes identified by GWAS do not overlap with those observed using post-mortem spatial transcriptomics. Lastly, while we did not observe genetic overlap between neuropsychiatric disorders and functional gradients, we found that regional gradient loadings are altered not only in neuropsychiatric disorders, but also in healthy individuals with polygenic risk scores for these disorders. Our findings highlight the complex interplay between genetic variation and intrinsic brain function. They offer new insights into the biological foundations of functional brain organization and its implications for neuropsychiatric vulnerability.