This study investigates the genetic architecture of structural connectivity in the human brain using genome-wide association studies (GWAS) of 206 structural connectivity measures derived from diffusion magnetic resonance imaging (dMRI) tractography in 26,333 UK Biobank participants. The researchers identified 30 independent genome-wide significant variants after Bonferroni correction, implicating genes involved in myelination, neurite elongation, neural cell proliferation, neuronal migration, cytoskeletal organization, and brain metal transport. These variants exhibit four broad patterns of spatial association with structural connectivity: some are strongly associated with corticothalamic or interhemispheric connectivity, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1% of common variants estimated to have non-zero effects. The measures also show signatures of negative selection, suggesting that variants affecting structural connectivity tend to have negative consequences on evolutionary fitness. Genetic correlations between structural connectivity and various neuropsychiatric and cognitive traits indicate that variants altering connectivity influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. The study highlights the pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, supporting the relevance of this genetic control to healthy brain function.This study investigates the genetic architecture of structural connectivity in the human brain using genome-wide association studies (GWAS) of 206 structural connectivity measures derived from diffusion magnetic resonance imaging (dMRI) tractography in 26,333 UK Biobank participants. The researchers identified 30 independent genome-wide significant variants after Bonferroni correction, implicating genes involved in myelination, neurite elongation, neural cell proliferation, neuronal migration, cytoskeletal organization, and brain metal transport. These variants exhibit four broad patterns of spatial association with structural connectivity: some are strongly associated with corticothalamic or interhemispheric connectivity, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1% of common variants estimated to have non-zero effects. The measures also show signatures of negative selection, suggesting that variants affecting structural connectivity tend to have negative consequences on evolutionary fitness. Genetic correlations between structural connectivity and various neuropsychiatric and cognitive traits indicate that variants altering connectivity influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. The study highlights the pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, supporting the relevance of this genetic control to healthy brain function.