A transcriptomic atlas of the human brain reveals genetically determined aspects of neuropsychiatric health

Summary Regulation of gene expression is a vital component of neurological homeostasis. Cataloging the consequences of endogenous gene expression on the physical structure and connectivity of the brain offers a means of unifying trait-associated genetic variation with trait-associated neurological features. We perform tissue-specific transcriptome-wide association studies (TWASs) on over 3,400 neuroimaging phenotypes in the UK Biobank (N = 33,224) using our joint-tissue imputation (JTI)-TWAS method. We identify highly significant associations between predicted expression for 7,192 genes and a wide variety of measures of the brain derived from magnetic resonance imaging (MRI). Our approach generates reproducible results in internal and external replication datasets. Genetically determined expression alone is sufficient for high-fidelity reconstruction of brain structure and organization. We demonstrate complementary benefits of cross-tissue and single-tissue analyses toward an integrated neurobiology and provide evidence that gene expression outside the central nervous system provides unique insights into brain health. As an application, we provide evidence suggesting that the genetically regulated expression of schizophrenia risk genes causally affects over 73% of neurological phenotypes that are altered in individuals with schizophrenia (as identified by neuroimaging studies). Imaging features associated with neuropsychiatric traits can provide valuable insights into underlying pathophysiology. By linking neuroimaging-derived phenotypes with expression levels of specific genes, this resource represents a powerful gene prioritization schema that can improve our understanding of brain function, development, and disease. The use of multiple different cortical and subcortical atlases in the resource facilitates direct integration of these data with findings from a diverse range of clinical neuroimaging studies. Regulation of gene expression is a vital component of neurological homeostasis. Cataloging the consequences of endogenous gene expression on the physical structure and connectivity of the brain offers a means of unifying trait-associated genetic variation with trait-associated neurological features. We perform tissue-specific transcriptome-wide association studies (TWASs) on over 3,400 neuroimaging phenotypes in the UK Biobank (N = 33,224) using our joint-tissue imputation (JTI)-TWAS method. We identify highly significant associations between predicted expression for 7,192 genes and a wide variety of measures of the brain derived from magnetic resonance imaging (MRI). Our approach generates reproducible results in internal and external replication datasets. Genetically determined expression alone is sufficient for high-fidelity reconstruction of brain structure and organization. We demonstrate complementary benefits of cross-tissue and single-tissue analyses toward an integrated neurobiology and provide evidence that gene expression outside the central nervous system provides unique insights into brain health. As an application, we provide evidence suggesting that the genetically regulated expression of schizophrenia risk genes causally affects over 73% of neurological phenotypes that are altered in individuals with schizophrenia (as identified by neuroimaging studies). Imaging features associated with neuropsychiatric traits can provide valuable insights into underlying pathophysiology. By linking neuroimaging-derived phenotypes with expression levels of specific genes, this resource represents a powerful gene prioritization schema that can improve our understanding of brain function, development, and disease. The use of multiple different cortical and subcortical atlases in the resource facilitates direct integration of these data with findings from a diverse range of clinical neuroimaging studies.