The advancement of large-scale magnetic resonance imaging (MRI) studies has enabled systematic investigations of cortical morphology, such as cortical thickness and surface area, across a variety of psychiatric disorders. In particular, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium has conducted some of the largest MRI studies characterizing group differences between patients (cases) and control individuals in the cerebral cortex for a number of disorders, including attention-deficit/hyperactivity disorder (ADHD),¹ autism spectrum disorder (ASD),² bipolar disorder (BD),³ major depressive disorder (MDD),⁴ obsessive-compulsive disorder (OCD),⁵ and schizophrenia.⁶ Nonetheless, the neurobiology underlying these MRI-derived macroscopic features is not well understood.

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Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.