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Cardiovascular health interacts with cognitive and mental health in complex ways, yet little is known about the phenotypic and genetic links of heart-brain systems. We quantified heart-brain connections using multiorgan magnetic resonance imaging (MRI) data from more than 40,000 subjects. Heart MRI traits displayed numerous association patterns with brain gray matter morphometry, white matter microstructure, and functional networks. We identified 80 associated genomic loci (P < 6.09 × 10−10) for heart MRI traits, which shared genetic influences with cardiovascular and brain diseases. Genetic correlations were observed between heart MRI traits and brain-related traits and disorders. Mendelian randomization suggests that heart conditions may causally contribute to brain disorders. Our results advance a multiorgan perspective on human health by revealing heart-brain connections and shared genetic influences. Description Editor’s summary It is known that cardiovascular disorders correlate with some neurological and psychiatric conditions, but it is not always clear what the connections are and whether they are caused by an innate predisposition or by the stress induced by having a medical condition. To detangle these questions, Zhao et al. examined imaging and genetic data from tens of thousands of participants in the UK Biobank and BioBank Japan (see the Perspective by Sacher and Witte). Through this large-scale analysis, the authors uncovered correlations between structure and function of both the heart and the brain, such as links between specific features of cardiac imaging and neuropsychiatric disorders. The authors also used Mendelian randomization to demonstrate shared genetic influences on both the brain and the heart. —Yevgeniya Nusinovich Biobank-scale imaging traits reveal phenotypic and genetic links between the human heart and brain. INTRODUCTION There is increasing evidence pointing to a close relationship between heart health and brain health, with cardiovascular diseases potentially leading to brain diseases such as stroke, dementia, and cognitive impairment. Magnetic resonance imaging (MRI) is a valuable tool that can be used to assess both the heart and brain, generating biomarkers and endophenotypes for various clinical outcomes. However, although recent large-scale analyses have been conducted on heart and brain MRI-derived traits separately, few studies have explored the potential for multiorgan MRI to examine heart-brain connections and identify shared genetic effects. The structural and functional links between the heart and the brain remain unclear. RATIONALE Using multiorgan MRI and genetic data from >40,000 subjects, we aimed to quantify interorgan connections between the heart and brain and identify the underlying genetic variants. Specifically, we analyzed 82 cardiac and aortic MRI-derived traits across six categories: left and right ventricles, left and right atria, and ascending and descending aortas, as well as 458 brain MRI traits that measured structure and function. RESULTS After controlling for various covariates, we found that heart MRI traits were clearly associated with the brain across all imaging modalities studied. We observed multiple patterns of association for brain gray matter morphometry, white matter microstructure, and functional networks. For example, we found that the left ventricle of the heart showed the strongest correlations with microstructure metrics of cerebral white matter tracts, suggesting that adverse heart features were associated with poorer white matter microstructure. Our genome-wide association analysis of heart MRI traits identified 80 associated genomic loci (P < 6.09 × 10−10). We performed sex-specific analysis and found that the genetic effects on heart structure and function were highly consistent between both sexes. Further, we conducted a systematic search of previously reported genetic results in these genomic loci and found that heart MRI traits had shared genetic influences and colocalized with heart and brain diseases and complex traits. We identified genetic correlations between heart MRI traits and various brain complex traits and diseases such as stroke, eating disorders, schizophrenia, cognitive function, and mental health traits. For example, adverse myocardial wall thickness condition was positively genetically correlated with stroke. We further used two-sample Mendelian randomization to explore causal genetic links between the heart and brain, and our findings suggest that adverse heart features have genetic causal effects on several brain diseases such as psychiatric disorders and depression. CONCLUSION This study deepened our understanding of heart-brain links and their genetic basis. We observed that MRI measurements of the two organs were associated with each other, and this was independent of a wide variety of body measures, shared risk factors, and imaging confounders. We also uncovered genetic colocalizations and correlations between heart structure and function and brain clinical end points, suggesting that adverse heart metrics may have implications for brain abnormalities and the risk of brain diseases. By understanding human health from a multiorgan perspective, we may be able to improve disease risk prediction and prevention and mitigate the negative effects of one organ disease on other organs that may be at risk. Heart-brain connections revealed by multiorgan imaging genetics. Top left: Quantifying the heart and brain structure and function in MRI. Top right: Examples of associations between heart MRI traits and brain white matter tracts. Bottom left: Genomic loci associated with heart MRI traits that overlapped with traits and disorders of the heart and/or brain. Bottom right: Selected genetic correlations between heart MRI traits and brain disorders.