Multitrait Analysis to Decipher the Intertwined Genetic Architecture of Neuroanatomical Phenotypes and Psychiatric Disorders

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BACKGROUND: There is increasing evidence of shared genetic factors between psychiatric disorders and brain magnetic resonance imaging (MRI) phenotypes. However, deciphering the joint genetic architecture of these outcomes has proven to be challenging, and new approaches are needed to infer the genetic structures that may underlie those phenotypes. Multivariate analyses are a meaningful approach to reveal links between MRI phenotypes and psychiatric disorders missed by univariate approaches. METHODS: First, we conducted univariate and multivariate genome-wide association studies for 9 MRI-derived brain volume phenotypes in 20,000 UK Biobank participants. Next, we performed various complementary enrichment analyses to assess whether and how univariate and multitrait approaches could distinguish disorder-associated and non-disorder-associated variants from 6 psychiatric disorders: bipolar disorder, attention-deficit/hyperactivity disorder, autism, schizophrenia, obsessive-compulsive disorder, and major depressive disorder. Finally, we conducted a clustering analysis of top associated variants based on their MRI multitrait association using an optimized k-medoids approach. RESULTS: A univariate MRI genome-wide association study revealed only negligible genetic correlations with psychiatric disorders, while a multitrait genome-wide association study identified multiple new associations and showed significant enrichment for variants related to both attention-deficit/hyperactivity disorder and schizophrenia. Clustering analyses also detected 2 clusters that showed not only enrichment for association with attention-deficit/hyperactivity disorder and schizophrenia but also a consistent direction of effects. Functional annotation analyses of those clusters pointed to multiple potential mechanisms, suggesting in particular a role of neurotrophin pathways in both MRI phenotypes and schizophrenia. CONCLUSIONS: Our results show that multitrait association signature can be used to infer genetically driven latent MRI variables associated with psychiatric disorders, thereby opening paths for future biomarker development.

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