Multitrait analysis to decipher the intertwined genetic architecture of neuroanatomical phenotypes and psychiatric disorders.

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 challenging, and new approaches are needed to infer potential genetic structure underlying those phenotypes. Multivariate analyses is arising as a meaningful approach to reveal links between MRI phenotypes and psychiatric disorders missed by univariate approaches.

Methods: We first conducted univariate and multivariate genome-wide association studies (GWAS) for nine MRI-derived brain volume phenotypes in 20K UK Biobank participants. We next performed various complementary enrichment analyses to assess whether and how univariate and multitrait approaches can distinguish disorder-associated and non-disorder-associated variants from six psychiatric disorders: bipolarity, attention-deficit/hyperactivity disorder (ADHD), 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: Univariate MRI GWAS displayed only negligible genetic correlation with psychiatric disorders, while multitrait GWAS identified multiple new associations and showed significant enrichment for variants related to both ADHD and schizophrenia. Clustering analyses further detected two clusters displaying not only enrichment for association with ADHD and schizophrenia, but also consistent direction of effects. Functional annotation analyses of those clusters pointed to multiple potential mechanisms, suggesting in particular a role of neurotrophins pathways on both MRI and schizophrenia.

Conclusions: Our results show that multitrait association signature can be used to infer genetically-driven latent MRI variables associated with psychiatric disorders, opening paths for future biomarker development.