Genetic influences on the shape of brain ventricular and subcortical structures

Brain ventricular and subcortical structures are heritable both in size and shape. Genetic influences on brain region size have been studied using conventional volumetric measures, but little is known about the genetic basis of ventricular and subcortical shapes. Here we developed pipelines to extract seven complementary shape measures for lateral ventricles, subcortical structures, and hippocampal subfields. Based on over 45,000 subjects in the UK Biobank and ABCD studies, 60 genetic loci were identified to be associated with brain shape features (P < 1.09 x 10-10), 19 of which were not detectable by volumetric measures of these brain structures. Ventricular and subcortical shape features were genetically related to cognitive functions, mental health traits, and multiple brain disorders, such as the attention-deficit/hyperactivity disorder. Vertex-based shape analysis was performed to precisely localize the brain regions with these shared genetic influences. Mendelian randomization suggests brain shape causally contributes to neurological and neuropsychiatric disorders, including Alzheimers disease and schizophrenia. Our results uncover the genetic architecture of brain shape for ventricular and subcortical structures and prioritize the genetic factors underlying disease-related shape variations.