Unveiling the Genetic Landscape of Basal Ganglia: Implications for Common Brain Disorders

The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted a multivariate genome-wide association analysis (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 European individuals with replication in 5,236 non-Europeans. We identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 87.5%, revealing a distributed genetic architecture across basal ganglia structures. Of the 72 loci, 51 are novel. Of these, APOE , NBR1 and HLAA , are all exonic and among the novel loci. Furthermore, we examined the genetic overlap between basal ganglia volumes and several neurological and psychiatric disorders. The most prominent overlap was seen with Parkinson’s disease, schizophrenia and migraine. HP and TMEM161B showed overlap between basal ganglia and Parkinson’s disease, but also three different psyciatric or nevrodevelopmental disorder(s), demonstrating important shared biology between brain disorders. Functional analyses implicated neurogenesis, neuron differentiation and development in basal ganglia volumes. These results enhance our understanding of the genetic architecture and molecular associations of basal ganglia structure and their role in brain disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The authors were funded by Norwegian Health Association (SB: 22731, KN: 25598), the South-Eastern Norway Regional Health Authority (OAA: 2013-123, 2017-112, 2019 108), the Research Council of Norway (TK: 276082, 323961. OAA: 213837, 223273, 248778, 273291, 262656, 229129, 283798, 311993. LTW: 204966, 249795, 273345). LTW: 2014 097, 2015 073, 2016 083), Stiftelsen Kristian Gerhard Jebsen, the European Research Council (LTW: ERCStG 802998) and the Department of Neurology at Oslo University Hospital (KN). The funding bodies had no role in the analysis or interpretation of the data; the preparation, review or approval of the manuscript; nor in the decision to submit the manuscript for publication. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) and on resources provided by UNINETT Sigma2 the National Infrastructure for High Performance Computing and Data Storage in Norway. The research has been conducted using the UK Biobank Resource (access code 27412) and using summary statistics for various brain disorders that partly included 23andMe data. We would like to thank the research participants and employees of UK Biobank, the 23andMe, the Psychiatric Genomics Consortium, International headache genetics Consortium, the International Genomics of Alzheimer Project and International Parkinson Disease Genomics Consortium for contributing summary statistics for making this work possible. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes In this study we used brain imaging and genetics data from the UK Biobank [], and GWAS summary statistics obtained from the Psychiatric Genomics Consortium [], 23andMe,inc. [], International headache genetics Consortium (IHGC) [], the International Genomics of Alzheimer Project [], and the International Parkinson Disease Genomics Consortium []. The latter included 23 and Me data, which was made available through 23andMe under an agreement with 23andMe that protects the privacy of the 23andMe participants []. The summary statistics for basal ganglia derived in this study is available in our github repository []. FUMA results are available online [].