Local genetic correlation analysis links depression with molecular and brain imaging endophenotypes

Major depressive disorder (MDD) is a heritable psychiatric disorder which is considered one of the leading causes of disability world-wide. Improved understanding of its genetic component could inform novel treatment developments, but so far, gaining functional insights from genome-wide association studies has been difficult. In this study, we sought to generate hypotheses about plausible mechanisms through which genetic variants could influence MDD using a novel approach. Considering the cis-regions of protein coding genes as the loci of interest, we applied local genetic correlation analysis to study the genetic relationship between MDD and a range of brain, endocrine, and immune related endophenotypes across several modalities (tissue specific gene expression and splicing, regional brain volumes, and brain network connectivity). We identify significant genetic relations between MDD and endophenotypes within the cis-regions of multiple genes, and perform endophenotype specific enrichment analyses of the top associated genes. Our results offer potential mechanisms through which MDD related variants in these genomic regions could act, and convergent evidence from multiple endophenotypes implicate FLOT1 as a gene which may exhibit wide-ranging pleiotropic effects and be particularly interesting for functional follow-up. Here, we have illustrated how local genetic correlation analysis applied to lower level endophenotypes has the power to prioritise genes and functional paths which warrant further investigation for their possible role in MDD aetiology. ### Competing Interest Statement C.A.d.L. is partially funded by Hoffman-La Roche, whom had no involvement in the design, analyses, or decision to publish this project. The other authors declare no competing financial interests. ### Funding Statement This work was funded by COSYN (Comorbidity and Synapse Biology in Clinically Overlapping Psychiatric Disorders: Horizon 2020 Program of the European Union under RIA grant agreement 667301, to D.P.), the Netherlands Organization for Scientific Research (NWO: VICI 435-14-005, to D.P.), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012, to D.P.), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057, to D.P.). The work of S.C.d.L. was supported by ZonMw, the Hague, The Netherlands, project 09120011910032 REMOVE and the European Research Council, Brussels, Belgium, Advanced Grant 101055383 OVERNIGHT. C.A.d.L. is funded by Hoffman-La Roche. The work of M.H. was supported by a VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and an ERC Consolidator of the European Research Council (101001062). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara and financed by the Netherlands Organization for Scientific Research (NWO: 480-05-003), the VU University (Amsterdam, The Netherlands) and the Dutch Brain Foundation. ### 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 All data produced in the study are available online at