Identification of 64 new risk loci for major depression, refinement of the genetic architecture and risk prediction of recurrence and comorbidities

Major depression (MD) is a common mental disorder and a leading cause of disability worldwide. We conducted a GWAS meta-analysis of more than 1.3 million individuals, including 371,184 with MD, identifying 243 risk loci. Sixty-four loci are novel, including glutamate and GABA receptors that are targets for antidepressant drugs. Several biological pathways and components were enriched for genetic MD risk, implicating neuronal development and function. Intersection with functional genomics data prioritized likely causal genes and revealed novel enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found MD to be highly polygenic, with around 11,700 variants explaining 90% of the SNP heritability. Bivariate Gaussian mixture modeling estimated that > 97% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and ADHD) are influencing MD risk when both concordant and discordant variants are considered, and nearly all MD risk variants influence educational attainment. Additionally, we demonstrated that MD genetic risk is associated with impaired complex cognition, including verbal reasoning, attention, abstraction and mental flexibility. Analyzing Danish nation-wide longitudinal data, we dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across case subgroups of MD recurrency and psychiatric comorbidity and demonstrating two-to six-fold increases in absolute risks for developing comorbid psychiatric disorders among MD cases with the highest versus the lowest polygenic burden. The results deepen the understanding of the biology underlying MD and its progression and inform precision medicine approaches in MD. ### Competing Interest Statement B.J.V. is a member of the advisory board for Allelica. D.D. has received a speaker fee from Takeda. B.W., T.T., H.S. and K.S. are employed at deCODE/Amgen. M.J.D. is a founder of Maze Therapeutics and on the Scientific Advisory Board of RBNC Therapeutics. The other authors declare no competing interests. ### Funding Statement The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003), the EU H2020 Program (Grant No. 667302, CoCA), NIH/NIMH (1U01MH109514-01 and 1R01MH124851-01 to ADB) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). The team at the Center for Disease Neurogenomics at Icahn School of Medicine at Mount Sinai was supported by the NIH (K08MH122911 to GV; T32MH087004 to KT; R01MH125246, R01AG067025, U01MH116442 and R01MH109677 to PR). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Scientific Ethics Committee in the Central Denmark Region gave ethical approval for this work. Ethics committee/IRB of the Danish Data Protection Agency gave ethical approval for this work. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics from this publication are available at . All relevant iPSYCH data are available from the authors after approval by the iPSYCH Data Access Committee and can only be accessed on the secured Danish server (GenomeDK, ) as the data are protected by Danish legislation. For data access please contact: Anders D. Borglum. Data used for brain transcriptome model generation are available from PsychENCODE (overview of available data sets at ); genotypes are controlled data and access instructions are provided at . Note that some datasets have been indirectly accessed at the respective analytical websites (through the FUMA website). Please refer to these websites (e.g., for FUMA and ) for availability of datasets used in the respective follow-up analyses / lookups.