loading . . . Symptom-specific genetics reveal heterogeneity within major depressive disorder Background Major Depressive Disorder (MDD) is clinically and biologically heterogeneous. Here, we leveraged the genetics of individual depressive symptoms to dissect the disorder’s underlying heterogeneity. Methods We utilized the BIObanks Netherlands Internet Collaboration (BIONIC). A series of genome-wide association studies (effective- N range: 14,407 - 47,110) compared controls (N=48,286) with partially different subsets of lifetime MDD cases (range: 3,892–15,577), each endorsing one of 12 individual DSM-based depressive symptoms. Results were combined in genetic correlations that informed factor analyses with Genomic Structural Equation Modeling, decomposing underlying MDD liability dimensions. The identified factors were assessed and further characterized using multivariate regression of neurodevelopmental/psychiatric and cardiometabolic traits. Results All symptoms demonstrated substantial SNP-based heritability ( h²SNP: 0.088 – 0.127). Despite high between-symptom genetic correlations, factor analyses yielded two highly correlated ( rg =0.85) but still distinct latent factors: factor 1 (F1), capturing appetite/weight loss, insomnia, guilt/worthlessness, psychomotor slowing and suicidality, and factor 2 (F2), reflecting concentration problems, anhedonia, depressed mood, appetite/weight gain and fatigue. Overall, F1 had a stronger genetic overlap with neurodevelopmental/psychiatric phenotypes (e.g., autism: standardized estimate β =0.45, p =4.49×10⁻⁴; schizophrenia: β =0.40, p =1.73×10⁻⁴), while F2 significantly overlapped with cardiometabolic traits (e.g., metabolic syndrome: β =0.44, p =8.69×10⁻⁴; coronary artery disease: β =0.31, p =0.009). Conclusions We identified two genetic dimensions of MDD, each linked to partially distinct clinical manifestations and underlying biology, with one reflecting neurodevelopmental/psychiatric liabilities and the other capturing a strong cardiometabolic vulnerability. Disentangling such distinct dimensions may help guide patient stratification and targeted treatment, thereby advancing precision psychiatry. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement YM is partially supported by Amsterdam UMC StarterGrant (Ronde2), Amsterdam Neuroscience (PoC funding 2024-2026), and the Immuno MIND consortium, funded by UK Research and Innovation as part of the UK national Mental Health Platform. HMvL was supported in part by a VENI grant from the Talent Program of the Netherlands Organization of Scientific Research (NWO-ZonMW 09150161810021) and by NIMH grant R01MH125902. We are very grateful to everyone who participated in this research or worked on this project and its contributing studies. Funding for the BIONIC project was awarded to Dorret Boomsma and Brenda Penninx by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL: 184.021.007; 184.033.111). Below are cohort-specific funding declarations and acknowledgements. We would like to thank the research participants and employees of 23andMe for making this work possible. Lifelines The Lifelines initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG), Groningen University and the Provinces in the North of the Netherlands (Drenthe, Friesland, Groningen). NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. VENI grant from the Talent Program of the Netherlands Organisation for Scientific Research (NWO-ZonMW 09150161810021). We thank Trynke de Jong for the contribution to Lifelines data collection. We thank Martje Bos and Victoria Trindade Pons for their help in preparing the Lifelines phenotype data. MooDFOOD European Union FP7 funding for MooDFOOD Project Multi-country cOllaborative project on the rOle of Diet, FOod-related behaviour, and Obesity in the prevention of Depression (grant agreement no. 613598). TRAILS Participating centers of the TRacking Adolescents Individual Lives Survey (TRAILS) include the University Medical Center and University of Groningen, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Group, all in the Netherlands. TRAILS has been financially supported by various grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grant 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 452-04-314 and GB-MaGW 452-06-004; ZonMw Longitudinal Cohort Research on Early Detection and Treatment in Mental Health Care grant 636340002; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013 and 481-11-001; NWO Vici 016.130.002, 453-16-007/2735, and Vi.C.191.021; NWO Gravitation 024.001.003), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), the European Research Council (ERC-2017-STG-757364 and ERC-CoG-2015-681466), Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL (CP 32), the Gratama foundation, the Jan Dekker foundation, the participating universities, and Accare. Statistical analyses are carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. LASA The Longitudinal Aging Study Amsterdam is largely supported by grants from the Netherlands Ministry of Health, Welfare and Sport, Directorate of Long-Term Care. NQplus NQplus was core funded by ZonMw (ZonMw, Grant 91110030); add-on funding was provided by ZonMW Gezonde Voeding (ZonMw, Grant 115100007), BBMRI (Grant BBMRI-NL RP9 and CP2011-38) and Wageningen University and Research. MOTAR The MOTAR study was funded by NWO VICI grant number 91811602 of B.W.J.H. Penninx. NWO had no role in the design of the study, the collection, analysis and interpretation of the data, or in the preparation, review, or approval of the manuscript. The Hoorn Studies The GWAS in the Hoorn studies was supported by the Amsterdam University Medical Center, a grant from the Foundation for the National Institutes of Health through the Accelerating Medicines Partnership (no. HART17AMP) and the Dutch String of Pearls Initiative. We appreciate the cooperation of the participants and research assistants who have been involved in the Hoorn Study and New Hoorn Study. We would like to thank Tootje Hoovers and Jolanda Bosman as well as all the researchers previously involved for the organization of both studies. Netherlands Twin Register NTR acknowledges funding from the Netherlands Organization for Scientific Research (NWO): Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, 184.033.111) and the BBMRI-NL funded BIOS Consortium (NWO184.021.007); The Netherlands Twin Register is supported by grant NWO 480-15-001/674: Netherlands Twin Registry Repository: researching the interplay between genome and environment, the Avera Institute for Human Genetics and by multiple grants from the Netherlands Organization for Scientific Research (NWO). Genotyping was made possible by grants from NWO/SPI 56-464-14192, Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH 068457-06), the Avera Institute, Sioux Falls (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995) and European Research Council (ERC-230374). DIB acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). Nijmegen Biomedical Study The Nijmegen Biomedical Study is a population-based survey conducted at the Department for Health Evidence and the Department of Laboratory Medicine of the Radboud university medical center. Principal investigators of the Nijmegen Biomedical Study are L.A.L.M. Kiemeney, A.L.M. Verbeek, D.W. Swinkels en B. Franke. Doetinchem Cohort Study The Doetinchem Cohort Study is supported by the Dutch Ministry of Health, Welfare and Sport and the National Institute for Public Health and the Environment. We thank the respondents, epidemiologists and fieldworkers of the Municipal Health Service in Doetinchem for their contribution to the data collection for this study. The authors want to acknowledge the logistic management which was provided by P Vissink, and the data managers J van der Laan, R J de Kleine, I Toxopeus. Further, we thank all (senior) researchers who contributed to the data for collection, in particular in (alphabetical order): J M A de Boer, H B Bueno de Mesquita, P Engelfriet, G C Herber-Gast, G Hulsegge, D Kromhout, L Launer, A C J Nooyens, M C Ocke, S H van Oostrom, K Proper, J C Seidell, H A Smit, W G C Wendel-Vos. NESDA & NESDAsib The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-0001002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). NESDO The infrastructure for NESDO is funded through the Fonds NutsOhra, Stichting tot Steun VCVGZ, NARSAD The Brain and Behaviour Research Fund, and the participating universities and mental health care organizations (VU University Medical Center, Leiden University Medical Center, University Medical Center Groningen, Radboud University Nijmegen Medical Center, and GGZ inGeest, GGNet, GGZ Nijmegen, GGZ Rivierduinen, Lentis, and Parnassia). ### 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: All relevant ethical regulations for working with human participants were followed in the conduct of the study, and written informed consent was obtained from all participants. The Medical Ethics Review Committee of the VU University Medical Center (IRB00002991) waived ethical approval for this work, 2014.449. 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 Summary statistics and analysis code will be made publicly available upon publication. http://bit.ly/3Nt43qA
