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| PMID |
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| TITLE |
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| Genetics of major depressive disorder in a homogeneous population with uniform phenotyping. |
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| ABSTRACT |
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| Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. Liability-scale SNP-based heritability was 12.0% (SE = 1.4%) as estimated by LDSC (assuming a lifetime prevalence of 15%) and 26.6% (SE = 1.1%) when estimated by LDAK-REML on individual-level genotype data, indicating substantial common-variant signal in this clinically harmonized sample. The genetic correlation with the latest major depression GWAS from the Psychiatric Genomics Consortium (PGC-MD) was high (r = 0.89, SE = 0.048). Polygenic scores (PGSs) based on BIONIC predicted depression in UK Biobank, and PGSs derived from PGC-MD predicted MDD in BIONIC, supporting transferability of depression polygenic signal across cohorts and phenotype definitions. Within-family PGS analyses in twins suggested that the observed prediction was not primarily driven by detectable family-level confounding, and twin concordance for MDD increased with polygenic burden. We identified one genome-wide significant locus, indexed by rs3818852 in PALMD, but this finding currently lacks independent replication and should be interpreted cautiously. Finally, genetic correlation and latent causal variable analyses identified multiple traits showing shared or directionally consistent genetic associations with MDD. Together, these findings underscore the value of clinically harmonized phenotyping in regional biobank collaborations for studying the genetic architecture of MDD. |
| © 2026. The Author(s), under exclusive licence to Springer Nature Limited. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2025/03/27 |
| accepted |
2026/05/22 |
| revised |
2026/04/23 |
| medline |
2026/06/03 00:36 |
| pubmed |
2026/06/03 00:36 |
| entrez |
2026/06/02 23:46 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Huider F |
|
Huider |
Floris |
F |
|
Department of Biological Psychology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. f.huider@vu.nl. |
| Milaneschi Y |
|
Milaneschi |
Yuri |
Y |
|
Amsterdam Neuroscience, Complex Trait Genetics, 1081, Amsterdam, The Netherlands. |
| Pool R |
|
Pool |
René |
R |
|
Department of Biological Psychology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| Maciel BAPC |
|
Maciel |
Bernardo de A P C |
BAPC |
|
Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Han J |
|
Han |
Jihee |
J |
|
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. |
| Rietman ML |
|
Rietman |
M Liset |
ML |
|
Center for Prevention, Lifestyle and Health, Dutch National Institute for Public Health and the Environment, 3721, Bilthoven, The Netherlands. |
| Kok AAL |
|
Kok |
Almar A L |
AAL |
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Department of Epidemiology and Data Science, Amsterdam UMC, 1081, Amsterdam, The Netherlands. |
| Galesloot TE |
|
Galesloot |
Tessel E |
TE |
|
IQ Health Science Department, Radboud University Medical Center, 6525, Nijmegen, The Netherlands. |
| Mitchell BL |
|
Mitchell |
Brittany L |
BL |
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Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| 't Hart LM |
|
't Hart |
Leen M |
LM |
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Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. |
| Rutters F |
|
Rutters |
Femke |
F |
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Department of Epidemiology and Data Science, Amsterdam UMC, 1081, Amsterdam, The Netherlands. |
| Blom MT |
|
Blom |
Marieke T |
MT |
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Department of General Practice, Amsterdam UMC, 1081, Amsterdam, The Netherlands. |
| Rhebergen D |
|
Rhebergen |
Didi |
D |
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Amsterdam Neuroscience, Complex Trait Genetics, 1081, Amsterdam, The Netherlands. |
| Visser M |
|
Visser |
Marjolein |
M |
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Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| Brouwer IA |
|
Brouwer |
Ingeborg A |
IA |
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Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| Feskens E |
|
Feskens |
Edith |
E |
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Division of Human Nutrition and Health, Wageningen University & Research, 6700, Wageningen, The Netherlands. |
| Hartman CA |
|
Hartman |
Catharina A |
CA |
|
Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9713, Groningen, The Netherlands. |
| Oldehinkel AJ |
|
Oldehinkel |
Albertine J |
AJ |
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Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9713, Groningen, The Netherlands. |
| Bot M |
|
Bot |
Mariska |
M |
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Amsterdam Neuroscience, Complex Trait Genetics, 1081, Amsterdam, The Netherlands. |
| de Geus EJC |
|
de Geus |
Eco J C |
EJC |
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Department of Biological Psychology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| Kiemeney LA |
|
Kiemeney |
Lambertus A |
LA |
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Department of Urology and Department for Health Evidence, Radboud University Medical Center, 6525, Nijmegen, The Netherlands. |
| Huisman M |
|
Huisman |
Martijn |
M |
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Department of Sociology, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| Picavet HSJ |
|
Picavet |
H Susan J |
HSJ |
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Center for Prevention, Lifestyle and Health, Dutch National Institute for Public Health and the Environment, 3721, Bilthoven, The Netherlands. |
| Verschuren WMM |
|
Verschuren |
W M Monique |
WMM |
|
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584, Utrecht, The Netherlands. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Dolan CV |
|
Dolan |
Conor V |
CV |
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Department of Biological Psychology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, 1081, Amsterdam, The Netherlands. |
| van Loo HM |
|
van Loo |
Hanna M |
HM |
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Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9713, Groningen, The Netherlands. |
| Penninx BWJH |
|
Penninx |
Brenda W J H |
BWJH |
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Amsterdam Neuroscience, Complex Trait Genetics, 1081, Amsterdam, The Netherlands. |
| Hottenga JJ |
|
Hottenga |
Jouke-Jan |
JJ |
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Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, P.O. Box 5825, Qatar. jhottenga@hbku.edu.qa. |
| Boomsma DI |
|
Boomsma |
Dorret I |
DI |
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Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Molecular psychiatry |
| ISOABBREVIATION: Mol Psychiatry |
| YEAR: 2026 |
| MONTH: Jun |
| DAY: 02 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1476-5578 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Mol Psychiatry |
| COUNTRY: England |
| ISSNLINKING: 1359-4184 |
| NLMUNIQUEID: 9607835 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
| UpdateOf |
Res Sq. 2025 Oct 31:rs.3.rs-6238738. doi: 10.21203/rs.3.rs-6238738/v1. |
41282258 |
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| GRANTS |
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| GRANTID |
AGENCY |
COUNTRY |
| 184.021.007 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) |
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| 184.033.111 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) |
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| 184.021.007 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) |
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| 184.033.111 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) |
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| GENERAL NOTE |
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