Meta-Analysis

. 2024 Sep;54(12):3459-3468.

doi: 10.1017/S0033291724001880. Epub 2024 Sep 26.

Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts

Mark J Adams¹, Jackson G Thorp², Bradley S Jermy³, Alex S F Kwong^{1

4}, Kadri Kõiv⁵, Andrew D Grotzinger^{6

7}, Michel G Nivard⁸, Sally Marshall⁹, Yuri Milaneschi¹⁰, Bernhard T Baune^{11

12

13}, Bertram Müller-Myhsok^{14

15

16}, Brenda W J H Penninx¹⁰, Dorret I Boomsma¹⁷, Douglas F Levinson¹⁸, Gerome Breen^{19

20}, Giorgio Pistis²¹, Hans J Grabe²², Henning Tiemeier^{23

24}, Klaus Berger²⁵, Marcella Rietschel²⁶, Patrik K Magnusson²⁷, Rudolf Uher²⁸, Steven P Hamilton²⁹, Susanne Lucae³⁰, Kelli Lehto⁵, Qingqin S Li³¹, Enda M Byrne³², Ian B Hickie³³, Nicholas G Martin², Sarah E Medland², Naomi R Wray^{34

35}, Elliot M Tucker-Drob^{36

37}; Estonian Biobank Research Team; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Cathryn M Lewis^{19

38}, Andrew M McIntosh^{1

39}, Eske M Derks²

Affiliations

¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
² Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁶ Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO, USA.
⁷ Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA.
⁸ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
⁹ Centre for Genomic & Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹¹ Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
¹² Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
¹³ Department of Psychiatry, University of Münster, Münster, NRW, Germany.
¹⁴ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, BY, Germany.
¹⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, BY, Germany.
¹⁶ Institute of Population Health, University of Liverpool, Liverpool, UK.
¹⁷ Department of Biological Psychology & Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹⁸ Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA.
¹⁹ Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
²⁰ NIHR Maudsley Biomedical Research Centre, King's College London, London, UK.
²¹ Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, VD, Switzerland.
²² Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, MV, Germany.
²³ Child and Adolescent Psychiatry, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.
²⁴ Social and Behavioral Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁵ Institute of Epidemiology and Social Medicine, University of Münster, Münster, NRW, Germany.
²⁶ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ Psychiatry, Dalhousie University, Halifax, NS, Canada.
²⁹ Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, USA.
³⁰ Max Planck Institute of Psychiatry, Munich, BY, Germany.
³¹ Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
³² Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia.
³³ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
³⁴ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
³⁵ Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
³⁶ Department of Psychology, University of Texas at Austin, Austin, TX, USA.
³⁷ Population Research Center, University of Texas at Austin, Austin, TX, USA.
³⁸ Department of Medical & Molecular Genetics, King's College London, London, UK.
³⁹ Institute for Genomics and Cancer, University of Edinburgh, Edinburgh, UK.

PMID: 39324397
PMCID: PMC11496230
DOI: 10.1017/S0033291724001880

Meta-Analysis

Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts

Mark J Adams et al. Psychol Med. 2024 Sep.

. 2024 Sep;54(12):3459-3468.

doi: 10.1017/S0033291724001880. Epub 2024 Sep 26.

Authors

Affiliations

¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
² Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁶ Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO, USA.
⁷ Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA.
⁸ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
⁹ Centre for Genomic & Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹¹ Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
¹² Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
¹³ Department of Psychiatry, University of Münster, Münster, NRW, Germany.
¹⁴ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, BY, Germany.
¹⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, BY, Germany.
¹⁶ Institute of Population Health, University of Liverpool, Liverpool, UK.
¹⁷ Department of Biological Psychology & Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹⁸ Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA.
¹⁹ Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
²⁰ NIHR Maudsley Biomedical Research Centre, King's College London, London, UK.
²¹ Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, VD, Switzerland.
²² Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, MV, Germany.
²³ Child and Adolescent Psychiatry, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.
²⁴ Social and Behavioral Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁵ Institute of Epidemiology and Social Medicine, University of Münster, Münster, NRW, Germany.
²⁶ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ Psychiatry, Dalhousie University, Halifax, NS, Canada.
²⁹ Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, USA.
³⁰ Max Planck Institute of Psychiatry, Munich, BY, Germany.
³¹ Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
³² Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia.
³³ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
³⁴ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
³⁵ Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
³⁶ Department of Psychology, University of Texas at Austin, Austin, TX, USA.
³⁷ Population Research Center, University of Texas at Austin, Austin, TX, USA.
³⁸ Department of Medical & Molecular Genetics, King's College London, London, UK.
³⁹ Institute for Genomics and Cancer, University of Edinburgh, Edinburgh, UK.

PMID: 39324397
PMCID: PMC11496230
DOI: 10.1017/S0033291724001880

Abstract

Background: Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.

Methods: We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.

Results: The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).

Conclusion: The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.

Keywords: Genomic SEM; depressive symptoms; genome-wide association study; major depressive disorder; psychometrics.

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Figures

**Figure 1.**
LDSC-estimated heritabilities. Heritably () calculated on the liability scale for summary statistics that met inclusion criteria (N_Eff > 5000, > 0). Depression symptoms abbreviations are listed in Table 1. Case-enriched = PGC + AGDS + GS:SFHS meta-analysis, Community = ALSPAC + EstBB + UKB-MHQ meta-analysis, UK Biobank = UKB-Touchscreen GWAS.

formula image — **Figure 1.**
LDSC-estimated heritabilities. Heritably () calculated on the liability scale for summary statistics that met inclusion criteria (N_Eff > 5000, > 0). Depression symptoms abbreviations are listed in Table 1. Case-enriched = PGC + AGDS + GS:SFHS meta-analysis, Community = ALSPAC + EstBB + UKB-MHQ meta-analysis, UK Biobank = UKB-Touchscreen GWAS.

**Figure 2.**
Structure and loadings of confirmatory factor models. Points representing loadings of each symptom (columns) onto each factor (rows) for confirmatory models and for the multivariate meta-analysis of well-powered GWASs to illustrate model structure, for Case-enriched (red), Community (green), and UKB Touchscreen (blue) GWASs. Size of points scaled to absolute value of factor loadings. Symptoms arranged in order so that symptoms (Affective/cognitive: Sui, Dep, :Anh, Guilt, Conc; typical somatic: MotoInc, SleDec, AppDec; and atypical somatic: AppInc, MotoDec, Fatig, SleInc) that tend to load onto the same factor are listed next to each other.

**Figure 3.**
Model structural diagram. Standardized loadings (standard errors) of factors on symptoms and genetic correlations among factors for the model (*CogMoodLeth-App*) used for further analysis. Symptom abbreviations are listed in Table 1.

**Figure 4.**
Genetic multivariable regression. (a) Model diagrams for single regressions and (b) multiple regressions of a phenotype Y on Appetite/Weight, Cognitive/Mood/Lethargy, and Gating symptom factors (symptom indicator variables omitted for clarity). (c) Single genetic regression standardized beta coefficients (green triangles) and multiple genetic regression (red circles) coefficients (point estimates plotted with 95% confidence intervals). FDR correction indicated for significant (darker shading) and non-significant (lighter shading) coefficients. Multiple regression models adjust for the other factors. AlcDep, alcohol dependence; Anxiety, anxiety disorder; BIP, bipolar disorder; BMI, body-mass index; EA, educational attainment; MD, major depression; MDD, major depressive disorder; Neu, neuroticism; Pain, chronic pain; PTSD, post-traumatic stress disorder; Sleep, long sleep duration; Smoking, cigarettes per day.

See this image and copyright information in PMC

References

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Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts

Affiliations

Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources