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Biol Psychiatry. 2017 Feb 15;81(4):325-335. doi: 10.1016/j.biopsych.2016.05.010. Epub 2016 May 24.

Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

Author information

1
Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London.
2
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
3
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
4
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia.
5
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
6
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
7
Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
8
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland; School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia.
9
Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
10
deCODE Genetics, Reykjavik, Iceland.
11
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
13
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland.
14
Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany.
15
Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
16
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Department of Biomedicine and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
17
Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
18
Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany; Department of Psychiatry, University of Marburg, Marburg, Germany.
19
Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
20
Institute of Human Genetics; Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
21
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
22
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
23
Department of Psychiatry, Kaiser Permanente San Francisco Medical Center, San Francisco, California.
24
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
25
Department of Psychiatry, Washington University St. Louis, St. Louis, Missouri.
26
Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom.
27
Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald.
28
Max Planck Institute of Psychiatry, Munich, Germany.
29
Mental Health Center Copenhagen, Mental Health Services in Capital Region, University of Copenhagen, Copenhagen, Denmark.
30
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
31
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
32
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
33
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom.
34
Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
35
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
36
Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
37
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
38
Therapeia, Reykjavik, Iceland.
39
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
40
Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida.
41
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
42
Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London; CIBERSAM-Universidad de Granada e Instituto de Investigación Biosanitaria ibs, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
43
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
44
Department of Psychiatry, Group Health, Seattle, Washington.
45
University of Iceland; Department of Psychiatry, Landspitali University Hospital, Reykjavik, Iceland.
46
Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
47
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
48
Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
49
College of Physicians and Surgeons and the Mailman School of Public Health, Columbia University and New York State Psychiatric Institute, New York, New York.
50
Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London. Electronic address: cathryn.lewis@kcl.ac.uk.

Abstract

BACKGROUND:

Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.

METHODS:

Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.

RESULTS:

We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.

CONCLUSIONS:

We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

KEYWORDS:

Age at onset; GWAS; Heterogeneity; Major depressive disorder; Polygenic scoring; Stratification

Comment in

PMID:
27519822
PMCID:
PMC5262436
DOI:
10.1016/j.biopsych.2016.05.010
[Indexed for MEDLINE]
Free PMC Article

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