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Biol Psychiatry. 2017 Sep 1;82(5):322-329. doi: 10.1016/j.biopsych.2016.11.013. Epub 2016 Dec 8.

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.

Author information

1
Department of Epidemiology, Erasmus University Medical Center, Rotterdam; Department of Psychiatry, Dokuz Eylul University, Izmir, Turkey.
2
Department of Genetics, Genomic Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
3
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
4
Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston; Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin.
5
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia.
6
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen; Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia.
7
Genetic Epidemiology Unit, Erasmus University Medical Center, Rotterdam.
8
Rush Alzheimer's Disease Center & Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
9
Division of Psychiatry, University of Edinburgh, Edinburgh.
10
Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
11
MRC Social, Genetic & Developmental Psychiatry Centre Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London.
12
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
13
Queensland Brain Institute, University of Queensland, St. Lucia, Queensland.
14
Department of Biomedicine and Centre for Integrative Sequencing, Aarhus University, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus.
15
Department of Psychiatry, Lausanne University Hospital, Lausanne.
16
Institute of Human Genetics, University of Bonn, Bonn; Department of Genomics, Life & Brain Center, Bonn; Institute of Neuroscience and Medicine, Research Centre Jülich, Jülich; Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
17
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
18
Department of Psychiatry and Psychotherapy, University of Münster, Münster.
19
Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge; Department of Neurology, Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, Harvard Medical School, Boston; Department of Neurology, Harvard Medical School, Boston.
20
Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F Hoffman-La Roche Ltd., Basel, Switzerland; Centre for Integrative Biology, University of Trento, Trento, Italy.
21
Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge; Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston; Department of Psychiatry, Harvard Medical School, Boston.
22
National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki; Unit of General Practice, Helsinki University Central Hospital, Helsinki; Folkhalsan Research Centre, Helsinki; Vasa Central Hospital, Vasa, Finland.
23
Program in Medical and Populational Genetics, The Broad Institute of Harvard and MIT, Cambridge; Division of Endocrinology, Boston Children's Hospital, Cambridge; Department of Genetics, Harvard Medical School, Boston; Estonian Genome Center, University of Tartu, Tartu, Estonia.
24
Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
25
Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland.
26
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
27
Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland.
28
QIMR Berghofer Medical Research Institute, Brisbane.
29
Department of Psychiatry and Psychotherapy, Helios Hospital Stralsund, Munich; Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Munich; German Center for Neurodegenerative Diseases, Site Rostock/Greifswald, Munich.
30
Department of Psychiatry, Neuroscience Campus Amsterdam and EMGO Institute of Health and Care Research, VU University, Amsterdam, The Netherlands.
31
Department of Psychiatry, Kaiser Permanente San Francisco Medical Center, San Francisco.
32
Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen.
33
Department of Psychiatry, Washington University, St. Louis, Missouri.
34
Department of Epidemiology, Erasmus University Medical Center, Rotterdam; Department of Psychiatry, Erasmus University Medical Center, Rotterdam.
35
Department of Epidemiology, Erasmus University Medical Center, Rotterdam.
36
Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Munich.
37
Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F Hoffman-La Roche Ltd., Basel, Switzerland.
38
Max Planck Institute of Psychiatry, Munich.
39
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
40
Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne.
41
Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich; Institute of Epidemiology II, Mental Health Research Unit, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg.
42
Folkhalsan Research Centre, Helsinki; Institute of Behavioural Sciences, University of Helsinki, Helsinki.
43
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
44
Division of Psychiatry, University College London, London.
45
Janssen Research & Development LLC, New Brunswick, New Jersey.
46
University of Exeter Medical School, Exeter.
47
Department of Biostatistics, Boston University School of Public Health, Framingham, Massachusetts; Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts.
48
Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
49
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus; Research Department P, Aarhus University Hospital, Risskov, Denmark.
50
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
51
Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine, Boston; Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts.
52
Max Planck Institute of Psychiatry, Munich; Munich Cluster for Systems Neurology, Munich; University of Liverpool, Institute of Translational Medicine, Liverpool.
53
Institute of Human Genetics, University of Bonn, Bonn; Department of Genomics, Life & Brain Center, Bonn.
54
QIMR Berghofer Medical Research Institute, Brisbane; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland.
55
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
56
Department of Psychiatry, Washington University, St. Louis, Missouri; Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida.
57
Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital and Harvard Medical School, Boston.
58
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
59
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
60
Solid GT, Boston; Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F Hoffman-La Roche Ltd., Basel, Switzerland.
61
Institute of Behavioural Sciences, University of Helsinki, Helsinki.
62
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim.
63
MRC Social, Genetic & Developmental Psychiatry Centre Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London; CIBERSAM-Universidad de Granada, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
64
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University, Munich; Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
65
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
66
Group Health, Seattle, Washington.
67
Department of Psychiatry and Psychiatric Neuroscience, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
68
Unit of Genetic Epidemiology & Bioinformatics, University Medical Center Groningen, University of Groningen, Groningen.
69
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Munich.
70
MRC Social, Genetic & Developmental Psychiatry Centre Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London; Dalhousie University, Halifax, Nova Scotia, Canada.
71
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Munich; German Center for Neurodegenerative Diseases, Site Rostock/Greifswald, Munich.
72
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan; Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
73
College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York, New York.
74
Department of Epidemiology, Erasmus University Medical Center, Rotterdam; Department of Psychiatry, Erasmus University Medical Center, Rotterdam. Electronic address: h.tiemeier@erasmusmc.nl.
75
Department of Psychiatry, Genomic Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Center for Psychiatric Genomics, Genomic Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.

Abstract

BACKGROUND:

The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.

METHODS:

We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.

RESULTS:

The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9).

CONCLUSIONS:

This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

KEYWORDS:

CHARGE consortium; Depressive symptoms; FHIT gene; Genome-wide association study; Major depressive disorder; Psychiatric Genomics Consortium

PMID:
28049566
PMCID:
PMC5462867
[Available on 2018-09-01]
DOI:
10.1016/j.biopsych.2016.11.013

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