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Am J Med Genet B Neuropsychiatr Genet. 2019 Feb 1. doi: 10.1002/ajmg.b.32713. [Epub ahead of print]

Quantifying between-cohort and between-sex genetic heterogeneity in major depressive disorder.

Author information

1
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
2
School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia.
3
Department of Psychiatry, Vrije Universiteit Medical Center and GGZ in Geest, Amsterdam, The Netherlands.
4
AGRF, The University of Queensland, Brisbane, Queensland, Australia.
5
Department of Psychiatry, Behavioural and Clinical Neuroscience Institute and Developmental Psychiatry, Cambridge University, Cambridge, England, United Kingdom.
6
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
7
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
8
Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
9
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
10
Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany.
11
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
12
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
13
Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia.
14
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
15
Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri.
16
Institute of Health & Society, University of Worcester, Worcester, United Kingdom.
17
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
18
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
19
MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom.
20
NIHR BRC for Mental Health, King's College London, London, United Kingdom.
21
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
22
Department of Biomedicine and iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
23
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
24
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
25
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
26
Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
27
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
28
Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
29
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.

Abstract

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

KEYWORDS:

LD score regression; MDD; depression; genetic heterogeneity; sex differences

PMID:
30708398
DOI:
10.1002/ajmg.b.32713

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