Investigating the genetic variation underlying episodicity in major depressive disorder: suggestive evidence for a bipolar contribution.
BACKGROUND
Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD.


METHODS
Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies.


RESULTS
Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly.


CONCLUSIONS
Episode count was self-reported and, therefore, subject to recall bias.


CONCLUSIONS
Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom. Electronic address: panagiotis.ferentinos@kcl.ac.uk.
Panagiotis
P
Ferentinos
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, University of Granada, Spain.
Margarita
M
Rivera
Max Planck Institute of Psychiatry, Munich, Germany.
Marcus
M
Ising
Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
Sarah L
SL
Spain
Department of Psychiatry, University of Adelaide, Adelaide, Australia.
Sarah
S
Cohen-Woods
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, China.
Amy W
AW
Butler
MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
Nicholas
N
Craddock
MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
Michael J
MJ
Owen
Barts and The London Medical School, Queen Mary University of London, London, United Kingdom.
Ania
A
Korszun
Department of Psychiatry, Neuropharmacology & Neurobiology Section, University of Birmingham, Birmingham, United Kingdom.
Lisa
L
Jones
MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
Ian
I
Jones
Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland.
Michael
M
Gill
Department of Psychiatry, Washington University, St. Louis, Missouri, United States.
John P
JP
Rice
Department of Psychiatry, University of Bonn, Bonn, Germany.
Wolfgang
W
Maier
Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
Ole
O
Mors
Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
Marcella
M
Rietschel
Max Planck Institute of Psychiatry, Munich, Germany.
Susanne
S
Lucae
Max Planck Institute of Psychiatry, Munich, Germany.
Elisabeth B
EB
Binder
University Hospital Center and University of Lausanne, Lausanne, Switzerland.
Martin
M
Preisig
Aptuit Center for Drug Discovery & Development, Verona, Italy.
Federica
F
Tozzi
Department of Psychiatry, University of Toronto, Toronto, Canada.
Pierandrea
P
Muglia
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, United Kingdom.
Gerome
G
Breen
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom.
Ian W
IW
Craig
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom.
Anne E
AE
Farmer
Max Planck Institute of Psychiatry, Munich, Germany.
Bertram
B
Müller-Myhsok
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom.
Peter
P
McGuffin
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
Cathryn M
CM
Lewis
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D055815:Young Adult
Bipolar spectrum; Episode count; Family history; Genome-wide association study; Major depression; Polygenic