TY - JOUR
T1 - Investigating the genetic variation underlying episodicity in major depressive disorder
T2 - Suggestive evidence for a bipolar contribution
AU - Ferentinos, Panagiotis
AU - Rivera, Margarita
AU - Ising, Marcus
AU - Spain, Sarah L.
AU - Cohen-Woods, Sarah
AU - Butler, Amy W.
AU - Craddock, Nicholas
AU - Owen, Michael J.
AU - Korszun, Ania
AU - Jones, Lisa
AU - Jones, Ian
AU - Gill, Michael
AU - Rice, John P.
AU - Maier, Wolfgang
AU - Mors, Ole
AU - Rietschel, Marcella
AU - Lucae, Susanne
AU - Binder, Elisabeth B.
AU - Preisig, Martin
AU - Tozzi, Federica
AU - Muglia, Pierandrea
AU - Breen, Gerome
AU - Craig, Ian W.
AU - Farmer, Anne E.
AU - Müller-Myhsok, Bertram
AU - McGuffin, Peter
AU - Lewis, Cathryn M.
N1 - Funding Information:
This work was funded by a joint Grant from the Medical Research Council, UK and GlaxoSmithKline [ G0701420 ], and by financial support from the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London . This work was also supported by the German Federal Ministry of Education and Research within the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. GlaxoSmithKline funded the collection of the DeNt cohort of depression cases, the genotyping of all RADIANT cases (with the MRC), and both the collection and genotyping of the GSK-Munich cohort of depression cases.
Funding Information:
Farmer and McGuffin have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies, including GlaxoSmithKline. Muglia and Tozzi were employees of GlaxoSmithKline when the research was performed. Ising has received consultancy honoraria from MSD Merck. Binder has received grant support from PharmaNeuroboost . There are no patents, products in development or marketed products to declare. All other authors (Ferentinos, Rivera, Spain, Cohen-Woods, Butler, Craddock, Owen, Korszun, Jones I, Jones L, Gill, Rice, Maier, Mors, Rietschel, Lucae, Preisig, Breen, Craig, Müller-Myhsok, and Lewis) declare no conflicts of interest.
PY - 2014/2
Y1 - 2014/2
N2 - 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. Limitations 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.
AB - 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. Limitations 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.
KW - Bipolar spectrum
KW - Episode count
KW - Family history
KW - Genome-wide association study
KW - Major depression
KW - Polygenic
UR - http://www.scopus.com/inward/record.url?scp=84891881330&partnerID=8YFLogxK
U2 - 10.1016/j.jad.2013.10.027
DO - 10.1016/j.jad.2013.10.027
M3 - Article
C2 - 24215895
AN - SCOPUS:84891881330
SN - 0165-0327
VL - 155
SP - 81
EP - 89
JO - Journal of affective disorders
JF - Journal of affective disorders
IS - 1
ER -