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      Genomewide Association for Major Depressive Disorder: A possible role for the presynaptic protein Piccolo

      research-article
      , MD, , PhD, , PhD, , PhD, , PhD, , MSc, , MD, , MD MPH, , MD, , PhD, , , MD MA, , MD PhD, , MD, , , , PhD, , PhD, , MD PhD, , MD PhD, , PhD, , , MSc, , PhD, , MD PhD, , MRCPsych, , MD, , PhD, , MD PhD, , PhD, , FRCPsych, , MD, , MD, , MD MSc, , , PhD, , MD PhD, , PhD, , MD, , PhD, , MD ScD, , PhD, , MD PhD, , PhD, , MD PhD, , PhD, , PhD, , PhD, , PhD
      Molecular psychiatry
      major depressive disorder, genome-wide association, Netherlands Study of Depression and Anxiety, Netherlands Twin Registry

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          Abstract

          Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network (GAIN) initiative of the US Foundation for the National Institutes of Health, we conducted a genomewide association study of 435,291 SNPs genotyped in 1,738 MDD cases and 1,802 controls selected to be at low liability for MDD. Eleven of the top 200 signals localized to a 167 kb region overlapping the gene piccolo ( PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and plays an important role in monoaminergic neurotransmission in the brain) with p-values of 7.7×10 −7 for rs2715148 and 1.2×10 −6 for rs2522833. We undertook replication of SNPs in this region in 5 independent samples (6,079 MDD independent cases and 5,893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded p=6.4×10 −8 for the non-synonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding-domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

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          Most cited references90

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Diagnostic and statistical manual of mental disorders.

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              Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

              This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.
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                Author and article information

                Contributors
                University of North Carolina, Chapel Hill pfsulliv@ 123456med.unc.edu
                VU University Amsterdam eco@ 123456psy.vu.nl
                VU University Amsterdam ahm.willemsen@ 123456psy.vu.nl
                Queensland Institute for Medical Research michael.james@ 123456qimr.edu.au
                VU University Medical Center Amsterdam jh.smit@ 123456ggzba.nl
                VU University Medical Center Amsterdam timz@ 123456ggzba.nl
                University of Münster volker.arolt@ 123456ukmuenster.de
                James Cook University Queensland bernhard.baune@ 123456jcu.edu.au
                University of Edinburgh d.blackwood@ 123456ed.ac.uk
                University of Bonn sven.cichon@ 123456uni-bonn.de
                University of New England wcovntr@ 123456une.edu.au
                University of Münster katharina.domschke@ 123456ukmuenster.de
                Institute of Psychiatry a.farmer@ 123456iop.kcl.ac.uk
                Harvard Medical School mfava@ 123456partners.org
                Queensland Institute for Medical Research scott.gordon@ 123456qimr.edu.au
                University of North Carolina, Chapel Hill heqianch@ 123456email.unc.edu
                Washington University, St. Louis heatha@ 123456psychiatry.wustl.edu
                VU University Medical Center Amsterdam p.heutink@ 123456vumc.nl
                Max-Planck Institute of Psychiatry holsboer@ 123456mpipsykl.mpg.de
                VU University Medical Center Amsterdam witteh@ 123456ggzba.nl
                VU University Amsterdam jj.hottenga@ 123456psy.vu.nl
                University of North Carolina, Chapel Hill yhu@ 123456bios.unc.edu
                Max-Planck Institute of Psychiatry kohlim@ 123456mpipsykl.mpg.de
                University of North Carolina, Chapel Hill lin@ 123456bios.unc.edu
                Max-Planck Institute of Psychiatry lucae@ 123456mpipsykl.mpg.de
                Royal Edinburgh Hospital donald.macintyre@ 123456nhslothian.scot.nhs.uk
                University of Bonn wolfgang.maier@ 123456ukb.uni-bonn.de
                University of Edinburgh kevin.mcghee@ 123456ed.ac.uk
                Institute of Psychiatry p.mcguffin@ 123456iop.kcl.ac.uk
                Queensland Institute for Medical Research grant.montgomery@ 123456qimr.edu.au
                University of Edinburgh walter.muir@ 123456ed.ac.uk
                University Medical Center Groningen w.a.nolen@ 123456psy.umcg.nl
                University of Bonn markus.noethen@ 123456uni-bonn.de
                Harvard Medical School rperlis@ 123456chgr.mgh.harvard.edu
                Institute of Psychiatry katrina.pirlo@ 123456iop.kcl.ac.uk
                VU University Amsterdam danielle@ 123456psy.vu.nl
                University of Heidelberg marcella.rietschel@ 123456zi-mannheim.de
                VU University Medical Center Amsterdam p.rizzu@ 123456vumc.nl
                Institute of Psychiatry alexandra.schosser@ 123456iop.kcl.ac.uk
                VU University Amsterdam guus.smit@ 123456falw.vu.nl
                Harvard Medical School jordan_smoller@ 123456hms.harvard.edu
                North Carolina State University jytzeng@ 123456stat.ncsu.edu
                VU University Medical Center Amsterdam r.van.dyck@ 123456ggzba.nl
                VU University Amsterdam matthijs@ 123456cncr.vu.nl
                Leiden University Medical Center f.g.zitman@ 123456lumc.nl
                Queensland Institute for Medical Research nick.martin@ 123456qimr.edu.au
                Queensland Institute for Medical Research naomi.wray@ 123456qimr.edu.au
                VU University Amsterdam dorret@ 123456psy.vu.nl
                VU University Medical Center Amsterdam b.penninx@ 123456vumc.nl
                Journal
                9607835
                20545
                Mol Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                23 October 2008
                9 December 2008
                April 2009
                1 October 2009
                : 14
                : 4
                : 359-375
                Affiliations
                University of North Carolina, Chapel Hill pfsulliv@ 123456med.unc.edu
                VU University Amsterdam eco@ 123456psy.vu.nl
                VU University Amsterdam ahm.willemsen@ 123456psy.vu.nl
                Queensland Institute for Medical Research michael.james@ 123456qimr.edu.au
                VU University Medical Center Amsterdam jh.smit@ 123456ggzba.nl
                VU University Medical Center Amsterdam timz@ 123456ggzba.nl
                University of Münster volker.arolt@ 123456ukmuenster.de
                James Cook University Queensland bernhard.baune@ 123456jcu.edu.au
                University of Edinburgh d.blackwood@ 123456ed.ac.uk
                University of Bonn sven.cichon@ 123456uni-bonn.de
                University of New England wcovntr@ 123456une.edu.au
                University of Münster katharina.domschke@ 123456ukmuenster.de
                Institute of Psychiatry a.farmer@ 123456iop.kcl.ac.uk
                Harvard Medical School mfava@ 123456partners.org
                Queensland Institute for Medical Research scott.gordon@ 123456qimr.edu.au
                University of North Carolina, Chapel Hill heqianch@ 123456email.unc.edu
                Washington University, St. Louis heatha@ 123456psychiatry.wustl.edu
                VU University Medical Center Amsterdam p.heutink@ 123456vumc.nl
                Max-Planck Institute of Psychiatry holsboer@ 123456mpipsykl.mpg.de
                VU University Medical Center Amsterdam witteh@ 123456ggzba.nl
                VU University Amsterdam jj.hottenga@ 123456psy.vu.nl
                University of North Carolina, Chapel Hill yhu@ 123456bios.unc.edu
                Max-Planck Institute of Psychiatry kohlim@ 123456mpipsykl.mpg.de
                University of North Carolina, Chapel Hill lin@ 123456bios.unc.edu
                Max-Planck Institute of Psychiatry lucae@ 123456mpipsykl.mpg.de
                Royal Edinburgh Hospital donald.macintyre@ 123456nhslothian.scot.nhs.uk
                University of Bonn wolfgang.maier@ 123456ukb.uni-bonn.de
                University of Edinburgh kevin.mcghee@ 123456ed.ac.uk
                Institute of Psychiatry p.mcguffin@ 123456iop.kcl.ac.uk
                Queensland Institute for Medical Research grant.montgomery@ 123456qimr.edu.au
                University of Edinburgh walter.muir@ 123456ed.ac.uk
                University Medical Center Groningen w.a.nolen@ 123456psy.umcg.nl
                University of Bonn markus.noethen@ 123456uni-bonn.de
                Harvard Medical School rperlis@ 123456chgr.mgh.harvard.edu
                Institute of Psychiatry katrina.pirlo@ 123456iop.kcl.ac.uk
                VU University Amsterdam danielle@ 123456psy.vu.nl
                University of Heidelberg marcella.rietschel@ 123456zi-mannheim.de
                VU University Medical Center Amsterdam p.rizzu@ 123456vumc.nl
                Institute of Psychiatry alexandra.schosser@ 123456iop.kcl.ac.uk
                VU University Amsterdam guus.smit@ 123456falw.vu.nl
                Harvard Medical School jordan_smoller@ 123456hms.harvard.edu
                North Carolina State University jytzeng@ 123456stat.ncsu.edu
                VU University Medical Center Amsterdam r.van.dyck@ 123456ggzba.nl
                VU University Amsterdam matthijs@ 123456cncr.vu.nl
                Leiden University Medical Center f.g.zitman@ 123456lumc.nl
                Queensland Institute for Medical Research nick.martin@ 123456qimr.edu.au
                Queensland Institute for Medical Research naomi.wray@ 123456qimr.edu.au
                VU University Amsterdam dorret@ 123456psy.vu.nl
                VU University Medical Center Amsterdam b.penninx@ 123456vumc.nl
                Author notes
                [†]

                These authors contributed equally.

                Correspond with Dr. Sullivan, Dept. of Genetics, CB#7264, 4109D Neurosciences Research Building, Univ. of North Carolina, Chapel Hill, NC, 27599-7264, USA. Voice: +919-966-3358, FAX: +919-966-3630. E-mail: pfsulliv@ 123456med.unc.edu .
                Article
                nihpa75279
                10.1038/mp.2008.125
                2717726
                19065144
                3009156d-c57d-4338-a095-9efab705dccb
                History
                Funding
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH084022-01A1 ||MH
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH081802-01 ||MH
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH059160-04 ||MH
                Categories
                Article

                Molecular medicine
                major depressive disorder,genome-wide association,netherlands study of depression and anxiety,netherlands twin registry

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