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

, 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 references 115

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      PLINK: a tool set for whole-genome association and population-based linkage analyses.

      Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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          Haploview: analysis and visualization of LD and haplotype maps.

          Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface. http://www.broad.mit.edu/mpg/haploview/ jcbarret@broad.mit.edu
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            Author and article information

            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 .
            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
            2717726
            19065144
            10.1038/mp.2008.125
            nihpa75279
            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
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