Patrick F. Sullivan , MD, Eco J.C. de Geus , PhD, Gonneke Willemsen , PhD, Michael R. James , PhD, Jan H. Smit , PhD, Tim Zandbelt , MSc, Volker Arolt , MD, Bernhard T. Baune , MD MPH, Douglas Blackwood , MD, Sven Cichon , PhD, William L. Coventry , Katharina Domschke , MD MA, Anne Farmer , MD PhD, Maurizio Fava , MD, Scott D. Gordon , Qianchuan He , Andrew Heath , PhD, Peter Heutink , PhD, Florian Holsboer , MD PhD, Witte J. Hoogendijk , MD PhD, Jouke Jan Hottenga , PhD, Yijuan Hu , Martin Kohli , MSc, Danyu Lin , PhD, Suzanne Lucae , MD PhD, Donald J. MacIntyre , MRCPsych, Wolfgang Maier , MD, Kevin A. McGhee , PhD, Peter McGuffin , MD PhD, Grant Montgomery , PhD, Walter J. Muir , FRCPsych, Willem Nolen , MD, Markus M. Nöthen , MD, Roy H. Perlis , MD MSc, Katrina Pirlo , Danielle Posthuma , PhD, Marcella Rietschel , MD PhD, Patizia Rizzu , PhD, Alexandra Schosser , MD, August B. Smit , PhD, Jordan W. Smoller , MD ScD, Jung-Ying Tzeng , PhD, Richard van Dyck , MD PhD, Matthijs Verhage , PhD, Frans G. Zitman , MD PhD, Nicholas G. Martin , PhD, Naomi R. Wray , PhD, Dorret I. Boomsma , PhD, Brenda W.J.H. Penninx , PhD
9 December 2008
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.