1. ¹Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
2. ²VU University Amsterdam, Amsterdam, The Netherlands
3. ³Queensland Institute for Medical Research, Brisbane, QLD, Australia
4. ⁴VU University Medical Center Amsterdam, Amsterdam, The Netherlands
5. ⁵University of Münster, Münster, Germany
6. ⁶James Cook University, Cairns, QLD, Australia
7. ⁷University of Edinburgh, Edinburgh, UK
8. ⁸University of Bonn, Bonn, Germany
9. ⁹University of New England, Armidale, NSW, Australia
10. ¹⁰Institute of Psychiatry, London, UK
11. ¹¹Harvard Medical School, Cambridge, MA, USA
12. ¹²Washington University, St. Louis, MO, USA
13. ¹³Max-Planck Institute of Psychiatry, Munich, Germany
14. ¹⁴Royal Edinburgh Hospital, Edinburgh, UK
15. ¹⁵University Medical Center Groningen, Groningen, The Netherlands
16. ¹⁶University of Heidelberg, Heidelberg, Germany
17. ¹⁷North Carolina State University, Raleigh, NC, USA
18. ¹⁸Leiden University Medical Center, Leiden, The Netherlands

Correspondence: Dr PF Sullivan, Department of Genetics, University of North Carolina, CB No. 7264, 4109D Neurosciences Research Building, Chapel Hill, NC 27599-7264, USA. E-mail: pfsulliv@med.unc.edu

¹⁹These authors contributed equally to this work.

Received 16 July 2008; Revised 19 September 2008; Accepted 21 October 2008; Published online 9 December 2008.

Abstract

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 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 is important 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 five independent samples (6079 MDD independent cases and 5893 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 nonsynonymous 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.