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Genome-wide association study of recurrent early-onset major depressive disorder

Molecular Psychiatry volume 16, pages 193–201 (2011)Cite this article

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Abstract

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10−8 approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10−7) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

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Acknowledgements

The GenRED project is supported by grants from NIMH. We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases) from the National Center for Research Resources. GWAS data for the GAIN-MDD data set were accessed by DFL through the Genetic Association Information Network (GAIN), through dbGaP accession number phs000020.v1.p1 (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000020.v2.p1); samples and associated phenotype data for Major Depression: Stage 1 Genome-Wide Association in Population-Based Samples were provided by P Sullivan. Data for Molecular Genetics of Schizophrenia (MGS) control subjects were used here by permission of the MGS project. Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. Genotyping of the controls was supported by grants from NIMH and by the Genetic Association Information Network (GAIN)(http://www.fnih.org/index.php?option=com_content&task=view&id=338&Itemid=454). Control data are available through dbGAP (http://www.ncbi.nlm.nih.gov/gap). We are grateful to Knowledge Networks Inc. (Menlo Park, CA, USA) for assistance in collecting the control data set. We express their profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study.

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Authors and Affiliations

  1. Department of Psychiatry, Stanford University, Stanford, CA, USA

    J Shi, J K Johnson, A Zvinyatskovskiy, N Ertman, M Gladis, N Ney & D F Levinson

  2. Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA

    J B Potash, J R DePaulo Jr, D Jancic, M Goodell & R Verma

  3. Department of Psychiatry, University of Southern California, Los Angeles, CA, USA

    J A Knowles & O Evgrafov

  4. Department of Psychiatry, Columbia University, New York, NY, USA

    M M Weissman, P Adams & S Chaudhury

  5. Department of Psychiatry, University of Iowa, Iowa City, IA, USA

    W Coryell & N Hale

  6. Department of Psychiatry, Rush University Hospital, Chicago, IL, USA

    W A Scheftner & K Neimanas

  7. Department of Psychiatry, Howard University, Washington, DC, USA

    W B Lawson

  8. NorthShore University HealthCare Research Institute, Evanston, IL, USA

    P V Gejman & A R Sanders

  9. Genetic Analysis Platform, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    D Mirel

  10. Department of Psychological Medicine, Cardiff University, Cardiff, UK

    P Holmans

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  1. J Shi
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Correspondence to D F Levinson.

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Shi, J., Potash, J., Knowles, J. et al. Genome-wide association study of recurrent early-onset major depressive disorder. Mol Psychiatry 16, 193–201 (2011). https://doi.org/10.1038/mp.2009.124

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