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      Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

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          Abstract

          Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 ( ADCY3, 2p23.3) and galanin ( GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C ( P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies ( P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

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          Genetic epidemiology of major depression: review and meta-analysis.

          Robert Sullivan, K Kendler, Benjamin M. Neale (2000)
          The authors conducted a meta-analysis of relevant data from primary studies of the genetic epidemiology of major depression. The authors searched MEDLINE and the reference lists of previous review articles to identify relevant primary studies. On the basis of a review of family, adoption, and twin studies that met specific inclusion criteria, the authors derived quantitative summary statistics. Five family studies met the inclusion criteria. The odds ratios for proband (subjects with major depression or comparison subjects) versus first-degree relative status (affected or unaffected with major depression) were homogeneous across the five studies (Mantel-Haenszel odds ratio=2.84, 95% CI=2.31-3.49). No adoption study met the inclusion criteria, but the results of two of the three reports were consistent with genetic influences on liability to major depression. Five twin studies met the inclusion criteria, and their statistical summation suggested that familial aggregation was due to additive genetic effects (point estimate of heritability of liability=37%, 95% CI=31%-42%), with a minimal contribution of environmental effects common to siblings (point estimate=0%, 95% CI=0%-5%), and substantial individual-specific environmental effects/measurement error (point estimate=63%, 95% CI=58%-67%). The literature suggests that recurrence best predicts the familial aggregation of major depression. Major depression is a familial disorder, and its familiality mostly or entirely results from genetic influences. Environmental influences specific to an individual are also etiologically significant. Major depression is a complex disorder that does not result from either genetic or environmental influences alone but rather from both. These findings are notably consistent across samples and methods and are likely to be generally applicable.
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            A diagnostic interview: the schedule for affective disorders and schizophrenia.

            J Endicott, A Spitzer (1978)
            The Schedule for Affective Disorders and Schizophrenia (SADS) was developed to reduce information variance in both the descriptive and diagnostic evaluation of a subject. The SADS is unique among rating scales in that it provides for (1) a detailed description of the features of the current episodes of illness when they were at their most severe; (2) a description of the level of severity of manifestations of major dimensions of psychopathology during the week preceding the evaluation, which can then be used as a measure of change; (3) a progression of questions and criteria, which provides information for making diagnoses; and (4) a detailed description of past psychopathology and functioning relevant to an evaluation of diagnosis, prognosis, and overall severity of disturbance. This article reports on initial scale development and reliability studies of the items and the scale scores.
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              Genomewide Association for Major Depressive Disorder: A possible role for the presynaptic protein Piccolo

              Patrick F. Sullivan, Eco J.C de Geus, Gonneke Willemsen … (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.
              Article 0 comments Cited 113 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Psychiatry
                Title: Molecular Psychiatry
                Publisher: Nature Publishing Group
                ISSN (Print): 1359-4184
                ISSN (Electronic): 1476-5578
                Publication date (Print): January 2012
                Publication date (Electronic): 02 November 2010
                Volume: 17
                Issue: 1
                Pages: 36-48
                Affiliations
                [1 ]simpleGenetic Epidemiology, Molecular Epidemiology, Psychiatric Genetics and Queensland Statistical Genetics Laboratories, Queensland Institute of Medical Research , Brisbane, QLD, Australia
                [2 ]simpleDepartment of Psychiatry, Washington University School of Medicine , St Louis, MO, USA
                [3 ]simpleDivision of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital , Edinburgh, UK
                [4 ]simpleDepartment of Biological Psychology and Medical Center, VU University , Amsterdam, The Netherlands
                [5 ]simpleCenter for Human Genetic Research, Massachusetts General Hospital , Boston, MA, USA
                [6 ]simpleBroad Institute of Harvard and MIT , Cambridge, MA, USA
                [7 ]simpleDepartment of Medical and Molecular Genetics, King's College London, MRC SGDP Centre, Institute of Psychiatry , London, UK
                [8 ]simpleClinical Research Unit, Brain and Mind Research Institute, University of Sydney , NSW, Australia
                [9 ]simpleCenter for Biomarker Research and Personalized Medicine, Virginia Commonwealth University , Richmond, VA, USA
                [10 ]simpleDepartment of Genetics, University of North Carolina , Chapel Hill, NC, USA
                Author notes
                [* ]simplePsychiatric Genetics Laboratory, Queensland Institute of Medical Research , Herston Road, Brisbane, 4029, QLD, Australia. E-mail: naomi.wray@ 123456qimr.edu.au
                [* ]simpleDepartment of Genetics, University of North Carolina , Chapel Hill, NC, USA. E-mail: pfsulliv@ 123456med.unc.edu
                [11]

                Current address: Faculty of Arts and Social Sciences, University of the Sunshine Coast, Maroochydore, QLD, Australia.

                Article
                Publisher Item ID: mp2010109
                DOI: 10.1038/mp.2010.109
                PMC ID: 3252611
                PubMed ID: 21042317
                SO-VID: 9c3bd410-89c7-4d9b-812c-b17129561e13
                Copyright © Copyright © 2012 Macmillan Publishers Limited
                License:

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                Date received : 16 May 2010
                Date revision received : 12 September 2010
                Date accepted : 27 September 2010
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Molecular medicine
                Keywords: major depressive disorder,depression,genome-wide association study,cacna1c,adcy3,gal
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: major depressive disorder, depression, genome-wide association study, cacna1c, adcy3, gal

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