Genetics of Depression


Probing the genetic basis of depression not only informs our understanding of the role that genes play in disease, but also further offers the potential to provide invaluable insights into the aetiology, classification and neurobiology of the disorder. Moreover, understanding the genetics of depression may offer a starting point for the development of novel, and potentially more efficacious treatments for patients.

Although a number of genes have been implicated in depression, a genetic variant that is unequivocally associated with an increased risk of the disease is yet to be identified. As genome‐wide approaches to analysing genetic variation gain momentum, large‐scale collaborations have brought insights into how best to conceptualise depression as an illness. Nonetheless, the identification of specific genetic variants associated with depression still eludes researchers. By building on the knowledge gained from these collaborative datasets, and utilising newer and more sophisticated technologies and methodologies, it is likely that researchers will be able to replicate in depression, the successes of genetic research in other complex disorders.

Key Concepts:

  • MDD is a complex genetic disorder involving interactions between multiple genetic variants and environmental factors.

  • Some areas of interest have been implicated via linkage methodologies in MDD, but this method is more suited to more strongly heritable forms of the disease.

  • Many candidate gene studies of MDD have been underpowered to detect small genetic influences, and are constrained by our limited understanding of the neurobiology of the disease.

  • Genome‐wide association methodologies have not yet identified any clear markers of the disease, but have informed our understanding of MDD.

  • Following the progress of genetic research into other disease phenotypes, the collection of larger patient cohorts is likely to yield success in identifying the genetic variants involved in MDD.

  • Newer technologies and analysis methods to model the biological complexity of the illness are also rapidly evolving.

Keywords: major depressive disorder (MDD); depression; genetics; genome‐wide association studies (GWAS); linkage; candidate gene studies; gene–environment interactions


Abkevich V, Camp NJ, Hensel CH et al. (2003) Predisposition locus for major depression at chromosome 12q22‐12q23.2. American Journal of Human Genetics 73(6): 1271–1281.

American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington DC: American Psychiatric Association.

Bosker FJ, Hartman CA, Nolte BP et al. (2011) Poor replication of candidate genes for major depressive disorder using genome‐wide association data. Molecular Psychiatry 16(5): 516–532.

Breen G, Webb BT, Butler AW et al. (2011a) A genome‐wide significant linkage for severe depression on chromosome 3: the depression network study. American Journal of Psychiatry 168(8): 840–847.

Breen G, Lewis CM, Vassos E et al. (2011b) Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression. Nature Genetics 43(1): 3–5.

Camp NJ, Lowry MR, Richards RL et al. (2005) Genome‐wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early‐onset major depression and anxiety disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 135B(1): 85–93.

Caspi A, Sugden K, Moffitt TE et al. (2003) Influence of life stress on depression: moderation by a polymorphism in the 5‐HTT gene. Science 301(5631): 386–389.

Conrad DF, Andrews TD, Carter NP et al. (2006) A high‐resolution survey of deletion polymorphism in the human genome. Nature Genetics 38(1): 75–81.

Cross‐Disorder Group of the Psychiatric Genomics Consortium (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome‐wide analysis. Lancet 381(9875): 1371–1379.

Degenhardt F, Priebe L, Herms S et al. (2012) Association between copy number variants in 16p11.2 and major depressive disorder in a German case‐control sample. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 159B(3): 263–273.

Dudbridge F and Gusnanto A (2008) Estimation of significance thresholds for genomewide association scans. Genetic Epidemiology 32(3): 227–234.

Farmer A, Harris T, Redman K et al. (2000) Cardiff depression study. A sib‐pair study of life events and familiality in major depression. British Journal of Psychiatry 176: 150–155.

Glessner JT, Wang K, Sleiman PM et al. (2010) Duplication of the SLIT3 locus on 5q35.1 predisposes to major depressive disorder. PLoS One 5(12): e15463.

Hauser ER, Boehnke M, Guo SW et al. (1996) Affected‐sib‐pair interval mapping and exclusion for complex genetic traits: sampling considerations. Genetic Epidemiology 13(2): 117–137.

Holmans P, Weissman MM, Zubenko GS et al. (2007) Genetics of recurrent early‐onset major depression (GenRED): final genome scan report. American Journal of Psychiatry 164(2): 248–258.

Holmans P, Zubenko GS, Crowe RR et al. (2004) Genomewide significant linkage to recurrent, early‐onset major depressive disorder on chromosome 15q. American Journal of Human Genetics 74(6): 1154–1167.

Jia P, Kao CF, Kuo PH et al. (2011) A comprehensive network and pathway analysis of candidate genes in major depressive disorder. BMC Systems Biology 5(Suppl. 3): S12.

Kendler KS, Neale MC, Kessler RC et al. (1993) The lifetime history of major depression in women: reliability of diagnosis and heritability. Archives of General Psychiatry 50(11): 863–870.

Lee PH, Perlis RH, Jung JY et al. (2012) Multi‐locus genome‐wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder. Translational Psychiatry 2: e184.

Levinson DF, Evgrafov OV, Knowles JA et al. (2007) Genetics of recurrent early‐onset major depression (GenRED): significant linkage on chromosome 15q25‐q26 after fine mapping with single nucleotide polymorphism markers. American Journal of Psychiatry 164(2): 259–264.

Lewis CM, Ng MY, Butler AW et al. (2010) Genome‐wide association study of major recurrent depression in the U.K. population. American Journal of Psychiatry 167(8): 949–957.

Lopez‐Leon S, Janssens AC, Gonzalez-Zuloeta Ladd AM et al. (2008) Meta‐analyses of genetic studies on major depressive disorder. Molecular Psychiatry 13(8): 772–785.

Lubke GH, Hottenga JJ, Walters R et al. (2012) Estimating the genetic variance of major depressive disorder due to all single nucleotide polymorphisms. Biological Psychiatry 72(8): 707–709.

Lyons MJ, Eisen SA, Goldberg J et al. (1998) A registry‐based twin study of depression in men. Archives of General Psychiatry 55(5): 468–472.

Maher BS, Marazita ML, Zubenko WN et al. (2002) Genetic segregation analysis of recurrent, early‐onset major depression: evidence for single major locus transmission. American Journal of Medical Genetics 114(2): 214–221.

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (2012) A mega‐analysis of genome‐wide association studies for major depressive disorder. Molecular Psychiatry 18(4): 497–511.

McGuffin P, Katz R, Watkins S et al. (1996) A hospital‐based twin register of the heritability of DSM‐IV unipolar depression. Archives of General Psychiatry 53(2): 129–136.

McGuffin P, Rijsdijk F, Andrew M et al. (2003) The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry 60(5): 497–502.

McGuffin P, Knight J, Breen G et al. (2005) Whole genome linkage scan of recurrent depressive disorder from the depression network study. Human Molecular Genetics 14(22): 3337–3345.

McKernan KJ, Peckham HE, Costa GL et al. (2009) Sequence and structural variation in a human genome uncovered by short‐read, massively parallel ligation sequencing using two‐base encoding. Genome Research 19(9): 1527–1541.

McMahon FJ, Akula N, Schultze TG et al. (2010) Meta‐analysis of genome‐wide association data identifies a risk locus for major mood disorders on 3p21.1. Nature Genetics 42(2): 128–131.

Middeldorp CM, Sullivan PF, Wray NR et al. (2009) Suggestive linkage on chromosome 2, 8, and 17 for lifetime major depression. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 150B(3): 352–358.

Muglia P, Tozzi F, Galwey NW et al. (2010) Genome‐wide association study of recurrent major depressive disorder in two European case‐control cohorts. Molecular Psychiatry 15(6): 589–601.

Murray CJL and Lopez AD (1996) Evidence‐based health policy‐lessons from the global burden of disease study. Science 274(5288): 740–743.

Pergadia ML, Glowinski AL, Wray NR et al. (2011) A 3p26‐3p25 genetic linkage finding for DSM‐IV major depression in heavy smoking families. American Journal of Psychiatry 168(8): 848–852.

Rucker JJ and McGuffin P (2010) Polygenic heterogeneity: a complex model of genetic inheritance in psychiatric disorders. Biological Psychiatry 68(4): 312–313.

Rucker JJ , Breen G, Pinto D et al. (2011) Genome‐wide association analysis of copy number variation in recurrent depressive disorder. Molecular Psychiatry.

Schulze TG, Akula N, Breuer R et al. (2012) Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder. World Journal of Biological Psychiatry.

Shi J, Potash JB, Knowles JA et al. (2011) Genome‐wide association study of recurrent early‐onset major depressive disorder. Molecular Psychiatry 16(2): 193–201.

Shyn SI and Hamilton SP (2010) The genetics of major depression: moving beyond the monoamine hypothesis. Psychiatric Clinics of North America 33(1): 125–140.

Shyn SI, Shi J, Kraft JB et al. (2011) Novel loci for major depression identified by genome‐wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta‐analysis of three studies. Molecular Psychiatry 16(2): 202–215.

Sullivan PF, de Geus EJ, Willemsen G et al. (2009) Genome‐wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Molecular Psychiatry 14(4): 359–375.

Sullivan PF, Neale MC and Kendler KS (2000) Genetic epidemiology of major depression: review and meta‐analysis. American Journal of Psychiatry 157(10): 1552–1562.

Uher R and McGuffin P (2010) The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Molecular Psychiatry 15(1): 18–22.

Uher R (2009) The role of genetic variation in the causation of mental illness: an evolution‐informed framework. Molecular Psychiatry 14(12): 1072–1082.

Verma R, Holmans P, Knowles JA et al. (2008) Linkage disequilibrium mapping of a chromosome 15q25‐26 major depression linkage region and sequencing of NTRK3. Biological Psychiatry 63(12): 1185–1189.

Wray NR, Pergadia ML, Blackwood DH et al. (2012) Genome‐wide association study of major depressive disorder: new results, meta‐analysis, and lessons learned. Molecular Psychiatry 17(1): 36–48.

Zbozinek TD, Rose RD, Wolitzky-Taylor KB et al. (2012) Diagnostic overlap of generalized anxiety disorder and major depressive disorder in a primary care sample. Depression and Anxiety 29(12): 1065–1071.

Zubenko GS, Maher B, Hughes HB et al. (2003) Genome‐wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early‐onset, major depression. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 123B(1): 1–18.

Further Reading

Conrad DF, Pinto D, Redon R et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464(7289): 704–712.

Gottesman II and Shields J (1967) A polygenic theory of schizophrenia. Proceedings of the National Academy of Sciences 58(1): 199–205.

Ioannidis JP (2005) Why most published research findings are false. PLoS Medicine 2(8): e124.

So HC, Gui AH, Cherny SS et al. (2011) Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genetic Epidemiology 35(5): 310–317.

Sullivan PF (2010) The psychiatric GWAS consortium: big science comes to psychiatry, Neuron 68(2): 182–186.

Yang J, Lee SH, Goddard ME and Visscher PM (2011) GCTA: a tool for genome‐wide complex trait analysis. American Journal of Human Genetics 88(1): 76–82.

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Hodgson, Karen, and McGuffin, Peter(Sep 2013) Genetics of Depression. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025048]