The Genetics of Major Depression: Moving Beyond the Monoamine Hypothesis

Abstract

SYNOPSISEfforts to unlock the biology of major depressive disorder (MDD) are proceeding on multiple fronts. In this article, we review our current understanding of epidemiologic evidence for a heritable component to MDD risk, as well as recent advances in linkage, candidate gene, and genome-wide association analyses of MDD and related disease subtypes and endophenotypes. While monoamine signaling has preoccupied the bulk of scientific investigation to date, non-traditional gene candidates such as PCLO and GRM7 are now emerging and beginning to change the landscape for future human and animal research on depression. Keywords genetics; major depression; genome-wide association INTRODUCTIONOver the course of a lifetime, major depressive disorder (MDD) afflicts one in six individuals in the general U.S. population 1 , women twice as often as men2, and is the leading cause of disability among adults younger than 45 years of age3. MDD is characterized by dysphoria and/or anhedonia plus several additional symptoms for diagnosis which may include: changes in sleep/appetite, excessive feelings of guilt or worthlessness, anergia, psychomotor slowing, impaired ability to think, and, in more severe cases, suicidality. The DSM-IV further defines MDD as the presence of at least one two-week depressive episode and excludes cases in which bipolar disorder, substances, or a general medical condition is etiologic4.The pathophysiology of MDD remains a mystery almost half a century since Joseph Schildkraut first proposed the monoamine hypothesis of depression 5, which followed the twin serendipitous discoveries of the therapeutic benefits of iproniazid (an antimycobacterial with inhibitory effects on monoamine oxidase) 6 and imipramine (a failed antipsychotic which came cCorresponding author for proof & reprints: Steven P. Hamilton, MD-PhD, Carol Cochran Schaffner Endowed Chair, In Mental Health, Box 0984 -NGL, 401 Parnassus Ave, San Francisco, Ph 415.476.7889, FAX 415.476.7800, steveh@lppi.ucsf.edu. d Coauthor address: Stanley Shyn, MD-PhD, Box 0984 -NGL, 401 Parnassus Ave, San Francisco, Ph 415.476.7898, FAX 415.476.7800, sshyn@lppi.ucsf.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPsychiatr Clin North Am. Author manuscript; available in PMC 2011 March 1. Published in final edited form as:Psychiatr Clin North Am. EPIDEMIOLOGY AND MDD SUBTYPESFamily studies demonstrate that first-degree relatives of MDD probands have a relative risk for MDD of 2.8 over the general population risk9. This number is further increased to between 3.0 and 8.0 for r...

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

“…This might be accomplished through a better understanding of the biological mechanisms underlying the heterogeneity of MDD. Research in human genetics has so far not succeeded in identifying biologically well-defined subpopulations in depression, but it is a rapidly advancing field that at some point is likely to deliver a break-through [202]. Another way forward would be to integrate several clinical research methods to refine drug treatments, for example, by using physiological stress response tests, measuring hormone levels (thyroid, sex hormones) and blood biomarkers, and recording brain circuity dynamics in depression-relevant brain regions with imaging and electrophysiology techniques.…”

Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms

“…In both types of mood disorders genetic and environmental factors have a significant role (Levinson, 2006;Barnett and Smoller, 2009). Based on twin studies, the heritability rates of MDD range from 37 to 50% (Shyn and Hamilton, 2010); whereas the heritability estimates are much higher in BPD (79-93%) (Barnett and Smoller, 2009). Overlapping genetic contribution of MDD and BPD is hypothesized, as a threefold increase of MDD was observed among the relatives of BPD patients compared to relatives of controls (14.1% vs 5.2%, Barnett and Smoller, 2009).…”

“…Overlapping genetic contribution of MDD and BPD is hypothesized, as a threefold increase of MDD was observed among the relatives of BPD patients compared to relatives of controls (14.1% vs 5.2%, Barnett and Smoller, 2009). A priori hypothesis free studies aiming to discover the genetic determinants of MDD and BPD are the classical linkage and the more recent genome wide association studies, both of them giving only limited numbers of chromosomal regions worthwhile to study in more detail (Barnett and Smoller, 2009;Shyn and Hamilton, 2010). A few linkage studies pointed to the 12q23-24 chromosomal region consistently both in BPD (Morissette et al, 1999;Curtis et al, 2003) and in MDD (Abkevich et al, 2003;McGuffin et al, 2005).…”

Genetics of Depression

“…However, often the candidates with the best evidence of association with MDD are those with a less obvious mechanistic connexion to the neurobiology of depression as we currently understand it (Shyn and Hamilton, 2010). This suggests that our current ability to select appropriate candidate genes is constrained by our lack of understanding of the pathological processes involved in depression.…”