References pertaining to depression and genetics:

Biol Psychiatry. 2006 Jul 15;60(2):84-92. Epub 2005 Nov 21.

http://www.stanford.edu/group/gbf/Levinson_GeneticsDepression.pdf

The genetics of depression: a review.

Levinson DF.

Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-3309, USA. DFL@mail.med.upenn.edu

Major depressive disorder (MDD) is common and moderately heritable. Recurrence and early age at onset characterize cases with the greatest familial risk. Major depressive disorder and the neuroticism personality trait have overlapping genetic susceptibilities. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behavior, and depression-related personality traits but not yet to MDD itself. This polymorphism might also influence traits related to stress vulnerability. Newer hypotheses of depression neurobiology suggest closer study of genes related to neurotoxic and neuroprotective (neurotrophic) processes and to overactivation of the hypothalamic-pituitary axis, with mixed evidence regarding association of MDD with polymorphisms in one such gene (brain-derived neurotrophic factor [BDNF]). Several genome-wide linkage studies of MDD and related traits have been reported or are near completion. There is some evidence for convergence of linkage findings across studies, but more data are needed to permit meta-analysis. Future directions will include more intensive, systematic study of linkage candidate regions and of the whole genome for genetic association; gene expression array studies; and larger-scale studies of gene-environment interactions and of depression-related endophenotypes.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 16300747 [PubMed - indexed for MEDLINE]

Metabolism. 2005 May;54(5 Suppl 1):16-9.

Genes, stress, and depression.

Wurtman RJ.

Department of Brain and Cognitive Sciences, and Clinical Research Center, Massachusetts Institute of Technology, Cambridge 02139, USA. dick@mit.edu

A relationship between genetic makeup and susceptibility to major depressive disorder (MDD) has long been suspected on the basis of family and twin studies. A metaanalysis of reports on the basis of twin studies has estimated MDD's degree of heritability to be 0.33 (confidence interval, 0.26-0.39). Among families exhibiting an increased prevalence of MDD, risk of developing the illness was enhanced in members exposed to a highly stressful environment. Aberrant genes can predispose to depression in a number of ways, for example, by diminishing production of growth factors that act during brain development. An aberrant gene could also increase or decrease a neurotransmitter's release into synapses, its actions, or its duration of activity. The gene products of greatest interest at present are those involved in the synthesis and actions of serotonin; among them, the serotonin-uptake protein localized within the terminals and dendrites of serotonin-releasing neurons. It has been found that the Vmax of platelet serotonin uptake is low in some patients with MDD; also, Vmax is highly correlated in twins. Antidepressant drugs such as the selective serotonin reuptake inhibitors act on this uptake protein. The specific genetic locus causing serotonin uptake to be lower in some patients with major depression involves a polymorphic region (5-HTTLPR) in the promoter region of the gene for the uptake protein. The gene itself exists as several alleles, the short "S" allele and the long "L" allele. The S variant is associated with less, and the L variant with more, of the uptake protein. The effect of stressful life events on depressive symptoms in young adults was found to be significantly stronger among SS or SL subjects than among LL subjects. Neuroimaging studies showed that people with the SS or SL alleles exhibited a greater activation of the amygdala in response to fearful stimuli than those with LL. It has been reported recently that mutations in the gene that controls serotonin synthesis in the human brain (tryptophan hydroxylase) also predispose to mood disturbances. It may be asked whether people who lack a psychiatric history should be advised to avoid stressful environments if they are found to carry the SS or SL alleles.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 15877307 [PubMed - indexed for MEDLINE]

Curr Psychiatry Rep. 2000 Apr;2(2):165-9.

The genetics of major depressive disorder.

Malhi GS, Moore J, McGuffin P.

SGDP Research Centre, Institute of Psychiatry, DeCrespigny Park, Denmark Hill, London SE5 8AF, UK.

There is consistent evidence that major depression is familial and population-based twin studies as well as hospital register-based twin studies find substantial heritability. However, there is also a large proportion of variation in liability left to be explained by nongenetic factors. Although there seems little doubt that life events play a role in precipitating depression, studies that have attempted to examine familial liability along with social adversity find that environmental measures tend to be contaminated by genetic effects. Thus, the tendency to experience (or report) life events appears to be influenced by shared family environment, and for certain types of events there is a genetic component. The molecular genetic basis of liability to depression is an under-researched area, but some candidate gene studies show potentially promising results. Systematic mapping studies aiming to cover the entire genome are currently being launched.

Publication Types:
Review

PMID: 11122950 [PubMed - indexed for MEDLINE]

Arch Gen Psychiatry. 1993 Nov;50(11):843-52.

A longitudinal twin study of 1-year prevalence of major depression in women.

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.

Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond.

OBJECTIVES: This study seeks to clarify the etiologic importance and temporal stability of the genetic and environmental risk factors for 1-year prevalence of major depression (1YP-MD) in women. DESIGN: One-year prevalence of major depression was personally assessed, using DSM-III-R criteria, at two time points a minimum of 1 year apart. PARTICIPANTS: Both members of 938 adult female-female twin pairs ascertained from the population-based Virginia Twin Registry. RESULTS: The correlation in liability to 1YP-MD was much greater in monozygotic (MZ) than in dizygotic (DZ) twins at time 1 alone, time 2 alone, or at either time 1 or time 2. Model fitting suggested that the liability to 1YP-MD was due to additive genes and individual specific environment with a heritability of 41% to 46% and was not biased by violations of the equal environment assumption. Jointly analyzing both times of assessment using a longitudinal twin model suggested that, over a 1-year period, genetic effects on the liability to 1YP-MD were entirely stable, while environmental effects were entirely occasion specific. CONCLUSIONS: These results suggest that: (1) genetic factors play a moderate etiologic role in the 1YP-MD, (2) the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and (3) environmental factors play a significant role in the etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liability to illness.

Publication Types:
Research Support, U.S. Gov't, P.H.S.

PMID: 8215810 [PubMed - indexed for MEDLINE]

Child Adolesc Psychiatr Clin N Am. 2001 Apr;10(2):375-90.

Family, genetic, and imaging studies of early-onset depression.

Todd RD, Botteron KN.

Division of Child and Adolescent Psychiatry, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

As with other psychiatric disorders, most studies dealing with the familiality and genetics of depression have been limited to adults; however, several studies suggest that there is continuity between childhood- and adolescent-onset depression and adult depression. More direct estimates of the heritability of depressive symptoms or episodes in children and adolescents are compatible with the genetic contributions being greater than 50%. A number of functional and structural imaging studies have implicated particular circuitry as being involved in the generation of emotion and depression. Imaging studies of twins have suggested that regional brain volume and characteristics of brain shape are heritable. This suggests that a potentially important new avenue of research will be the correlation of the genetics of brain structure and/or function with the genetics of depression. Preliminary studies of adolescent and young adult twins suggest a significant correspondence between the genetic contributions to some regional brain volumes and early-onset depression.

Neuroscientist. 2004 Dec;10(6):575-93.

5-HT1A receptors, gene repression, and depression: guilt by association.

Albert PR, Lemonde S.

Ottawa Health Research Institute, Neuroscience University of Ottawa, Ottawa, Canada.

The serotonin system is implicated in major depression and suicide and is negatively regulated by somatodendritic 5-HT1A autoreceptors. Desensitization of 5-HT1A autoreceptors is implicated in the 2- to 3-week latency for antidepressant treatments. Alterations in 5-HT1A receptor levels are reported in depression and suicide, and gene knockout of the 5-HT1A receptor results in an anxiety phenotype, suggesting that abnormal transcriptional regulation of this receptor gene may underlie these disorders. The 5-HT1A receptor gene is negatively regulated in neurons by repressors including REST/NRSF, Freud-1, NUDR/Deaf-1, and Hes5. The association with major depression, suicide, and panic disorder of a new functional 5-HT1A polymorphism at C(-1019)G that selectively blocks repression of the 5-HT1A autoreceptor by NUDR further suggests a causative role for altered regulation of this receptor in predisposition to mental illness. The authors review evidence that altered transcription of the 5-HT1A receptor can affect the serotonin system and limbic and cortical areas, leading to predisposition to depression.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15534042 [PubMed - indexed for MEDLINE]

Psychopharmacology (Berl). 2004 Aug;174(4):512-24. Epub 2004 Jul 13.

Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter.

Neumeister A, Young T, Stastny J.

Clinical Neuroscience Division, Department of Psychiatry, VA National Center for PTSD (116-A), Yale University School of Medicine, 950 Campbell Avenue, West Haven, CT 06516, USA. Alexander.Neumeister@yale.edu

Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1(A) receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders.

Publication Types:
Review

PMID: 15249991 [PubMed - indexed for MEDLINE]

Dialogues Clin Neurosci. 2007;9(3):333-42.

The role of circadian clock genes in mental disorders.

Lamont EW, Legault-Coutu D, Cermakian N, Boivin DB.

Centre for Study and Treatment of Circadian Rhythms, Douglas Mental Health University Institute, Montreal, QC, Canada.

The study of molecular clock mechanisms in psychiatric disorders is gaining significant interest due to data suggesting that a misalignment between the endogenous circadian system and the sleep-wake cycle might contribute to the clinical status of patients suffering from a variety of psychiatric disorders. Sleep disturbances in major depressive disorder (MDD) are characterized by increased sleep latency, poorer sleep efficiency reduced latency to the first rapid eye movement (REM) sleep episode, and early-morning awakening, but there is little data to indicate a role of circadian clock genes in MDD. There is also relatively little information regarding the role of clock genes in anxiety. In contrast, a significant amount of evidence gathered in bipolar disorder (BPD) patients suggests a circadian rhythm disorder, namely an advanced circadian rhythm and state-dependent alterations of REM sleep latency. Most research on the role of clock genes in BPD has focused on polymorphisms of CLOCK, but the lithium target GSK3 may also play a significant role. A circadian phase shift is also theorized to contribute to the pathophysiology of winter seasonal affective disorder (SAD). Certain allelic combinations of NPAS2, PER3, and BMAL1 appear to contribute to the risk of SAD. In chronic schizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK, PER1, PER3, and TIMELESS. Sleep and circadian changes associated with dementia due to Alzheimer's disease suggest a functional change in the circadian master clock, which is supported by postmortem studies of clock gene expression in the brain.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17969870 [PubMed - indexed for MEDLINE]