Major Depressive Disorder

A number sign (#) is used with this entry because multiple genetic loci are involved in the causation of this complex trait.

One susceptibility locus for major depressive disorder (MDD1; 608520) has been mapped to chromosome 12q22-q23.2. Another susceptibility locus for major depressive disorder (MDD2; 608691) has been mapped to 15q25.3-q26.2.

Polymorphism in the FKBP5 gene (602623), which plays a role in the stress hormone-regulating hypothalamic-pituitary-adrenal axis, has been found to be related to a faster response to antidepressant drug treatment and to increased recurrence of depressive episodes.

A mutation in the tryptophan hydroxylase-2 gene (TPH2; 607478), which encodes the rate-limiting enzyme of neuronal serotonin synthesis and maps to 12q21, was found in individuals with unipolar major depression.

A polymorphism in the HTR2A gene (182135.0003), which encodes the serotonin 2A receptor, has been associated with citalopram treatment outcome in major depressive disorder.

According to the DSM-IV-TR (American Psychiatric Association, 2000), major depressive disorder is characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning.

Major depressive disorder is commonly recurrent and can be lethal. Up to 15% of individuals with severe major depressive disorder die by suicide. There is a 4-fold increase in death rate of individuals with major depressive disorder over 55 years of age (American Psychiatric Association, 2000).

In a brain imaging study of 131 individuals, 66 at high risk for depression, including those with a parental history of depression, and 65 at low risk, Peterson et al. (2009) found that high-risk individuals had large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere compared to low-risk individuals. An average reduction of 28% in cortical thickness was observed in this area, which included the inferior and middle frontal gyri, somatosensory and motor cortices, the dorsal and inferior parietal regions, the inferior occipital gyrus, and the posterior temporal cortex. Although cortical thickness was not associated with a lifetime history of depression, thinning correlated with measures of current symptom severity, inattention, and visual memory for social and emotional stimuli. Peterson et al. (2009) suggested that cortical thinning in the right hemisphere is a familial trait and may produce disturbances in arousal, attention, and memory for social stimuli, which in turn may increase the risk of developing depressive illness.

In 209 patients with migraine without aura (MO) and 151 patients with migraine with aura (MA) and 617 controls, all of whom were from a genetically isolated Dutch population, Stam et al. (2010) found a significant association between migraine with aura and depression (p less than 0.001; OR, 1.70). Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96) patients, and decreased somewhat after adjustment for depression, especially in MA. The findings indicated a bidirectional association between depression and migraine, in particular migraine with aura, which may be partly due to shared genetic factors.

Mathe et al. (1994) examined the concentration of calcitonin gene-related peptide (CALCA, or CGRP; 114130) immunoreactivity in the CSF of 63 patients with major depression with the concentration found in the CSF of 28 patients with schizophrenia (181500) and 20 controls. Patients with all forms of major depression had higher levels of this peptide in the spinal fluid than did patients with schizophrenia or controls. The authors suggested that the increased concentration of CGRP may be a marker trait of major depressive disorder.

Using whole-genome expression profiling of postmortem hippocampal tissue from 21 patients with major depressive disorder and 18 controls, Duric et al. (2010) found significantly increased expression of MKP1 (DUSP1; 600714) in patients with depression. There was 2.3-fold increase in the dentate gyrus and a 2.4-fold increase in the CA1 pyramidal cell layer. Similar results were found in a second cohort, with MDD patients having 31% and 16% increased MKP1 mRNA levels in the dentate gyrus and CA1 region, respectively, compared to controls. This increase was associated with downregulation of the neurotrophic factor-MAPK cascade and an inhibition of downstream ERK signaling. Studies in rats showed that chronic unpredictable stress was associated with increased Mkp1 expression in the hippocampus, and that injection of Mkp1 into hippocampus of wildtype rats induced depressive behavior. Finally, Mkp1-null rats were resistant to chronic stress-induced depressive behavior compared to controls. The findings implicated MKP1 as a key factor in the pathophysiology of MDD.

Major depressive disorder is one of the most common psychiatric disorders (Murray and Lopez, 1996). According to the DSM-IV-TR (American Psychiatric Association, 2000), the rate of major depressive disorder is highest in the 25- to 44-year-old age group. The lifetime risk of major depressive disorder in community samples varies from 10 to 25% for women and 5 to 12% for men. Point prevalence varies from 5 to 9% for women and 2 to 3% for men. Prevalence rates appear to be unrelated to ethnicity, education, income, or marital status. Fifty to 60% of individuals who have had a single major depressive disorder episode can be expected to have a second episode. Those who have had 2 episodes stand a 70% chance of having a third episode, and those with 3 episodes have a 90% chance of having a fourth.

Although epidemiologic studies indicate an environmental component in the etiology of major depressive disorder, a genetic component has also been found. Twin studies estimate the heritability of major depressive disorder at 0.36 to 0.70 (Torgersen, 1986; McGuffin et al. (1991, 1996); Kendler et al. (1993, 2001); Bierut et al., 1999; Sullivan et al., 2000).

Several studies have found the risk of major depressive disorder in first-degree relatives of probands to be 2 to 4 times that of controls (Tsuang et al., 1994; Gershon et al., 1982; Weissman et al. (1984, 1993); Maier et al., 1993).

In a complex segregation analysis of 832 individuals from 50 multigenerational families ascertained through a proband with recurrent, early-onset major depressive disorder, Marazita et al. (1997) found the relative risk of the disorder to be 4 to 8 times greater in relatives of probands.

Levinson et al. (2003) described 838 affected individuals from 305 families containing 613 affected sib pairs with a mean age of onset of 18.5 years and a mean of 7.3 episodes of depression. They found that panic disorder was a more common comorbidity of affected women, whereas substance use was more common in affected men.

In a study of 2,287 Australian and 1,185 Dutch twins and sibs, Middeldorp et al. (2005) found a correlation of 0.20 for major depression, yielding an upper heritability estimate of 36%.

In a questionnaire-based study of 3,053 Australian twin individuals aged 50 to 94 years, including 654 monozygotic twin pairs, Mosing et al. (2009) found that genetic factors could explain 36%, 34%, and 46% of the variation in optimism, mental health, and self-rated health, respectively. Genetic variance accounted for 14 to 20% of covariance between these variables. The overall findings suggested that high optimism, which may be genetically determined, is related to good mental health and self-rated health. There was some evidence for possible sex differences.

Bartels and Boomsma (2009) used a questionnaire-based method to assess measurements of subjective well-being (SWB) as defined by 4 measures: quality of life in general, satisfaction with life, quality of life at the moment, and subjective happiness, in 5,024 individuals aged 12 to 23 years, including 770 monozygotic and 590 dizygotic twin pairs and nontwin sibs, from 2,157 families. The results indicated a broad-sense heritability for SWB between 40 and 50%, and implicated both additive and nonadditive genetic factors on the phenotype.

St Clair et al. (1990) studied a family with 23 cases of mental and/or behavioral disorders. Of the 77 family members available for cytogenetic analysis, 34 were found to carry a balanced translocation t(1;11)(q43;q21). Psychiatric diagnoses had been recorded for 16 of the 34 members with the translocation compared with only 5 of the 43 without it. Lod scores were greatest when the mental disorders in the phenotype were restricted to schizophrenia, schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. St Clair et al. (1990) suggested that the 11q21-q22 region may be the site of a gene or genes predisposing to major mental illness.

In a study of 38 female outpatients with depression to investigate the effect of antidepressant treatment on hippocampal volumes, Sheline et al. (2003) found that longer durations during which depressive episodes went untreated with antidepressant medication were associated with reductions in hippocampal volume. There was no significant relationship between hippocampal volume loss and time depressed while taking antidepressant medication or with lifetime exposure to antidepressants. Sheline et al. (2003) concluded that antidepressants may have a neuroprotective effect during depression.

Patients with major depressive disorder whose treatment is unsuccessful with one medication often have a response when treated with an antidepressant of a different chemical class. In a search for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram and were prospectively assessed, McMahon et al. (2006) found significant and reproducible association between treatment outcome and a marker in intron 2 of the HTR2A gene (182135.0003). Citalopram downregulates the serotonin 2A receptor, which is encoded by the HTR2A gene. The A allele was over 6 times more frequent in white than in black participants, and treatment was less effective among black participants. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment compared with those homozygous for the other allele. McMahon et al. (2006) concluded that the A allele of the intron 2 HTR2A polymorphism may contribute to racial differences in outcomes of antidepressant treatment.

Association with the MTHFR Gene on Chromosome 1p36

Bjelland et al. (2003) examined the association between folate, total homocysteine, vitamin B12, and the MTHFR 677C/T polymorphism (607093.0003) and anxiety and depression in a population-based study of 5,948 subjects, aged 46 to 49 years and 70 to 74 years, from the Hordaland Homocysteine Study cohort. Hyperhomocysteinemia (plasma total homocysteine level greater than or equal to 15.0 micromol/L) and the T/T genotype, but not low plasma folate or B12 levels, were significantly related to depression without comorbid anxiety disorder.

Lewis et al. (2006) genotyped the 677C/T polymorphism in 3,478 women in the British Women's Heart and Health Study to look for an association between genotype and 3 indicators of depression: ever diagnosed as depressed, currently taking antidepressants, and the EuroQol mood question. Subsequently, they performed a systematic review and metaanalysis of all published studies associated with this polymorphism. In the British Women's Heart and Health Study, they found an increased risk of having been diagnosed as depressed in TT compared to CC individuals (OR, 1.35; 95% CI, 1.01, 1.80). A metaanalysis of the other studies combined with this study yielded an OR of 1.36 (95% CI, 1.11, 1.67, p = 0.003), suggesting that folate or its derivatives may be causally related to risk of depression.

Association with the CREB1 Gene on Chromosome 2q34

Zubenko et al. (2003) conducted a genomewide linkage survey for genetic loci that influence the development of unipolar mood disorders in 81 families identified through individuals with recurrent early-onset MDD (RE-MDD). Model-free linkage analysis was performed using genotypes for 389 highly informative simple sequence tandem repeat polymorphisms (SSTRPs) with an average spacing of 9 cM. In light of previous evidence suggesting that sex-specific susceptibility genes for mood disorders may be commonplace (Zubenko et al., 2002), as well as evidence implicating the region of chromosome 2q33-q35 that includes the CREB1 gene (123810) as a sex-limited susceptibility locus (Zubenko et al. (2002, 2002, 2002); Philibert et al., 2003), linkage analysis was also performed using a model with covariates to control for the effects of sex and linkage to CREB1. Simulations were performed to determine lod thresholds that corresponded to genomewide levels of significance for each phenotype/model. Nineteen chromosomal regions contained linkage peaks reaching genomewide statistical significance (genomewide adjusted p less than 0.05) and 10 of these were 'highly significant' (adjusted p less than 0.001). The findings indicated that these 19 loci (1) frequently have sex-specific effects, predominantly affecting the risk of depression in women; (2) often work together to influence risk; and (3) typically affect the risk of a spectrum of depressive disorders as well as alcoholism and other addictions. The highest multipoint lod score observed, 8.19 (adjusted p less than 0.0001), occurred for recurrent MDD at marker D2S2321 (205 cM), located 121 kb proximal to CREB1. In a previous linkage analysis that controlled only for sex, the multipoint lod score reached 6.89 at this location (Zubenko et al., 2002). Zubenko et al. (2003) detected sequence variations in the promoter and intron 8 of CREB1 that cosegregated with mood disorders, or their absence, in women from their collection of 81 RE-MDD families, identifying CREB1 as a likely sex-limited susceptibility gene for unipolar mood disorders, and implicating the cAMP signaling pathway in the pathophysiology of mood disorders and related conditions. Since these signaling pathways are used ubiquitously, not just by brain cells, Zubenko et al. (2003) suggested that the susceptibility genes for MDD may contribute directly to the development of systemic medical problems. Zubenko et al. (2001) noted that nearly half the deceased members of the 81 RE-MDD families studied died before reaching 65 years of age, typically of 'natural' causes.

Burcescu et al. (2005) investigated the association of CREB1 with childhood-onset mood disorder in a sample of 195 nuclear families (225 affected children) collected in Hungary and in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matching controls. Genotyping for 2 DNA variants previously found to be associated, -656G/A and a C ins/del in intron 8, as well as for 3 additional polymorphisms spanning CREB1, revealed no evidence for association with early-onset mood disorder or for sex-specific relationship.

Association with the FKBP5 Gene on Chromosome 6p21

The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. Binder et al. (2004) investigated the possible association between genes regulating the HPA axis and response to antidepressants and susceptibility to depression. By genotyping single-nucleotide polymorphisms (SNPs) in 8 of these genes in depressed individuals and matched controls, they found significant associations of response to antidepressants and the recurrence of depressive episodes with SNPs in FKBP5 (602623), a glucocorticoid receptor-regulation cochaperone of heat-shock 90-kD protein-1 (HSPCA; 140571), in 2 independent samples.

Association with the CHRM2 Gene on Chromosome 7q35

Wang et al. (2004) examined 11 SNPs within and flanking CHRM2 gene (118493) in 262 families with alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (COGA). Three SNPs showed highly significant association with alcoholism (103780) (p = 0.004, 0.004, and 0.007, respectively). Two SNPs were significantly associated with major depressive syndrome (p = 0.004 and 0.017). Haplotype analyses revealed that the most common haplotype, T-T-T (rs1824024, rs2061174, and rs324650), was undertransmitted to affected individuals with alcohol dependence and major depressive syndrome.

In a large, adequately powered, clinical depression case-control sample (1,420 cases and 1,624 controls), Cohen-Woods et al. (2009) found no association between previously implicated SNPs in the CHRM2 gene and major depression.

Association with the TOR1A Gene on Chromosome 9q34

Heiman et al. (2004) administered a standard psychiatric interview to 96 manifesting carriers of the torsin dystonia (DYT1; 128100) deletion mutation (605204.0001), 60 nonmanifesting carriers of the mutation, and 65 noncarriers. The risk for early-onset (before 30 years) recurrent major depression was increased in both manifesting mutation carriers (relative risk of 3.62) and nonmanifesting mutation carriers (relative risk of 4.95) compared to noncarriers. The severity of dystonia in manifesting carriers was not associated with the likelihood of major depression, and mutation carriers did not have an increased risk for other affective disorders. Heiman et al. (2004) concluded that early-onset recurrent major depression is a clinical expression of the DYT1 gene mutation that is independent of dystonia. In an accompanying commentary, Richard and McDonald (2004) noted that the DYT1 gene is likely involved in dopamine release or turnover and that the findings of Heiman et al. (2004) suggested a link between basal ganglia disease and depression. The authors noted that other basal ganglia diseases, including Parkinson disease (168600), Huntington disease (143100), and caudate stroke are associated with high rates of depression.

Association with the DRD4 Gene on Chromosome 11p15

Lopez Leon et al. (2005) conducted a metaanalysis to reevaluate the role of the 48-bp repeat polymorphism in the dopamine D4 receptor (DRD4; 126452) gene on chromosome 11p15 in mood disorders. In 917 patients with unipolar or bipolar affective disorder and 1,164 control subjects from 12 samples, an association was found between the DRD4 2-repeat (2R) allele and unipolar depression (p less than 0.001) and unipolar and bipolar depression combined (p less than 0.001).

Association with the TPH1 Gene on Chromosome 11p15

Nash et al. (2005) noted that genetic susceptibility to depression and anxiety is both overlapping and dimensional. To index this common genetic susceptibility, they created a quantitative phenotype from several depression and anxiety-related measures. They studied 119 sibships comprising 312 individuals from a community-based sample of 34,371 individuals, selected for extreme scores on this measure. A pathway-based candidate gene study examined 5 microsatellite markers located within or close to 5 serotonin system genes, i.e., HTR2C (312861), HTR1D (182133), HTR1B (182131), TPH1 (191060), and MAOB (309860). Statistical analysis using the quantitative TDT gave significant association with a microsatellite downstream of TPH1. When further analysis included a life-events composite as a covariable, a stronger association with TPH1 was observed.

Gizatullin et al. (2006) screened TPH1 SNPs spanning over 23 kb (promoter to exon 8) in 228 patients with major depression and 253 healthy control subjects. Several haplotypes were associated with depression, and the 6-SNP haplotypes that occurred in less than 5% of both groups were associated with the disease (31.6% vs 18.0% in controls, p less than 0.00005). A sliding window analysis attributed the strongest disease association to a 2-SNP haplotype comprising rs1799913 (A779C) and rs7933505 localized between intron 7 and 8 (p less than 0.00005). Gizatullin et al. (2006) concluded that the most common variants appear not to carry risk while some less frequent variants might contribute to major depression.

Association with the TPH2 Gene on Chromosome 12q21

Zhang et al. (2005) identified a 1465G-A SNP (607478.0001) in the rate-limiting enzyme of neuronal serotonin synthesis, tryptophan hydroxylase-2 (TPH2; 607478). This functional SNP replaces the highly conserved arg441 with his (R441H) and resulted in about 80% loss of function in serotonin production when TPH2 was expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that 9 patients carried the mutant (1463A) allele, while among 219 controls, 3 subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in TPH2 suggested that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression. Garriock et al. (2005), however, found no evidence of the TPH2 1463G-A SNP by sequence analysis of 182 patients with unipolar depression (83 were treatment resistant), 186 nondepressed controls, and 8 bipolar patients. The ethnicity and gender distribution was similar to that studied by Zhang et al. (2005).

Association with the SLC6A4 Gene on Chromosome 17q

Ogilvie et al. (1996) identified polymorphisms of the serotonin transporter gene (SLC6A4; 182138) and detected 3 novel alleles of the variable number tandem repeat (VNTR) region, containing 9, 10, or 12 copies of the VNTR element. They found a significant difference between a control and an affective disorder group, largely explained by an excess association of the 9-copy allele with risk of unipolar depression.

Caspi et al. (2003) tested why stressful experiences led to depression in some people but not in others. A functional polymorphism in the promoter region of the SLC6A4 gene (182138.0001) was found to moderate the influence of stressful life events on depression. Individuals with 1 or 2 copies of the short allele of the promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele.

In a study of 466 patients with major depressive disorder and 836 control subjects of German descent, Hoefgen et al. (2005) found that the short allele of the promoter polymorphism of the SLC6A4 gene was significantly more frequent in patients than in control subjects (45.5% vs 39.9%; p = 0.006; odds ratio = 1.26).

Taylor et al. (2005) studied the influence of serotonin transporter promoter polymorphisms on hippocampal volumes in late-life depression. They genotyped and performed brain MRIs on 72 individuals with early-onset depression, 63 with late-onset depression, and 83 healthy controls. Subjects with late-onset depression who were homozygous for the long allele (L/L) had significantly smaller right hippocampal volumes than did L/L individuals with early-onset depression (p = 0.046) or L/L control individuals (p = 0.01). Post hoc analysis also showed that later age of depression onset was associated with smaller hippocampal volumes in individuals with the L/L genotype, but earlier age of onset was associated with smaller hippocampal volumes in individuals who were homozygous for the short allele.

Willeit et al. (2003) genotyped 138 patients with seasonal affective disorder (SAD), which is usually a variant of major depressive disorder, and 146 healthy volunteers for the long/short promoter polymorphism of serotonin transporter. No difference between patients and controls was found for genotype distribution and allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depressive subtypes such that melancholic depression was associated with the long allele and atypical depression with the short allele (2-sided Fisher exact test: genotype distribution, p = 0.0038; allele frequencies, p = 0.007). Willeit et al. (2003) concluded that the findings support the notion that the promoter region of the serotonin transporter influences phenotypic expression of disease but does not cause the disease.

Association with the BCR Gene on Chromosome 21q11

Hashimoto et al. (2005) genotyped 171 patients with bipolar disorder (125480), 329 patients with major depressive disorder, and 351 controls, all of whom were Japanese, for 11 SNPs in the breakpoint cluster region gene (BCR; 151410) on chromosome 22q11, and found significant association with major depression for 6 polymorphisms.

Other Associations

Nash et al. (2004) sought to identify genetic variants associated with liability to depression and anxiety (607834) in a large community-based sample of 34,371 individuals. A composite index of liability (G) was constructed and used to select a smaller but statistically powerful sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. Linkage analysis revealed 2 potential quantitative trait loci (QTL): 1 on chromosome 1p (lod = 2.2) around 64 cM near D1S2892 and another on chromosome 6p (lod = 2.7) around 47 cM near D6S1610. The authors further noted that these QTLs might have sex-limited effects.

For a discussion of a possible association between seasonal affective disorder and variation in the PER3 gene, see 603427.0001 and FASPS3 (616882).

Reviews

Kato (2007) reviewed molecular genetic findings on bipolar disorder and major depression from 2004 to 2006.

Malkesman et al. (2006) examined whether existing genetic animal models of depression in adult rats were also valid in prepubertal rats. Specifically they studied the Flinders Sensitivity Line and their controls (Sprague-Dawley); and the Wistar Kyoto line and their controls (Wistar) to test the hypothesis that male prepubertal animal models would show increased swim test immobility and different patterns of social play as well as different basal plasma levels of corticosteroid and ACTH compared to control rats. Prepubertal Flinders and Wistar Kyoto rats exhibited significantly longer duration of immobility than control rats in the swim test. Flinders rats demonstrated significantly higher levels of social play behaviors and lower levels of corticosterone and ACTH compared with controls, whereas Wistar Kyoto rats demonstrated significantly lower levels of social play behaviors and higher plasma levels of corticosterone and ACTH compound. Malkesman et al. (2006) suggested that prepubertal Flinders Sensitivity Line and Wistar Kyoto rats are both putative genetic animal models for childhood depression but exhibit separate patterns and symptoms of the disorder.