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Genetics of Depression

The research on genetics is starting to find specific genetic abnormalities linked to markedly higher risks of developing severe depression.  While this type of testing is not yet available in clinical practice, my sense is that it is just a few years away.  This should help make treatment more precise and provide genetic counseling opportunities for those so interested.  The studies below are highly technical and not yet of any value to the practicing clinician.  Some day, hundreds or thousands of genetic abnormalities linked to depression and tens or hundreds of thousands linked to other diseases will be put on a single gene chips and the doctor will order testing to see what your genetic background contains.

Some depression genes are polymorphism abnormalities of the: breakpoint cluster, tryptophan hydroxylase, CREB1, FKBP5, GABA(A) Receptor Beta 3, Serotonin 5-HT2A, 3A and 3B Receptors, Serotonin Transporter, Tryptophan Hydroxylase-2, and Wolfram Gene abnormalities also very likely involved.  However, this is just scratching the surface.  Some abnormalities may result in a high risk of depression, while other increase it only modestly. 

Affective Spectrum Disorder: Study of families with MDD found that other affective disorders strongly linked and may share genetic features. Bulimia, bipolar, ADHD, cataplexy, dysthymic disorder, fibromyalgia, generalized anxiety disorder, irritable bowel syndrome, migraine, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and social phobia. Family study of affective spectrum disorder. Hudson JI, Mangweth B, et al. McLean, Arch Gen Psychiatry 2003 Feb;60(2):170-7

Brain Derived Neurotrophic Factor Polymorphism Minor Effect: Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. The Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. In a study of 343 unrelated German adults who were carefully screened for psychiatric health, the trait-related anxiety score was higher in Val/Val (35.0) compared to Val/Met (33.4) and Met/Met (32.0) genotypes (p<0.042). The NEO neuroticism scores were also higher in Val/Val (29.5) than in Val/Met (28.4) or Met/Met (26.8), but not at a significant rate.  Association of a functional BDNF polymorphism and anxiety-related personality traits. Lang UE, Hellweg R, et al. University of Tuebingen,  Germany. Psychopharmacology (Berl). 2005 Jun;180(1):95-9.

Brain Derived Neurotropic Factor Polymorphisms Associated with Major Depression: In a single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects), single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)(n)-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). The finding in schizophrenia appeared to be attributable mainly to the presence of depressive symptoms. Evidence for a Relationship Between Genetic Variants at the Brain-Derived Neurotrophic Factor (BDNF) Locus and Major Depression. Schumacher J, et al. Institute of Human Genetics. Biol Psychiatry. 2005 Jul 6

Breakpoint Cluster Gene Abnormalities Linked to Bipolar and Major Depression: The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which play important roles in neurite growth and axonal guidance. In a study of Japanese patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) testing eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR, allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was an association with major depression in six SNPs. S796 allele carriers were 210% more common in bipolar II patients (p = .0046). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). The Breakpoint Cluster Region Gene on Chromosome 22q11 is Associated with Bipolar Disorder. Hashimoto R, Okada T, et al. National Center of Neurology and Psychiatry, Kodaira. Biol Psychiatry. 2005 May 15;57(10):1097-102.

CCKAR Haplotype Linked to Depression in Estonia: In a study of 91 single-nucleotide polymorphisms (SNPs) in 21 candidate genes in 160 healthy controls and 177 patients with major depression, only the GAGT haplotype on the CCKAR gene to be associated with increased risk for MDD (OR 7.42, p=0.002). This haplotype effect remained significant after Bonferroni correction (p=0.04 after Bonferroni's adjustment).  Analysis of SNP profiles in patients with major depressive disorder. Koks S, et al. University of Tartu, Estonia. Int J Neuropsychopharmacol. 2005 Jun 1;:1-8

CREB1 Abnormality Usually Causes Severe Depression: 9 of 11 women with rare mutation suffer severe depression. U Pitt. George Zubenko, New Scientist 7/19/03. Studied 1200 from 81 families with depression. The mutation stops one protein binding to a promoter region and switching on produciton of CREB protein which regulates activity of several other genes and numerous functions in body. Thus, mutation causes low level of CREB protein. Another mutation in CREB1 junk DNA area increases production and protects women against depression. CREB1 could account for up to 10% depression in families studied. CREB protein regulates activity of several other genes including estrogen receptors. Men with mutation do not get depression.

FKBP5 Polymorphisms Linked to Recurrence of Depression and Medication Response: The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis is involved in depression. Response to antidepressants and the recurrence of depressive episodes were found connected to single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Binder EB, et al. Max-Planck Institute of Psychiatry, Munich, Germany. Nat Genet. 2004 Dec;36(12):1319-25

GABA(A) Receptor Beta 3 Heterozygoticity in PTSD: heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity. Psychiatry Res 2001 Nov 1;104(2):109-17

GABA(A) Receptor Gene Polymorphism Increase Susceptibility: subunit genes on 5q34. Polymorphisms on GABRA1 and GABRA6 genes displayed significant associations with mood disorders in female patients. These data offer genetic support for a role of GABA(A) receptor genes in susceptibility to mood disorders. Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders. Yamada K, Watanabe A, Iwayama-Shigeno Y, Yoshikawa T. Neurosci Lett. 2003 Sep 25;349(1):9-12

MAO-A Gene Linked: data suggest that an excess of high-activity MAO-A gene promoter alleles resulting in an elevated MAO-A activity is a risk factor for major depressive disorder in females. Schulze, U Bonn, Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:801-803, 2000.

Serotonin 5-HT2A Polymorphism Receptor & Transport Genes: 102 C allele in 5-HT2A receptor gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005) in depressed patients. Patients with a 102 C/C genotype had a significantly higher mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression and not with depression itself. We also found that the 5-HT transporter gene S/L polymorphism was significantly associated with completed suicide. The frequency of the L/L genotype in depressed suicide victims was almost double of that found in control group (48.6% vs. 26.2%). The odds ratio for the L allele was 2.1. Ottawa, Canada. Crisis 2001;22(2):54-60. There are 14 different types of serotonin (5-HT) receptors in human brain. 5-HT(6) not involved in depression. Neuropsychobiology 2001;44(4):172-5

Serotonin 5HT2 Receptors Fewer: 5HT2 receptors are altered in depression. We present evidence for a reduction of the receptor density, which might be usable as trait marker of subjects susceptible for depressive illness. Germany, Larisch, Nuklearmedizin 2001 Aug;40(4):129-34

Serotonin 5HT3B Receptor Polymorphism Involved: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. In a Japanese study, in HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Distinguishable Haplotype Blocks in the HTR3A and HTR3B Region in the Japanese Reveal Evidence of Association of HTR3B with Female Major Depression. Yamada K, et al. RIKEN Brain Science Institute. Biol Psychiatry 2006 Feb 15.

Serotonin Transporter Gene Polymorphism Affects Fluvoxamine, Improved with Pindolol: serotonin transporter (5-HTT) gene-linked functional polymorphic region (5-HTTLPR) influences SSRI response. 155 uni- and bipolars were treated with fluvoxamine 300 mg and either placebo or pindolol in DB 6 weeks with weekly assessed with HAM-Ds. Allelic variation of 5-HTTLPR determined by PCR. 5-HTTLPR short variant was associated with a poor response to fluvoxamine treatment, independently from the recorded clinical variables. More specifically, the diagnosis, the presence of psychotic features, and the severity of depressive symptomatology did not influence this association. Conversely, pindolol augmentation may ameliorate the rate of response in 5-HTTLPR short variant subjects. Zanardi, Milan, Biol Psychiatry 2001 Sep 1;50(5):323-30

Serotonin Transporter Gene Short Copy Leads to More Depression: 847 New Zealanders followed 26 years. 17 percent of the subjects had two copies of the stress-sensitive short version of 5-HTT, 31 percent had two copies of the longer version of the gene and 51 percent had one of each. Of those who had more than one major stressful event, 43 percent with at least one short version of the 5-HTT gene developed depression, the researchers found. Just 17 percent who had two long copies developed depression. Moffitt, Science 7/18/03.

Serotonin 5-HT2C Receptor Gene Polymorphism Linked: Studied structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were from nine European countries participating in the European Collaborative Project on Affective Disorders. Hadassah, Mol Psychiatry 2001 Sep;6(5):579-85

Tryptophan Hydroxylase-2 Gene G1463A SNP Found in 10% of Depressed: Researchers have found a (G1463A) single nucleotide polymorphism (SNP) in the gene for the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. SNP analysis of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, only three did. The dysfunctional SNP was not found in 60 bipolar disorder patients. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Zhang X, Gainetdinov RR, et al. Duke University. Neuron. 2005 Jan 6;45(1):11-6.

Tryptophan Hydroxylase Gene A218C Variant Affects Paroxetine Benefit: A218C tryptophan hydroxylase (TPH) gene variant with paroxetine was investigated in 121 inpatients with a major depressive episode treated with paroxetine 20-40 mg with either placebo or pindolol in 4 weeks DB with weekly Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject using a PCR-based technique. TPH*A/A and TPH*A/C variants were associated with a poorer response to paroxetine treatment when compared to TPH*C/C (P=0.005); this difference was not present in the pindolol augmented group. Serretti, Italy, Eur Neuropsychopharmacol 2001 Oct;11(5):375-80

Tyrosine Hydroxylase Gene Variants Affect Paroxitene Response: A218C tryptophan hydroxylase (TPH) gene variant with the antidepressant activity of 121 inpatients affected by a major depression treated with paroxetine 20-40 mg with either placebo or pindolol in a double blind, 4 weeks. Weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined using a PCR-based technique. TPH*A/A and TPH*A/C variants were associated with a poorer response to paroxetine treatment when compared to TPH*C/C (P=0.005); this difference was not present in the pindolol augmented group. Eur Neuropsychopharmacol 2001 Oct;11(5):375-80

Wolfram Gene SNPs Increase Mood Disorders: Wolfram syndrome is an extremely rare autosomal-recessive disorder that predisposes the development of type 1 diabetes and progressive optic atrophy. The WFS1 gene encodes a transmembrane protein called wolframin, which may serve as an endoplasmic reticulum calcium channel in pancreatic beta-cells and neurons. Researchers found a 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers. In another study of 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects, five SNPs were associated with major depressive disorder, and three SNPs with bipolar disorder. The GTA haplotype, formed by SNPs 684CG, 1185CT and 1832GA, confers a risk for major depression with an OR of 1.59 (p=0.01) and for bipolar disorder an OR of 1.89 (p=0.03). Polymorphisms in the wolframin (WFS1) gene are possibly related to increased risk for mood disorders. Koido K, Kks S, et al. University of Tartu, Estonia. Int J Neuropsychopharmacol. 2004 Oct 11:1-10. Ed: This is a minor, but apparently real increase. It shows the extreme complexity and diversity of human genetics.

One Wolfram Gene Abnormal Increased Risk of Depression Hospitalization 600%: Heterozygous carriers of wolframin mutations are relatively frequent in the population. Members of 25 Wolfram Syndrome families were tested. Eleven had psychiatric hospitalizations and were genotyped through mutation analysis. Eight carried the wolframin mutation transmitted in their family (one-sided P=0.0022). All had been hospitalized for a major depression.  The relative risk of psychiatric hospitalization for depression was increased 610% for carriers of a single wolframin mutation compared to noncarriers. Wolframin mutations and hospitalization for psychiatric illness. Swift M, Swift RG. Disease Insight Research Foundation, Ardsley, NY, USA. Molecular Psychiatry 26 April 2005

Thomas E. Radecki, M.D., J.D.