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Depressive Disorders Genetic Studies

Depression: What Is It?

It's natural to feel down sometimes, but if that low mood lingers day after day, it could signal depression. Major depression is an episode of sadness or apathy along with other symptoms that lasts at least two consecutive weeks and is severe enough to interrupt daily activities. Depression is not a sign of weakness or a negative personality. It is a major public health problem and a treatable medical condition. PET scans of the brain show different activity levels in a person with depression, compared to a person without depression.


Depression Study examined Familial Transmission

In 1998 in a formal commentary about research into the familial transmission of depression, Farsone & Biederman stated:

  • Weissman and colleagues found offspring of depressed parents showed greater social impairment and had a three-fold increased risk of depression and phobias as well as a five-fold increased risk of panic disorder and alcohol dependence
  • They went on to say: this finding confirmed a report from the UK that adult mood disorders were found in nearly half of a sample that had been diagnosed as having depression while in childhood
  • They concluded: If symptoms of depression represented normal responses to development transitions, they should have waxed and waned with development.


Farasone, S.V. & Biederman, J. (1998). Depression: A family affair.  Lancet, 351 (9097). 00995355

Depression Study examined Serotonergic Genes impact on Amygdala

Dannlowski et al (2007) looked at serotonergic genes implicated in the pathogenesis of depression probably via their influence on neural activity during emotion processing


They used an imaging genomics approach to investigate amygdala activity in major depression as a function of common functional polymorphisms in the serotonin transporter gene (5-HTTLPR) and the serotonin receptor 1A gene (5-HT1A-1019C/G)


In 27 medicated patients with major depression, amygdala responses to happy, sad and angry faces were assessed using functional magnetic resonance imaging at 3 Tesla


Patients were genotyped for the 5-HT1A-1019C/G and the 5-HTTLPR polymorphism, including the newly described 5-HTT-rs25531 single nucleotide polymorphism


Risk allele carriers for either gene showed significantly increased bilateral amygdala activation in response to emotional stimuli, implicating an additive effect of both genotypes


Their  data suggest that the genetic susceptibility for major depression might be transported via dysfunctional neural activity in brain regions critical for emotion processing.


Dannlowski, U. U., Ohrmann, P. P., Bauer, J. J., Kugel, H. H., Baune, B. T., Hohoff, C. C., & ... Suslow, T. T. (2007). Serotonergic genes modulate amygdala activity in major depression. Genes, Brain & Behavior, 6(7), 672-676. doi:10.1111/j.1601-183X.2006.00297.x
Depression Study examined Relatedness of LHPP & HTRIA genotype

Neff et al (2009) reported that the HTR1A −1019C>G genotype was associated with major depression in the Utah population.


Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A −1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD=4.4)


Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatas- Gene ID: 64077)


LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations

Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype


LHPP or a product of a collinear brain-specific transcript, therefore, may interact with HTR1A in the pathogenesis of major depression



Neff, C. D., Abkevich, V. V., Packer, J. L., Chen, Y. Y., Potter, J. J., Riley, R. R., & ... Katz, D. A. (2009). Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Molecular Psychiatry, 14(6), 621-630. doi:10.1038/mp.2008.8

Depression Study examined Somatization Impact

Klengel et al (2011) found that thirty SNPs exhibit nominally significant associations with somatization


One SNP (rs9534505) located in intron 2 of the HTR2A gene withstood correction for multiple testing


Clinical data provided further evidence for strong impact of somatization on the presentation of depressive symptoms and description of a patient subgroup with unfavorable clinical outcome


Conclusion: Results demonstrate the influence of a HTR2A polymorphism on aspects of somatization in major depression, which co-occurs with an unfavorable antidepressant treatment outcome. These results confirm and expand previous findings on somatization as a risk factor for treatment outcome in major depression.


Klengel, T. T., Heck, A. A., Pfister, H. H., Brückl, T. T., Hennings, J. M., Menke, A. A., & ... Ising, M. M. (2011). Somatization in major depression - clinical features and genetic associations. Acta Psychiatrica Scandinavica,124(4), 317-328. doi:10.1111/j.1600-0447.2011.01743.x

Depression Study examined Multiple Genetic Variants

Wong et al (2012) found that risk-classification tree analysis, using 15 nsSNPs that had a nominal association with Major Depressive Disorder (MDD) diagnosis, identified multiple increased-MDD genotype clusters and significant additive interactions in combinations of genotype variants that were significantly associated with MDD.


The results in the dbGaP for major depression disclosed a multidimensional dependent phenotype constituted of MDD plus significant modifiers (smoking, marriage status, age, alcohol abuse/dependence and gender), which then was used for the association tree analysis.


The reconstructed tree analysis for the dbGaP data showed robust reliability and replicated most of the genes involved in the branching process found in their exploratory analyses.


Pathway analysis using all six major events of branching (PSMD9, HSD3B1, BDNF, GHRHR, PDE6C and PDLIM5) was significant for positive regulation of cellular and biological processes that are relevant to growth and organ development.


Their findings not only provide important insights into the biological pathways underlying innate susceptibility to MDD but also offer a predictive framework based on interactions of multiple functional genetic variants and environmental factors.


Wong, M., Dong, C., Andreev, V., Arcos-Burgos, M., & Licinio, J. (2012). Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Molecular Psychiatry, 17(6), 624-633. doi:10.1038/mp.2012.13

Depression Study examined Testing Impact of Socioeconomic Disparity in Depression

Mezuk et al (2013) found consistent with the social causation hypothesis, education (odds ratio [OR] = 0.78; 95% confidence interval [CI] = 0.66, 0.93; P < .01) and income (OR =0.93; 95% CI = 0.89, 0.98; P < .01) were significantly related to past-year major depression


Upward social mobility was associated with lower risk of depression


There was no evidence that childhood SES was related to development of major depression (OR = 0.98; 95% CI = 0.89, 1.09; P > .1)


Consistent with a common genetic cause, there was a negative correlation between the genetic components of major depression and education (r2 = –0.22)


Co-twin control analyses indicated a protective effect of education and income on major depression even after accounting for genetic liability


Conclusion: This study utilized a genetically informed design to address how social position relates to major depression. Results generally supported the social causation model


Mezuk, B., Myers, J. M., & Kendler, K. S. (2013). Integrating social science and behavioral genetics: Testing the origin of socioeconomic disparities in depression using a genetically informed design. American Journal Of Public Health, 103(S1), S145-S151. doi:10.2105/AJPH.2013.301247
Depression Study examined CNRI Gene

Mitjans et al (2013) observed a higher frequency of rs806371 G carriers in Major Depression (MD) patients with both presence of melancholia ( p = 0.018) and psychotic symptoms ( p = 0.007) than in controls.

  • Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368-rs1049353-rs806371) ( p = 0.008).
  • This haplotype finding was consistent when compared controls with MD subsample stratified by melancholia ( p = 0.0009) and psychotic symptoms ( p = 0.014)
  • The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers ( p = 0.008 and 0.012, respectively)
  • Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 ( p = 0.032)
  • Also observed were significant effect of time-sex-genotype interaction for the rs806368, showing that the C carrier men presented a better response to antidepressant treatment throughout the follow-up than TT homozygous men and women group ( p = 0.026)
Conclusion: These results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram. 


Mitjans, M., Serretti, A., Fabbri, C., Gastó, C., Catalán, R., Fañanás, L., & Arias, B. (2013). Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment. Psychopharmacology, 227(3), 509-519. doi:10.1007/s00213-013-2995-y

DEPRESSION GENETIC STUDY REFERENCES

 

Dannlowski, U. U., Ohrmann, P. P., Bauer, J. J., Kugel, H. H., Baune, B. T., Hohoff, C.

C., & ... Suslow, T. T. (2007). Serotonergic genes modulate amygdala activity in major depression. Genes, Brain & Behavior, 6(7), 672-676. doi:10.1111/j.1601-183X.2006.00297.x

 

Farasone, S.V. & Biederman, J. (1998). Depression: A family affair.  Lancet, 351 (9097).

00995355

 

Klengel, T. T., Heck, A. A., Pfister, H. H., Brückl, T. T., Hennings, J. M., Menke, A. A., &

... Ising, M. M. (2011). Somatization in major depression - clinical features and genetic associations. Acta Psychiatrica Scandinavica,124(4), 317-328. doi:10.1111/j.1600-0447.2011.01743.x

 

Mezuk, B., Myers, J. M., & Kendler, K. S. (2013). Integrating social science and

behavioral genetics: Testing the origin of socioeconomic disparities in depression using a genetically informed design. American Journal Of Public Health, 103(S1), S145-S151. doi:10.2105/AJPH.2013.301247

 

Mitjans, M., Serretti, A., Fabbri, C., Gastó, C., Catalán, R., Fañanás, L., & Arias, B.

(2013). Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment. Psychopharmacology, 227(3), 509-519.doi:10.1007/s00213-013-2995-y

 

Neff, C. D., Abkevich, V. V., Packer, J. L., Chen, Y. Y., Potter, J. J., Riley, R. R., & ...

Katz, D. A. (2009). Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Molecular Psychiatry, 14(6), 621-630. doi:10.1038/mp.2008.8

 

Wong, M., Dong, C., Andreev, V., Arcos-Burgos, M., & Licinio, J. (2012). Prediction of

susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Molecular Psychiatry, 17(6), 624-633. doi:10.1038/mp.2012.13