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Sunday, March 9, 2008

Why Can't We find a Gene for Depression?

The estimated heritability of depression is 40-50%. This is based on twin studies and family studies. Than why is it we can't find the gene?

  • There are different subtypes of depression such as melancholic type, Seasonal Affective Disorder, Bipolar depression. These different types of depression will not be explained by one gene or set of genes, or polymorphisms of genes.

  • Research until now may have varied in inclusion criteria and diagnostic criteria

  • Genes responsible for depression may differ with ethnicity. Chines might have different gene locations responsible for depression than Caucasian depressed patients

  • Besides ethnicity, gender may also play a role in genetics, depression is twice as common in females than males.

  • Depression is a complicated disease. Different systems could affected. A variety of different neurotransmitters and hormones can be involved. In some patients the cortisol stress system is involved with depression in others not. In some patients SSRIs are effective, others need other kind of antidepressants or treatments.

  • And last but not least, depression can have many causes of which heritability is just one and it doesn't have to be present at all.

There was some hope when Caspi et al showed that the 5-HTT genotype (serotonin transporter gene)moderates the depressogenic influence of stressful life events. It moderated the effect of life events that occurred not just in adulthood but also of stressful experiences that occurred in earlier developmental periods. Consistent with the Gene x Environment hypothesis, the longitudinal prediction from childhood maltreatment to adult depression was significantly moderated by 5-HTTLPR. Childhood maltreatment predicted adult depression only among individuals carrying an s allele but not among l/l homozygotes.

Since then some research and meta analyzes revealed contradictory results of this G x E interaction. Sometimes a modest association of the short allele and depression was shown and sometimes no association could be found.

This could be due to the aforementioned reasons in this post. In a recent publication of research with the serotonin transporter polymorphisms the authors investigated in 340 Caucasian patients with a major depressive episode the influence of the subtype of depression (melancholic depression versus atypical depression) and gender.

They found support for an association of genetic variation increasing serotonin transporter activity with the melancholic subtype of depression as well as evidence for a potential female-specific mechanism underlying this effect. The longer more active L allele of the serotonin transporter gene is significantly associated with melancholic depression, particularly in female patients. A L allele increases serotonin transporter activity and/or density

This contradicts the earlier finding by Caspi, they showed an influence of the short allele and early life stress and depression.
The authors argue that the short s allele increases the risk of neuroticism , harm avoidance and a depressogenic effect of neuroticism. The long allele increases the risk of melancholic type of depression without prior neuroticism. This remains entirely speculative and brings us back to the previous mentioned reasons why we can't find a gene for depression.
Baune, B.T., Hohoff, C., Mortensen, L.S., Deckert, J., Arolt, V., Domschke, K. (2007). Serotonin transporter polymorphism (5-HTTLPR) association with melancholic depression: a female specific effect?. Depression and Anxiety DOI: 10.1002/da.20433

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