Monday May 16 2011
“Scientists have for the first time established a genetic cause for depression narrowing it down to a specific chromosome,” reported The Independent. It said that the study has found “clear evidence” that a region on chromosome 3 (called 3p25-26) is linked to severe recurrent depression.
This study looked at DNA from 971 sibling pairs who have European ancestry and who are affected by recurrent depression. Its findings are supported by another study published at the same time that found a link between the same region of chromosome 3 and depression in a sample of families of heavy smokers. This was reported to be the first time such a link had been independently confirmed in two studies.
One point worth noting is that these results may not apply to less severe, non-recurrent depression, or to individuals of non-European ancestry, who were not included in this study. Also, this finding does not mean that this is the only region containing genes that contribute to depression.
Furthermore, the study was not able to pinpoint single letter variations in the regions that were linked to severe recurrent depression, and the gene(s) involved have yet to be identified. Future work is likely to focus on studying the genes within the region, to identify which ones may be having an effect.
Where did the story come from?
The study was carried out by researchers from the Institute of Psychiatry at King’s College, London, and many other research centres in Europe and North America. Some of the researchers worked for GlaxoSmithKline, who also provided funding for the recruitment of participants and the collection DNA samples.
The study was published in the peer-reviewed American Journal of Psychiatry.
This story was covered by The Independent, Daily Mail, Financial Times and the Daily Mirror. The Independent and Financial Times provided balanced coverage, with The Independent noting the region identified may only contribute a small amount to a person’s susceptibility to depression. The Financial Times noted that many genes are likely to play a role. The Daily Mail suggested that ‘depression could be caused by a single rogue gene’ but this is not likely to be the case.
What kind of research was this?
This was a ‘genome wide linkage study’, called the Depression Network Study, which aimed to identify areas of DNA that might contain genes contributing to a person’s susceptibility to major depression. Both genetic and environmental factors are thought to play a role in the development of disorders such as depression. Studies have suggested that genetics play a greater role in depression that is severe and recurrent than in less severe, non-recurrent depression.
This type of study looks at DNA inheritance patterns within families that include sibling pairs affected by the disease in question. They use identifiable variations within the DNA called ‘markers’ to find pieces of DNA that are consistently passed on to the affected sibling pairs. Once such a region is identified the researchers look at the genes within that region in more detail, to see if they could be contributing to causing the disease.
This method is commonly used in looking for genes that cause diseases.
What did the research involve?
The researchers enrolled 839 families, which included 971 pairs of siblings who had recurrent major depression (the families also included 118 pairs where one sibling was affected but not the other), and 12 unaffected sibling pairs.
Adult siblings of European ancestry were recruited from eight sites across Europe and the UK. Sibling pairs were excluded if either sibling had ever had mania (bipolar), hypomania, schizophrenia or psychotic symptoms, or had intravenous drug dependency or depression associated with alcohol use. To be eligible, both siblings had to have experienced at least two depressive episodes of at least moderate severity, with the episodes separated by at least two months of remission, according to accepted criteria.
As well as the sibling pairs, the study recruited additional siblings and parents if they were available. All participants were interviewed using a standard clinical interview to assess the presence of psychiatric diagnoses. The interview also asked participants to rate the presence and severity of various symptoms during the worst four to six weeks of their worst and second worst episodes of depression. This information was used to categorise the severity of a person’s depression.
In total, 2,412 people were included:
- 2,164 of these had recurrent depression
- 1,447 were classified as having severe or worse recurrent depression
- 827 with very severe recurrent depression
Participants provided a blood sample for DNA extraction and their DNA was assessed for 1,130 genetic markers spread across the chromosomes. Statistical programmes were then used to analyse the results to identify regions of DNA that showed a pattern of inheritance consistent with the possibility that a gene contributing to the development of depression was nearby.
The researchers carried out separate analyses for the overall sample with recurrent depression, for severe recurrent depression and very severe recurrent depression.
Once the researchers identified a region of DNA that showed linkage to recurrent depression, they aimed to test these results using a case control analysis of a sample of 2,960 individuals with recurrent depression (cases) and 1,594 healthy individuals (controls).
The cases came from the current study, as well as 1,346 individuals with recurrent depression from another study of depression in the UK. The controls were from the UK Medical Research Council General Practice Research Framework, and staff and student volunteers from King’s College London. Using DNA samples from these individuals, the researchers looked at 1,878 single ‘letter’ variations in the region identified as being linked to recurrent depression in the first part of the study.
What were the basic results?
The researchers identified a region on the short arm of chromosome 3 (called 3p25-26) that was linked to severe recurrent depression. Importantly, this link remained significant after the researchers took into account the fact that many markers had been tested for linkage. There were 214 genes within the region of chromosome 3 identified as being linked to severe recurrent depression.
Based on what is known about the proteins that these genes encode, a number of these genes seemed like strong potential candidates for being involved in depression. For example, some of the genes in the region encoded the receptors for various brain signalling chemicals.
Some other regions showed weaker signs of linkage to recurrent depression as a whole, or very severe recurrent depression, but only the region on chromosome 3 was investigated further as it showed the strongest linkage.
Because the linkage with the region on chromosome 3 was greatest in sibling pairs with severe recurrent depression, in their case-control analysis the researchers only analysed the 1,590 cases with severe recurrent depression, and 1,589 controls. The researchers found that 95 single letter genetic variations showed some evidence of an association with the cases. However, these associations lost their significance once the many statistical tests that were carried out were taken into account. They say that this lack of significant findings may be because there are multiple rare variations having an effect, or that their sample may not have been large enough to detect common variants each having a mild effect.
In their discussion, the researchers highlight another study published in the same journal, which has also found linkage with the same region of chromosome 3 in a sample of families of heavy smokers with depression.
How did the researchers interpret the results?
The researchers conclude that they have identified a region of chromosome 3 that shows linkage to recurrent depression. They say that this region includes genes that could plausibly be involved in this condition.
They researchers added that this is the first report of a region showing linkage to depression from a genome-wide study, which has then been supported by findings from an independent sample. They say that future work will involve determining the DNA sequence of this region in the affected siblings and their families, and assessing the region in other samples with severe recurrent depression.
Depression is thought to involve both genetic and environmental factors, with genetics playing a larger role in the type of depression that is severe and recurrent. This study has identified a region of DNA that may include a gene or genes that affect an individual’s susceptibility to severe recurrent depression.
One point worth noting is that these results may not apply to less severe, non-recurrent depression, or to individuals of non-European ancestry, who were not included in this study. Also, the regions identified in this study are unlikely to be the only ones containing genes that contribute to depression.
The authors have been appropriately circumspect with regard to their findings, noting that it is still possible these results are false positives, and their statistical results suggest there is a 1.5% chance this is the case. They say their results need replication in other studies, and for the genes actually responsible for this link to be identified. The fact that another study published concurrently has also found a link with the same region of chromosome 3 lends support to the findings but, ideally, further confirmation in other samples will be obtained.
This study appears to give an important clue to the genetic contribution to severe recurrent depression, and future work is likely to focus on studying the genes within the region, to identify which one(s) may be contributing.