November 05, 2003
Excess Serotonin 5-HT1A Receptor Increases Depression, Suicide

A genetic variation (aka allele) has been identified that increases the risk of suicide. (same press release here)

OTTAWA, Oct 17, 2003 (Canada NewsWire via COMTEX) -- After a pioneering seven-year study, Canadian scientists have discovered a new genetic difference in people suffering from severe depression and in those who have committed suicide. The findings by collaborative researchers at the University of Ottawa and the Institute of Mental Health Research, and McGill University's Douglas Hospital, Montreal -- represent a significant step forward in identifying individuals at risk for debilitating depression or even death.

The study - "Impaired repression at a 5-hydroxytryptamine -1A receptor gene polymorphism associated with major depression and suicide", published in a recent issue of the Journal of Neuroscience, showed the same genetic difference or 'single nucleotide polymorphism (SNP)' in a gene that contributes to the serotonin system which regulates mood cycles in human beings. This SNP in the serotonin-1A gene was two-fold enriched in people with depression, and four-fold enriched in those who had completed suicide, as compared to normal control groups.

...

The studies showed for the first time that the polymorphism of the serotonin-1A gene impacts by inhibiting the function of a protein called NUDR, leading to abnormal levels of serotonin-1A gene expression and decreased serotonin, and a key factor in the incidence of depression.

Frequency of variations in serotonin receptor 5-HT2A may differ between populations that have different rates of suicide

The researchers found a mutation in the gene encoding for the receptor, a protein that transmits brain signals, which more than doubles the risk of suicidal behaviour in those who carry it.

An analysis of the DNA showed 41% of the suicidal patients had the 5-HT2A receptor mutation, compared with 24% of the non-suicidal patients and 18% of the healthy subjects.

...

A genetic variability might also explain why suicide rates vary strongly between populations with different ethnic origins. For example, the annual suicide rate in Finland (for males) is 43 per 100,000 people, one of the highest rates in the world.

But the rate for neighbouring Norway is only 21 per 100,000, less than half.

"It may be interesting to look into the distribution of the [mutation] in these countries," said Dr. Hrdina.

As the costs of DNA Single Nucleotide Polymorphism (SNP) testing of single letter differences (a.k.a. alleles) in DNA sequences become cheaper the distributions of various alleles that affect mental state and behavior will become better known. Populations at greater risk for assorted mental illnesses and behavioral problems will have their problems traced down to a genetic level.

Whether it will be possible to develop compounds to target the various alleles that cause mental problems remains to be seen. Certainly pharmaceutical companies will try. My guess is that the answer will be "Yes" for some but not all. An allele that causes overexpression, for instance, may simply have no easy way for a compound to be designed that can reach all the way into the nucleus and selectively bind somewhere to repress it. The level of specificity needed may be beyond what a conventional drug can achieve. Also, for more rare alleles the market may not be big enough for a drug company to spend hundreds of milions on development. If you are going to have a major mental problem caused by a genetic variation best to have a variation that is fairly common in industrialized countries.

Aside: I think the above article misspells the receptor abbreviation. The journal abstract below for the original paper spells it slightly differently.

From the abstract of the published paper Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide in the Journal of Neuroscience:

Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.

Update: Here is another article on the 5HT2A link to suicide:

The discovery could lead to the development of genetic tests to identify those at risk. But it also poses questions about the ramifications of such testing. During their 10-year study investigating the causes of suicide, the Canadian team discovered a genetic variation that affects brain chemistry. They found that depressed individuals with a mutation in the gene encoding the serotonin 5-HT2A receptor are more than twice as likely to attempt suicide as those who suffered from depression but did not carry the mutation, says Pavel Hrdina, a neurobiologist at the Royal Ottawa Hospital and study co-author. Serotonin is a neurotransmitter that carries messages between brain cells and is thought to be involved in the regulation of emotion, among other functions. For some years, scientists have suspected that the genes regulating the serotonin system could be one of the culprits.

Here is an abstract of work by Pavel Hrdina and David Bakish on their work in this area from 2000.

Share |      Randall Parker, 2003 November 05 02:23 PM  Brain Genetics


Comments
Michael said at December 17, 2004 6:49 AM:

I have all too often wondered if the wierd, spaced out, head in orbit sensations I get as part of CFS/CFIDS/ME, Chronic Pain, Sleep Apnea, Insomnia Intermittent Depression, are the result of excess serotonin??? Often there is a correlation between them and my taking herbs to help with sleep, such as valerian?

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