Approaching the Genetics of Suicide

August 3, 2015 |

approaching-the-genetics-of-suicide_medium_smallThe Question
Are there genes related specifically to suicide?

Background
Each gene has varying forms and we each inherit one variant or allele at each gene location from each parent.  When studying genes, the goal is often to examine the ratio of each variant in a sample and see if it is associated with a specific characteristic or behavior.  In suicide research, the aim is to determine if any gene variants are more likely to be present when someone has engaged in suicidal behavior.  Since 90% of individuals who die by suicide have a diagnosable mental health condition it is important to separate the genetics of specific mental health conditions from the genetics of suicide. One allele that has been suggested to be unique to suicide is the Val66Met allele of brain-derived neurotrophic factor (BDNF), a growth factor in the brain. Dr. Zai examined the relationship between BDNF and suicide using three different methods.  He also examined two other genes among people with schizophrenia that are thought to be related to suicide. The first is gamma-amino-butyric acid (GABA) a neurotransmitter that inhibits excitability in the brain. The second is the dopamine receptor DRD3 gene that plays a role in thought and emotions and can have an antidepressant effect.

The Study
Four separate groups of people participated in the study. All participants were over 18 years of age, of European ancestry and without active substance use.
From the Centre for Addiction and Mental Health in Toronto:

  • 197 people with schizophrenia
  • 308 people with bipolar disorder
  • 189 parent-child families with bipolar disorder

From the Institute of Psychiatry in London, UK:

  • 462 people with bipolar disorder

Dr. Zai used several techniques to learn about genes that may be associated with suicidal behavior.

  • Candidate gene studies that examine specific genes: BDNF, GABA and DRD3 genes.
  • Genome-Wide Association Studies (GWAS) to examine the entire genome trying to identify genes that may be associated with suicide attempts and suicide severity (ranging from ideation to attempts).
  • Meta-analysis to review the literature of studies involving the study of BDNF.

Results
Several possible gene signals were identified that related to suicidal behavior and the genes depended somewhat on the diagnosis and the method.

  • Candidate gene studies in schizophrenia
    • BDNF was found to be associated with suicide and to interact with DRD3 genes in association with suicide.
    • Two gene areas on the GABRG2 gene were identified as related to suicidal behavior among people with a history of an alcohol use disorder
  • GWAS Study of Bipolar Disorder
    • BDNF gene was associated with suicidal behavior and areas of chromosomes 8 and 10 were also identified as areas of possible association with suicidal behavior
  • Meta-analysis
    • The BDNF Met allele was associated with suicidal behavior regardless of diagnosis

Due to small sample sizes and the fact that the study did not account for non-genetic contributors to suicide such as life stress, health, or social, the findings are only suggestive.  Genetic findings always need to be confirmed by other studies.

Takeaway

  • Many genes are involved in suicide and BDNF is strongly implicated.
  • One day we may have genetic tests to identify potential risk for suicide and to match treatment to a person’s genetic profile. This will help people to more closely take care of their mental health.
  • Genes are only part of the story, many factors contribute to suicide.
  • The process of understanding the role of genetics in suicide is complicated and will take time and a great deal of effort by many researchers. Postdoctoral fellowships offer the opportunity to bring new researchers to the study of suicide.

Publications from AFSP grant

  • Zai CC;  Zai GC;  Tiwari AK;  Manchia M;  de Luca V;  Shaikh SA;  Strauss J;  Kennedy JL. Association study of GABRG2 polymorphisms with suicidal behaviour in schizophrenia patients with alcohol use disorder. Neuropsychobiology.  69(3):154-8, 2014.
  • Zai CC;  Manchia M;  De Luca V;  Tiwari AK;  Chowdhury NI;  Zai GC;  Tong RP;  Yimaz Z;  Shaikh SA;  Strauss J;  Kennedy JL. The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis. International Journal of Neuropsychopharmacology.  15(8):1037-42, 2012 Sep.
  • Zai CC, Gonçalves VF, Tiwari AK, Gagliano SA, Hosang G, de Luca V, Shaikh SA, King N, Chen Q, Xu W, Strauss J, Breen G, Lewis CM, Farmer AE, McGuffin P, Knight J, Vincent JB, Kennedy JL. A genome-wide association study of suicide severity scores in bipolar disorder.J Psychiatr Res. 2015 Jun;65:23-9. doi: 10.1016/j.jpsychires.2014.11.002. Epub 2014 Nov 20.
  • Zai G, Zai CC, Arnold PD, Freeman N, Burroughs E, Kennedy JL, Richter MA. Meta-analysis and association of brain-derived neurotrophic factor (BDNF) gene with obsessive-compulsive disorder. Psychiatr Genet. 2015 Apr;25(2):95-6.
  • Zai CC, Manchia M, Sønderby IE, Yilmaz Z, De Luca V, Tiwari AK, Squassina A, Zai GC, Shaikh SA, Strauss J, King N, Le Foll B, Kaplan AS, Finseth PI, Vaaler AE, Djurovic S, Andreassen OA, Vincent JB, Kennedy JL. Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders. World J Biol Psychiatry. 2015 Apr;16(3):171-9. doi: 10.3109/15622975.2014.953011. Epub 2014 Sep 29.

Dr. Zai is a project scientist at the Centre for Addiction and Mental Health.

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