Abstract
Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.
Highlights
Suicide is one of the ten leading causes of death and rates of suicide are far exceeded by suicide attempts, which occur up to 20 times more frequently [World Health Organisation, 2005; Lim et al, 2012]
In the RADIANT validation sample, only polygenic scores for TESI/ treatment worsening suicidal ideation (TWOSI) derived from Genome Based Therapeutic Drugs for Depression (GENDEP) showed significant predictive ability for suicide attempt (P 1⁄4 0.021) (Fig. 2)
The Nagelkerke R2 was 0.005 indicating that 0.5% of variance in the phenotype could be explained by SNPs within PT < 0.01 of the GENDEP polygenic score, with no significant prediction obtained at other P value thresholds
Summary
Suicide is one of the ten leading causes of death and rates of suicide are far exceeded by suicide attempts, which occur up to 20 times more frequently [World Health Organisation, 2005; Lim et al, 2012]. Twin, family and adoption studies have recognized a genetic component to suicidal behavior, which is independent of other psychiatric disorders [Schulsinger et al, 1979; Brent et al, 1996; Roy and Segal, 2001]. This supports a stress-diathesis model whereby psychiatric illnesses or other life stressors are not exclusively responsible for suicide attempts (SA) but rather that they may aggravate an individual’s genetic predisposition to suicidal behavior [Mann et al, 1999]. Candidate gene association studies on suicidal behavior have yielded either inconsistent or negative results.
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