Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: a genome-wide association and polygenic scoring study

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.

Keywords: association; meta-analysis; pleiotropy; prediction.

Figure 1

Manhattan plot of meta-analysis between RADIANT, GSK-Munich, and BACCs samples.

Figure 2

Polygenic scores for suicide attempt, suicidal ideation, and psychiatric disorders from seven discovery datasets used to predict suicide attempt in the RADIANT, GSK-Munich, and BACCs validation datasets and suicidal ideation in GENDEP. The y-axis indicates Nagelkerke's pseudo R², a measure of the variance explained and the x-axis indicates the discovery datasets from which the polygenic scores were derived. The five P-value thresholds used (P_T < 0.01, P_T < 0.05, P_T < 0.10, P_T < 0.30, P_T < 0.50) to select SNPs are plotted left to right for each discovery dataset. Stars indicate polygenic scores with significant predictive ability (P < 0.05).