Genome-wide association study meta-analysis of suicide death and suicidal behavior

Abstract

Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts (n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed. One locus in neuroligin 1 (NLGN1) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 × 10^-8 before and p = 4.55 × 10^-8 after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength (p = 6.02 × 10^-8), suggesting suicide death specificity. NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia. We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples. Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD.

Fig. 1. Genome-wide significant association signals.

Manhattan plots for suicide death GWAS meta-analysis: SNP-level (A), gene-level (B); and suicidal behavior GWAS meta-analysis: SNP-level (C), gene-level (D). Regional plot for NLGN1 (E); regional plot for ROBO2 (F). The dotted line indicates a genome-wide significance threshold of 5 × 10^–8. For the regional association plot generated by LocusZoom [95], SNPs in genomic risk loci are color-coded as a function of their r² to the index SNP in the locus, as follows: red (r² > 0.8), orange (r² > 0.6), green (r² > 0.4) and light blue (r² > 0.2). SNPs that are not in LD with the index SNP (with r² ≤ 0.2) are dark blue, while SNPs with missing LD information are shown in gray.

Fig. 2. Polygenic risk score association with suicide death.

P values plotted are association p value for the respective PRS and suicide death status in cohorts 1 and 2, respectively. Bar plots filled in red denote a negative association coefficient, while green ones denote a positive association coefficient. ADHD attention-deficit/hyperactivity disorder, ASD autism spectrum disorder, BIP bipolar disorder, CAD coronary artery disease, ICV intracranial volume, MDD major depressive disorder, PTSD posttraumatic stress disorder, SCZ schizophrenia, SWB subjective well-being, TG triglycerides, WHR waist-to-hip ratio.

Fig. 3. Genetic correlation between suicide death, suicidal attempt, and suicidal behavior (p1), and selected psychiatric/non-psychiatry traits (p2).

Triangle points indicate genetic correlations that passed the Bonferroni-corrected significance threshold (p < 2.78 × 10^–3). Error bars represent the standard error. ADHD attention-deficit/hyperactivity disorder, ASD autism spectrum disorder, BIP bipolar disorder, MDD major depressive disorder, PTSD posttraumatic stress disorder, SA suicidal attempt, SB suicidal behavior, SB|MDD SB results after conditioning on MDD, SCZ schizophrenia, SD suicide death, SD|MDD SD results after conditioning on MDD, SD|SA SD results after conditioning on SA, SD|MDD and SA SD results after conditioning on MDD and SA.