Genetics of suicide attempts in individuals with and without mental disorders: a population-based genome-wide association study

Abstract

Family studies have shown an aggregation of suicidal behavior in families. Yet, molecular studies are needed to identify loci accounting for genetic heritability. We conducted a genome-wide association study and estimated single nucleotide polymorphisms (SNP) heritability for a suicide attempt. In a case-cohort study, national data on all individuals born in Denmark after 1981 and diagnosed with severe mental disorders prior to 2013 (n = 57,377) and individuals from the general population (n = 30,000) were obtained. After quality control, the sample consisted of 6024 cases with an incidence of suicide attempt and 44,240 controls with no record of a suicide attempt. Suggestive associations between SNPs, rs6880062 (p-value: 5.4 × 10^-8) and rs6880461 (p-value: 9.5 × 10^-8), and suicide attempt were identified when adjusting for socio-demographics. Adjusting for mental disorders, three significant associations, all on chromosome 20, were identified: rs4809706 (p-value: 2.8 × 10^-8), rs4810824 (p-value: 3.5 × 10^-8), and rs6019297 (p-value: 4.7 × 10⁸). Sub-group analysis of cases with affective disorders revealed SNPs associated with suicide attempts when compared to the general population for gene PDE4B. All SNPs explained 4.6% [CI-95: 2.9-6.3%] of the variation in suicide attempt. Controlling for mental disorders reduced the heritability to 1.9% [CI-95: 0.3-3.5%]. Affective and autism spectrum disorders exhibited a SNP heritability of 5.6% [CI-95: 1.9-9.3%] and 9.6% [CI-95: 1.1-18.1%], respectively. Using the largest sample to date, we identified significant SNP associations with suicide attempts and support for a genetic transmission of suicide attempt, which might not solely be explained by mental disorders.

Fig. 1

Manhattan plot of genome-wide association study (GWAS) of suicide attempt adjusted for: gender, number of years under follow-up being (aged ≥15 years), first 10 principal components of genetic ancestry (Model 1). Note: The red line marks the threshold of p = 5 × 10⁻⁸ for significant associations while the blue line marks the threshold of p = 5 × 10⁻⁶ for suggestive associations

Fig. 2

Manhattan plot of genome-wide association study (GWAS) of suicide attempt adjusted for: gender, number of years under follow-up being (aged ≥15 years), first 10 principal components of genetic ancestry, diagnosis of any mental disorder as well as diagnosis of schizophrenia, bipolar disorders, affective disorders, autism spectrum disorders, anorexia, and ADHD (Model 2). Note: The red line marks the threshold of p = 5 × 10⁻⁸ for significant associations while the blue line marks the threshold of p = 5 × 10⁻⁶ for suggestive associations

Fig. 3

Region plot of the association evidence in gene PDE4B in the chromosome 1p31.3 in a sub-group analysis of cases with affective disorders vs. healthy controls (hg19, LocusZoom viewer) [76].