Genetic aetiology of self-harm ideation and behaviour

Abstract

Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability (h_snp²) estimates were ~10%, and both traits were highly genetically correlated (LDSC r_g > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant.

Figure 1

GWAS results and genetic correlations of broad sense self-harm thoughts and behaviours. Miami plot (left panel) depicts the genome-wide association results for the phenotypes studied. The x-axis represents the genomic position, while the y axis represents the significance of the association between each SNP and the phenotype; the top panel represents significance as –log10 (pvalue), while the bottom panel uses log10 (pvalue), in both cases, the farther from the x axis (middle) line, the more significant the association between the phenotype and the variant. On the right side, a heat map depicts the genetic correlations (rg) between published trait GWAS and our GWAS for self-harm ideation or self-harm behaviour. Only traits with a Benjamini-Hochberg fdr <0.01 for at least one phenotype and generated using studies independent from the UK-Biobank are depicted here (All the results, including UK-B traits, are available in Supplementary Data 1).

Figure 2

Gene based association. Manhattan plots depicting gene-based test results of the GWAS. The x-axis represents the genes genomic position, and the y axis the significance (−log₁₀(p-value)) of the association between the genes and the studied phenotype. The phenotypes for the top and bottom panels are self-harm ideation and self-harm behaviour respectively.

Figure 3

Polygenic prediction of self-harm behaviours. Bar plots represent the amount of variance explained by the polygenic risk scores on the self-harm phenotypes. The red colour (left side) shows the associations of the PRS for self-harm ideation whereas the blue colour (right side) depicts the associations of the PRS for self-harm behaviour. For each phenotype studied, the amount of variance explained by a PRS including variants with an increasingly liberal p-value threshold (from left to right) is shown. The bars are ordered based on the p-value cut-off used to construct the PRS (increasingly liberal p-values). The height of each bar represents the amount of variance explained. The p-value for the association between the PRS and the phenotype is shown with a colour scale. *Represents p < 0.05; **represents significant after multiple testing correction).

Figure 4

Assessing the shared genetic aetiology of self-harm behaviours. The PRS-phenotype associations were repeated but accounting for the other significantly associated phenotype as a covariate (see methods). Panel (a) shows the result of PRS for self-harm ideation while accounting for suicide thoughts, (b) PRS for self-harm ideation while accounting for NSSH, (c) PRS for self-harm behaviour while accounting for suicide attempt and (d) PRS for self-harm behaviour while accounting for suicide thoughts. *p < 0.05, **significant after multiple testing correction.