Novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide

Abstract

Background: Suicide is a major issue for global public health. 'Suicidality' describes a broad clinical spectrum of thoughts and behaviours, some of which are common in the general population.Methods: UK Biobank recruited ~0·5 million middle age individuals from the UK, of whom 157,000 completed an assessment of suicidality. Mutually exclusive groups were assessed in an ordinal genome-wide association study of suicidality: 'no suicidality' controls (N=83,557); 'thoughts that life was not worth living' (N=21,063); 'ever contemplated selfharm' (N=13,038); 'an act of deliberate self-harm in the past' (N=2,498); and 'a previous suicide attempt' (N=2,666). Linkage of UK Biobank to death certification records identified a small sub-group of 'completed suicide' (N=137).Outcomes: We identified three novel genome-wide significant loci for suicidality (on Chromosomes 9, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81). Higher polygenic risk scores for suicidality were associated with increased risk of completed suicide relative to controls in an independent sub-group (N=137 vs N=5,330, OR 1·23, 95%CI 1·06 to 1·41, p=0.03). Rs598046-G (chromosome 11) demonstrated a similar effect size and direction (p=0·05) within a Danish suicidality study.Interpretation: These findings have significant implications for our understanding of genetic vulnerability to suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level.

Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality

“…In line with previous studies 4 , 7 , 8 , our PRS analysis confirmed the genetic overlap of MD with outcomes related to suicidality spectrum. However, we did not find any interactive effect between MD PRS and polysubstance dependence in the context of SI.…”

“…Subsequently, we conducted a discovery GEWIS to verify whether SDs interact with the individual genetic variability in the context of SI. Finally, based on the high genetic overlap between suicidality and depression observed across multiple large-scale GWAS 4 , 7 , 8 , we verified whether depression genetic risk interacts with polysubstance dependence in the context of suicidality spectrum. Supplemental Fig.…”

“…We leveraged the Psychiatric Genomic Consortium (PGC) GWAS of major depression (MD) 33 to generate polygenic risk scores (PRS) in Yale-Penn participants of European descent ( N = 3,407). We focused our attention on MD because of the consistent genetic overlap of this trait with suicidality 4 , 7 , 8 . Due to the data sharing restrictions of the 23andMe personal genomics and biotechnology company (a contributor to the PGC MD cohort), GWAS data were publicly available only for a sample subset (59,851 MD cases and 113,154 controls).…”

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood

“…10,11,[13][14][15][16][17][18] In humans, an autosomal-dominant DCC mutation results in structural and functional alterations in the connectivity of mesocortical pathways, with an associated decrease in novelty-seeking behaviour and cigarette use. 19,20 An increasing number of meta-analyses of genome-wide association studies and postmortem human studies have shown that altered levels of DCC expression and the presence of specific genetic polymorphisms in the DCC gene are associated with psychiatric conditions, 21 most notably major depressive disorder, 15,17,[22][23][24][25][26][27][28][29][30][31][32][33][34][35] schizophrenia 34,[36][37][38] and drug abuse. 19,[39][40][41][42] A study by the Cross-Disorder Group of the Psychiatric Genomics Consortium 3 revealed that a PFC-enriched network of genes prominently affected 8 psychiatric disorders, and a DCC single nucleotide polymorphism (SNP) showed the highest pleiotropic association with all 8 disorders.…”

Trauma and posttraumatic stress interact with sex-specific risk loci for suicidality and converge on brain extracellular matrix biology and synaptic plasticity

“…GWAS summary statistics for each environment were accessed via the UKB (see http://www.nealelab.is/uk-biobank) and formatted with Linkage Disequilibrium Score Regression (LDSC) using the 1000 Genomes Project European populations as a linkage disequilibrium reference panel. 18 GWAS summary statistics for suicidality were retrieved from Strawbridge, et al 7 All environments and the ordinal suicidality phenotype exhibited significant heritability (h 2 ) with h 2 z-scores ≥ 4, indicating sufficient power for genetic correlation. After multiple testing correction (FDR<5%), suicidality was genetically correlated with all but four environments: UKB Field ID 738: average total household income before tax, UKB Field ID20525: able to pay rent/mortgage as an adult, UKB Field ID 20527: been involved in combat or exposed to war-zone, and UKB Field ID 20491: someone to take you to doctor when needed as a child ( Figure S3).…”