Significant shared heritability underlies suicide attempt and clinically predicted probability of attempting suicide

Ruderfer, Douglas M.; Walsh, Colin G.; Aguirre, Matthew; Ribeiro, Jessica D.; Franklin, Joseph C.; Rivas, Manuel A.

doi:10.1101/266411

Cited by 42 publications

(59 citation statements)

References 38 publications

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“…The usage of PRS for independent traits to predict self-harm results in a tool of great power to test for pleiotropy and genetic overlap between them. For example, a significant genetic correlation of suicide attempt with insomnia has been reported 35 , and we have detected insomnia to also correlate with broad sense self-harm. The existence of GWAS summary statistics for insomnia 65 makes this hypothesis testable using the approach implemented herein.…”

Section: Discussionsupporting

confidence: 59%

Genetic aetiology of self-harm ideation and behaviour

Campos

Verweij

Statham

et al. 2020

Sci Rep

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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 snp 2) 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. Every year nearly one million people take their own lives 1 , making suicide a pressing issue of considerable social and economic burden. Moreover, self-harm behaviours are now recognized by the American Psychiatric Association as independent conditions for further study. Namely, non-suicidal self-injury and suicidal behaviour disorder were recently introduced in the section 3 of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) 2. The lifetime prevalence estimate for suicide thoughts is ~10%, while suicide attempt and non-suicidal self-harm (NSSH) affect ~2.5 and ~5% of the population, respectively 3-5. Higher rates have been reported amongst children and adolescents 6. The key difference between suicidal and non-suicidal self-harm is that the former implies an intent to die as a consequence of the act. Non-suicidal self-harm acts include equally dangerous behaviours such as cutting, burning or poisoning, but are underlined by a different motivation such as seeking attention or the desire to feel pain. Twin and family studies indicate that NSSH, suicide thoughts and suicide attempt are moderately heritable 7,8. Multiple studies have documented that the presence of a psychiatric disorder considerably increases the risk for both suicidal and non-...

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Section: Discussionsupporting

confidence: 59%

Genetic aetiology of self-harm ideation and behaviour

Campos

Verweij

Statham

et al. 2020

Sci Rep

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“…32 Polygenic risk scores for SA have shown modest predictive capability in independent samples, and small but significant single-nucleotide polymorphism (SNP) heritability estimates for SA have been reported. 28,33,34 A significant association between two SNPs (rs12415800 and rs4746720 in 3'UTR) and CS amongst MDD women aged more than 50 years compared to healthy controls. 35 The FKBP5 gene which encodes the FK506 binding protein 51 (FKBP51) and participates as regulator of the glucocorticoid receptor (GR) activity, has received an increasing attention as well, in relation to the suicidal behaviour.…”

Section: Genetic Vulnerability and Epigenetic Modulationmentioning

confidence: 98%

Understanding the Complex of Suicide in Depression: from Research to Clinics

Orsolini

Latini²,

Pompili³

et al. 2020

Psychiatry Investig

253

167

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Objective Amongst psychiatric disorders, major depressive disorder (MDD) is the most prevalent, by affecting approximately 15–17% of the population and showing a high suicide risk rate equivalent to around 15%. The present comprehensive overview aims at evaluating main research studies in the field of MDD at suicide risk, by proposing as well as a schematic suicide risk stratification and useful flow-chart for planning suicide preventive and therapeutic interventions for clinicians.Methods A broad and comprehensive overview has been here conducted by using PubMed/Medline, combining the search strategy of free text terms and exploded MESH headings for the topics of ‘Major Depressive Disorder’ and ‘Suicide’ as following: ((<i>suicide</i> [Title/Abstract]) AND (<i>major depressive disorder</i> [Title/Abstract])). All articles published in English through May 31, 2019 were summarized in a comprehensive way.Results Despite possible pathophysiological factors which may explain the complexity of suicide in MDD, scientific evidence supposed the synergic role of genetics, exogenous and endogenous stressors (i.e., interpersonal, professional, financial, as well as psychiatric disorders), epigenetic, the hypothalamic-pituitary-adrenal stress-response system, the involvement of the monoaminergic neurotransmitter systems, particularly the serotonergic ones, the lipid profile, neuro-immunological biomarkers, the Brain-derived neurotrophic factor and other neuromodulators.Conclusion The present overview reported that suicide is a highly complex and multifaceted phenomenon in which a large plethora of mechanisms could be variable implicated, particularly amongst MDD subjects. Beyond these consideration, modern psychiatry needs a better interpretation of suicide risk with a more careful assessment of suicide risk stratification and planning of clinical and treatment interventions.

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“…A subset of BioVU patients (n = 24,262) was genotyped as part of various institutional and investigator-initiated projects on the Illumina MEGA EX platform, which contains more than two million markers. Quality control proceeded as previously described [19]. Genotypes were imputed using SHAPEIT [20]/IMPUTE4 [21] with the 1000 genomes phase I reference panel, and variants with INFO < 0.3 were excluded.…”

Section: Genotyping and Quality Controlmentioning

confidence: 99%

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

et al. 2019

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Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10 −4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10 −6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

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Significant shared heritability underlies suicide attempt and clinically predicted probability of attempting suicide

Cited by 42 publications

References 38 publications

Genetic aetiology of self-harm ideation and behaviour

Genetic aetiology of self-harm ideation and behaviour

Understanding the Complex of Suicide in Depression: from Research to Clinics

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

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