Mapping the genetic architecture of suicide attempt and suicide death using polygenic risk scores for clinically-related psychiatric disorders and traits

Abstract Background Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death. Methods We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis. Results PRSs for major depressive disorder, bipolar disorder, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10−4). The polygenic effects of all 22 psychiatric disorders/traits had the same direction (p for binomial tests = 4.8 × 10−7) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents. Conclusions We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.

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Genome-wide association study of suicide attempt in psychiatric disorders identifies association with major depression polygenic risk scores

10.1101/416008 ◽

2018 ◽

Cited By ~ 2

Author(s):

Niamh Mullins ◽

Tim B. Bigdeli ◽

Anders D Børglum ◽

Jonathan R I Coleman ◽

Ditte Demontis ◽

...

Keyword(s):

Major Depression ◽

Suicide Attempt ◽

Psychiatric Disorders ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Risk Scores ◽

Genetic Associations ◽

Suicide Attempters ◽

Polygenic Risk ◽

Genome Wide

AbstractObjectiveOver 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium.MethodSamples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders.ResultsThree genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006).ConclusionsThis study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.

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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores

American Journal of Psychiatry ◽

10.1176/appi.ajp.2019.18080957 ◽

2019 ◽

Vol 176 (8) ◽

pp. 651-660 ◽

Cited By ~ 49

Author(s):

Niamh Mullins ◽

Tim B. Bigdeli ◽

Anders D. Børglum ◽

Jonathan R.I. Coleman ◽

Ditte Demontis ◽

...

Keyword(s):

Major Depression ◽

Suicide Attempt ◽

Psychiatric Disorders ◽

Risk Scores ◽

Polygenic Risk

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Genetic liability to suicide attempt, suicide death, and psychiatric and substance use disorders on the risk for suicide attempt and suicide death: a Swedish national study

Psychological Medicine ◽

10.1017/s0033291721003354 ◽

2021 ◽

pp. 1-10

Author(s):

Kenneth S. Kendler ◽

Henrik Ohlsson ◽

Eve K. Mościcki ◽

Jan Sundquist ◽

Alexis C. Edwards ◽

...

Keyword(s):

Suicide Attempt ◽

Psychiatric Disorders ◽

Genetic Risk ◽

Risk Scores ◽

National Study ◽

Multivariate Models ◽

Genetic Liability ◽

Suicide Death ◽

Younger Age ◽

The Impact

Abstract Background How does genetic liability to suicide attempt (SA), suicide death (SD), major depression (MD), bipolar disorder (BD), schizophrenia (SZ), alcohol use disorder (AUD), and drug use disorder (DUD) impact on risk for SA and SD? Methods In the Swedish general population born 1932–1995 and followed through 2017 (n = 7 661 519), we calculate family genetic risk scores (FGRS) for SA, SD, MD, BD, SZ, AUD, and DUD. Registration for SA and SD was assessed from Swedish national registers. Results In univariate and multivariate models predicting SA, FGRS were highest for SA, AUD, DUD, and MD. In univariate models predicting SD, the strongest FGRS were AUD, DUD, SA, and SD. In multivariate models, the FGRS for SA and AUD were higher in predicting SA while the FGRS for SD, BD, and SZ were higher in predicting SD. Higher FGRS for all disorders significantly predicted both younger age at first SA and frequency of attempts. For SD, higher FGRS for MD, AUD, and SD predicted later age at SD. Mediation of FGRS effects on SA and SD was more pronounced for SD than SA, strongest for AUD, DUD, and SZ FGRS and weakest for MD. Conclusions FGRS for both SA and SD and for our five psychiatric disorders impact on risk for SA and SD in a complex manner. While some of the impact of genetic risk factors for psychiatric disorders on risk for SA and SD is mediated through developing the disorders, these risks also predispose directly to suicidal behaviors.

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Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling

10.31234/osf.io/fykuh ◽

2019 ◽

Author(s):

Thomas M. Piasecki ◽

Ian R. Gizer ◽

Wendy S. Slutske

Keyword(s):

Psychiatric Disorders ◽

Association Studies ◽

Common Variant ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Adult Health ◽

Disordered Gambling ◽

Polygenic Risk ◽

Common Genetic Variants

Background and Aims: Twin studies indicate that disordered gambling (DG) is heritable but are silent with respect to specific genes or pathways involved. Genome-wide association studies of other psychiatric disorders permit calculation of polygenic risk scores (PRS) that reflect the aggregated effects of common genetic variants contributing to risk for the target condition. We investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys. Design and Setting: Data were drawn from the Wave IV assessment of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-5 and followed into young adulthood. Participants: Analyses were limited to unrelated individuals classified as having European ancestry based on analysis of genetic principal components (N = 5,215). Measurements: Participants were surveyed about lifetime gambling and DG. Genotyping data were used to construct PRSs quantifying participants’ common variant genetic risk for major depression (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD), and schizophrenia (SCZ). Findings: Most participants (78.4%) reported ever having gambled, and 1.3% of those reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = 0.12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .020, pseudo-R2 (%) = 0.85. Polygenic risk for MDD and ADHD were not related to either gambling outcome. Conclusions: Common variant risk for SCZ is associated with DG. Investigating features common to both SCZ and DG might generate valuable clues about the genetically-influenced liabilities to DG.

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Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling

Twin Research and Human Genetics ◽

10.1017/thg.2019.90 ◽

2019 ◽

Vol 22 (5) ◽

pp. 283-289

Author(s):

Thomas M. Piasecki ◽

Ian R. Gizer ◽

Wendy S. Slutske

Keyword(s):

Psychiatric Disorders ◽

Association Studies ◽

Twin Studies ◽

European Ancestry ◽

Risk Scores ◽

Adult Health ◽

Disordered Gambling ◽

Polygenic Risk ◽

Common Genetic Variants ◽

Survey Responses

AbstractDisordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994–1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

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Chromosome 22 Deletions and Suicidal Behavior in Schizophrenia

Neuropsychobiology ◽

10.1159/000513645 ◽

2021 ◽

pp. 1-8

Author(s):

Ali Bani-Fatemi ◽

Christopher Adanty ◽

Nasia Dai ◽

Ariel Graff ◽

Philip Gerretsen ◽

...

Keyword(s):

Suicide Attempt ◽

Suicidal Behavior ◽

Copy Number ◽

Rating Scale ◽

Copy Number Variant ◽

Chromosome 22 ◽

Suicide Attempters ◽

Severity Rating ◽

Neuropsychiatric Diseases ◽

Significant Difference

Background: Studies have shown that the overall copy number variant (CNV) load is associated with schizophrenia. Schizophrenia is a mental disorder that is frequently associated with suicidal behavior. Methods: We recruited 263 patients with schizophrenia from the Centre for Addiction and Mental Health. The Columbia Suicide Severity Rating Scale was used to assess the presence of lifetime suicide attempt. Genotyping was completed using the Illumina Omni 2.5 chip. We tested the association between deletion events on chromosome 22 with suicide attempt in our schizophrenia sample. Results: There was no significant difference between suicide attempters and non-attempters considering the presence/absence of deletion events on chromosome 22. Conclusion: Although our results did not show a significant association between deletions on chromosome 22 and suicide attempt in schizophrenia, CNV studies may reveal important, novel insights and open further investigation for the treatment of neuropsychiatric diseases.

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General v. specific vulnerabilities: polygenic risk scores and higher-order psychopathology dimensions in the Adolescent Brain Cognitive Development (ABCD) Study

Psychological Medicine ◽

10.1017/s0033291721003639 ◽

2021 ◽

pp. 1-10

Author(s):

Monika A. Waszczuk ◽

Jiaju Miao ◽

Anna R. Docherty ◽

Andrey A. Shabalin ◽

Katherine G. Jonas ◽

...

Keyword(s):

Clinical Practice ◽

Behavioral Problems ◽

Mental Health Problems ◽

Chronic Back Pain ◽

European Ancestry ◽

Risk Scores ◽

General Factor ◽

Childhood Psychopathology ◽

Polygenic Risk ◽

Partial Correlations

Abstract Background Polygenic risk scores (PRSs) capture genetic vulnerability to psychiatric conditions. However, PRSs are often associated with multiple mental health problems in children, complicating their use in research and clinical practice. The current study is the first to systematically test which PRSs associate broadly with all forms of childhood psychopathology, and which PRSs are more specific to one or a handful of forms of psychopathology. Methods The sample consisted of 4717 unrelated children (mean age = 9.92, s.d. = 0.62; 47.1% female; all European ancestry). Psychopathology was conceptualized hierarchically as empirically derived general factor (p-factor) and five specific factors: externalizing, internalizing, neurodevelopmental, somatoform, and detachment. Partial correlations explored associations between psychopathology factors and 22 psychopathology-related PRSs. Regressions tested which level of the psychopathology hierarchy was most strongly associated with each PRS. Results Thirteen PRSs were significantly associated with the general factor, most prominently Chronic Multisite Pain-PRS (r = 0.098), ADHD-PRS (r = 0.079), and Depression-PRS (r = 0.078). After adjusting for the general factor, Depression-PRS, Neuroticism-PRS, PTSD-PRS, Insomnia-PRS, Chronic Back Pain-PRS, and Autism-PRS were not associated with lower order factors. Conversely, several externalizing PRSs, including Adventurousness-PRS and Disinhibition-PRS, remained associated with the externalizing factor (|r| = 0.040–0.058). The ADHD-PRS remained uniquely associated with the neurodevelopmental factor (r = 062). Conclusions PRSs developed to predict vulnerability to emotional difficulties and chronic pain generally captured genetic risk for all forms of childhood psychopathology. PRSs developed to predict vulnerability to externalizing difficulties, e.g. disinhibition, tended to be more specific in predicting behavioral problems. The results may inform translation of existing PRSs to pediatric research and future clinical practice.

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Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

10.1101/2020.03.31.20044800 ◽

2020 ◽

Author(s):

Brandon J. Coombes ◽

Matej Markota ◽

J. John Mann ◽

Colin Colby ◽

Eli Stahl ◽

...

Keyword(s):

Bipolar Disorder ◽

Psychiatric Disorders ◽

Suicide Attempts ◽

Risk Scores ◽

Rapid Cycling ◽

Clinical Heterogeneity ◽

Polygenic Risk ◽

Clinical Observations ◽

History Of ◽

Dsm Iv

AbstractBipolar disorder (BD) has high clinical heterogeneity, frequent psychiatric comorbidities, and elevated suicide risk. To determine genetic differences between common clinical sub-phenotypes of BD, we performed a systematic PRS analysis using multiple polygenic risk scores (PRSs) from a range of psychiatric, personality, and lifestyle traits to dissect differences in BD sub-phenotypes in two BD cohorts: the Mayo Clinic BD Biobank (N = 968) and Genetic Association Information Network (N = 1001). Participants were assessed for history of psychosis, early-onset BD, rapid cycling (defined as four or more episodes in a year), and suicide attempts using questionnaires and the Structured Clinical Interview for DSM-IV. In a combined sample of 1969 bipolar cases (45.5% male), those with psychosis had higher PRS for SCZ (OR = 1.3 per S.D.; p = 3e-5) but lower PRSs for anhedonia (OR = 0.87; p = 0.003) and BMI (OR = 0.87; p = 0.003). Rapid cycling cases had higher PRS for ADHD (OR = 1.23; p = 7e-5) and MDD (OR = 1.23; p = 4e-5) and lower BD PRS (OR = 0.8; p = 0.004). Cases with a suicide attempt had higher PRS for MDD (OR = 1.26; p = 1e-6) and anhedonia (OR = 1.22; p = 2e-5) as well as lower PRS for educational attainment (OR = 0.87; p = 0.003). The observed novel PRS associations with sub-phenotypes align with clinical observations such as rapid cycling BD patients having a greater lifetime prevalence of ADHD. Our findings confirm that genetic heterogeneity underlies the clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.

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