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- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 2. |
- Mattheisen, Manuel, et al.
(författare)
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2.127 The Relationship of ADHD with PTSD : A Mendelian Randomization and Population-Based Sibling Comparison Study
- 2022
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Ingår i: Journal of the American Academy of Child and Adolescent Psychiatry. - : Elsevier. - 0890-8567 .- 1527-5418. ; 61:10, Sup., s. S225-S225
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Observational studies have reported associations between ADHD and PTSD. But these observed associations can reflect causal relationships in either direction or be confounding. We thus aimed to estimate the potential causal effect of ADHD on the risk of subsequently developing PTSD conducting a 2-sample Mendelian randomization (MR) and a population-based sibling comparison study.Methods: This 2-sample MR and population-based sibling comparison study assessed the association between ADHD and PTSD using a genome-wide association study (GWAS) summary data of European individuals and a population-based cohort of 2,082,118 individuals. The ADHD GWAS data consisted of 20,183 cases and 35,191 controls. PTSD GWAS data sets included up to 320,369 individuals. Two-sample MR tested potential causal associations of genetic variants associated with ADHD and PTSD symptoms adjusting for potential confounders. In the population-based comparisons, Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons).Results: Based on large GWAS data sources, regression (rg) analyses revealed consistent associations (rg range, 0.43-0.52; p < .001) between ADHD and PTSD. ADHD genetic liability was causally linked with increased risk for PTSD (inverse variance weighted [IVW] OR = 1.45; 95% CI, 1.20-1.74; p = 7.68x10-5). This result was not affected by heterogeneity or horizontal pleiotropy (MR Egger intercept = 4.34x10-4; p = .961), and was consistent across PTSD data sets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Results from the sibling comparison showed an increased risk for developing PTSD in individuals diagnosed with ADHD compared to their undiagnosed full siblings (hazard ratio = 2.64 [95% CI, 1.98-3.53]) after adjustments. Adjusting for plausible mediators did not affect the MR results but attenuated the estimates in sibling comparisons.Conclusions: Our findings add impetus to the need for early and effective treatment of ADHD because the condition may put individuals at risk for PTSD later in life.
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| 3. |
- Wendt, Frank R., et al.
(författare)
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The Relationship of Attention-deficit/Hyperactivity Disorder with Post-traumatic Stress Disorder : A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study
- 2023
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 93:4, s. 362-369
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Tidskriftsartikel (refereegranskat)abstract
- Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction this relationship.Methods: Linkage Disequilibrium Score Regression and two-sample Mendelian randomization (MR) were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and six PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N=2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons).Results: ADHD and PTSD had consistent rg (rg range, 0.43-0.52; P < .001). ADHD genetic liability was causally linked with increased risk for PTSD (Beta=0.367, 95% confidence interval (CI), 0.186-0.552, P=7.68x10-5). This result was not affected by heterogeneity, horizontal pleiotropy (MR Egger intercept=4.34x10-4, P=0.961), or other phenotypes, and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio=2.37, 95% CI 1.98-3.53).Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.
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