| 1. |
- Mullins, Niamh, et al.
(författare)
-
Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
-
Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
|
|
| 2. |
- Docherty, Anna R, et al.
(författare)
-
GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
-
Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
-
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.
|
|
| 3. |
- Frick, Matilda A, 1979-
(författare)
-
Self-Regulation in Childhood : Developmental Mechanisms and Relations to ADHD Symptoms
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Self-regulation is a multi-faceted construct that concerns goal-directed behaviors, which aid individuals in everyday life and in achieving long-term goals. Self-regulation in believed to progress in a hierarchical fashion, in that simple cognitive functions are integrated into more complex functions across development. Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous childhood-onset disorder, characterized by deficits in various aspects of self-regulation, including core symptoms of inattention and hyperactivity/impulsivity, and comorbidity with externalizing disorders such as oppositional defiant disorder (ODD). The last decade has seen a shift from simple etiological models towards more complex ones, which stress multiple pathways to the disorder. In addition, there is an ongoing search for early markers of the condition, which will increase our understanding, enable early detection, intervention, and perhaps even prevention of the full disorder. Cognitive regulation, aspects of temperament (i.e. negative affect, surgency, and effortful control), and parenting are three areas of importance for self-regulation in general and of ADHD symptoms in particular. Grounded in these three constructs, informed by the hierarchical model of self-regulation development, and a multiple pathway perspective on ADHD, the present thesis aimed to map development of self-regulation, with a special focus on inattention and hyperactivity/impulsivity. Four studies were conducted based on three samples, ranging from infancy to 12 years, including both typically developing children and children diagnosed with ADHD. Study I found that early sustained attention predicted later cognitive regulation, providing support for the hierarchical model of self-regulation development. In addition, maternal sensitivity contributed to higher levels of emotion regulation whereas surgency contributed to lower levels of emotion regulation. Study II gained support for a multiple pathway perspective on ADHD, in that higher temperamental regulation and maternal sensitivity contributed to lower levels of inattention and hyperactivity/impulsivity, and higher surgency contributed to higher levels of hyperactivity/impulsivity. Study III replicated findings from Study II and confirmed early temperament markers of later inattention and hyperactivity/impulsivity, and that early cognitive regulation was a poor predictor of later symptoms. Study IV proposed contributions of multiple regulatory functions to ADHD symptoms and elevated negative affect in ODD. The latter was moderated by parental support, which seemed to be a protective factor for children with high levels of negative affect. In all, the findings point to the importance of both intrinsic and extrinsic factors in the development of self-regulation, which seems to progress in a hierarchical fashion. Aspects of temperament rather than cognitive regulation seem to be valid early markers of later inattention and hyperactivity/impulsivity. Multiple pathways to ADHD symptoms are proposed, with contributions of maternal sensitivity and temperament early in development and different regulatory functions in school-aged children. In addition, elevated negative affect in combination with low parental support seem to be characteristic of ODD rather than of core symptoms of ADHD. The thesis contributes to the complexity and heterogeneity of ADHD and that ADHD is best viewed as a developmental disorder, in that the influence of various regulatory factors change over time.
|
|
