The shared genetic architecture of suicidal behaviour and psychiatric disorders: A genomic structural equation modelling study

Tahira Kootbodien; Leslie London; Lorna J Martin; Joel Defo; Raj Ramesar

doi:10.3389/fgene.2023.1083969

The shared genetic architecture of suicidal behaviour and psychiatric disorders: A genomic structural equation modelling study

Front Genet. 2023 Mar 7:14:1083969. doi: 10.3389/fgene.2023.1083969. eCollection 2023.

Authors

Tahira Kootbodien¹, Leslie London², Lorna J Martin³, Joel Defo¹, Raj Ramesar¹

Affiliations

¹ UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa.
² School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
³ Division of Forensic Medicine and Toxicology, Department of Pathology, University of Cape Town, Cape Town, South Africa.

Abstract

Background: Suicidal behaviour (SB) refers to behaviours, ranging from non-fatal suicidal behaviour, such as suicidal ideation and attempt, to completed suicide. Despite recent advancements in genomic technology and statistical methods, it is unclear to what extent the spectrum of suicidal behaviour is explained by shared genetic aetiology. Methods: We identified nine genome-wide association statistics of suicidal behaviour (sample sizes, n, ranging from 62,648 to 125,844), ten psychiatric traits [n up to 386,533] and collectively, nine summary datasets of anthropometric, behavioural and socioeconomic-related traits [n ranging from 58,610 to 941,280]. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling, identified shared biological processes and pathways between suicidal behaviour and psychiatric disorders and evaluated potential causal associations using Mendelian randomisation. Results: Among populations of European ancestry, we observed strong positive genetic correlations between suicide ideation, attempt and self-harm (rg range, 0.71-1.09) and moderate to strong genetic correlations between suicidal behaviour traits and a range of psychiatric disorders, most notably, major depression disorder (rg = 0.86, p = 1.62 × 10^-36). Multivariate analysis revealed a common factor structure for suicidal behaviour traits, major depression, attention deficit hyperactivity disorder (ADHD) and alcohol use disorder. The derived common factor explained 38.7% of the shared variance across the traits. We identified 2,951 genes and 98 sub-network hub genes associated with the common factor, including pathways associated with developmental biology, signal transduction and RNA degradation. We found suggestive evidence for the protective effects of higher household income level on suicide attempt [OR = 0.55 (0.44-0.70), p = 1.29 × 10^-5] and while further investigation is needed, a nominal significant effect of smoking on suicide attempt [OR = 1.24 (1.04-1.44), p = 0.026]. Conclusion: Our findings provide evidence of shared aetiology between suicidal behaviour and psychiatric disorders and indicate potential common molecular mechanisms contributing to the overlapping pathophysiology. These findings provide a better understanding of the complex genetic architecture of suicidal behaviour and have implications for the prevention and treatment of suicidal behaviour.

Keywords: GWAS-genome-wide association study; genetic correlation; genomic structural equation modeling; mendelian randomization; psychiastric disorders; suicidal behavior (SB).

Grants and funding

The work reported herein was made possible through funding by the South African Medical Research Council through its Division of Research Capacity Development under the SAMRC Clinician Researcher Programme.