Summary: Researchers have identified a notable genetic overlap between suicide attempts and major depressive disorder.
Source: Yale.
Yale researchers report the discovery of multiple genetic variants associated with serious suicide attempts and show that several of these variants overlap with genes linked to major depressive disorder, according to a study published Jan. 17 in the journal Translational Psychiatry.
In the first whole-genome analysis to demonstrate a shared genetic signal between suicide attempt severity and major depression, investigators examined genetic data across diverse populations and identified key loci that may contribute to risk.
Prior research has indicated that suicidal behavior can cluster in families, suggesting a hereditary component, but few studies have systematically searched the genome for specific risk variants. Suicide remains a major public health problem: in 2015, more than 800,000 people died by suicide worldwide.
Led by senior author Joel Gelernter, Foundations Fund Professor of Psychiatry and Professor of Genetics and Neuroscience at Yale, and lead author Daniel Levey, a postdoctoral researcher at Yale, the team performed a genome-wide association study (GWAS) focused on the severity of suicide attempts. They analyzed nearly 2,500 European American participants and more than 3,800 African American participants. To sharpen the analysis, the researchers excluded individuals who reported only suicidal thoughts and instead ranked participants by objective indicators of attempt severity, for example attempts that required medical attention.
The GWAS identified distinct genetic signals in each ancestry group. In European Americans, a genome-wide significant association appeared near the LDHB gene, which is involved in anaerobic energy production. In African Americans, three genome-wide significant associations emerged: one near ARNTL2, a gene implicated in circadian rhythm regulation; another near FAH, a gene involved in tyrosine catabolism, which affects precursor pathways for neurotransmitters such as dopamine; and a third locus on chromosome 18 with an as-yet-unknown function.
To validate and extend their findings, the researchers compared these suicide-attempt associations with results from large GWAS efforts in major depressive disorder. Using polygenic risk scores derived from a major depression GWAS, they demonstrated statistically significant genetic overlap between suicide attempt severity and major depressive disorder, indicating that some of the same common genetic variants contribute to both outcomes.
When performing replication analyses in independent cohorts, several loci showed supporting evidence across populations. For example, the LDHB variant replicated in a Latino cohort, while a variant in linkage with the FAH signal replicated in African American samples. Combined trans-population meta-analysis expanded the total sample size and strengthened the evidence for these associations.
These results highlight molecular pathways that may be important for suicidal behavior, including energy metabolism, circadian regulation, and amino-acid catabolism linked to neurotransmitter synthesis. Identifying these pathways can help guide future biological and clinical research into mechanisms of risk and potential intervention points.
Gelernter and colleagues plan to expand their analyses using larger, ongoing genetic datasets, including data collected through the U.S. Department of Veterans Affairs Million Veterans Program. The VA has prioritized research and programs aimed at reducing suicide among veterans, and the larger sample sizes and extensive clinical data available in such cohorts will improve statistical power to detect additional genetic signals and to clarify how genetics interacts with environmental and clinical risk factors.
Source: Bill Hathaway, Yale University.
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Original research: Open-access study titled “Genetic associations with suicide attempt severity and genetic overlap with major depression” by Daniel F. Levey et al., published in Translational Psychiatry, January 17, 2019.
DOI: 10.1038/s41398-018-0340-2
Genetic associations with suicide attempt severity and genetic overlap with major depression
Suicide is a leading cause of death worldwide, with approximately 800,000 deaths in 2015 and many more nonfatal attempts that contribute to morbidity. To investigate the genetic basis of suicide attempt severity, the authors conducted a genome-wide association study in Yale-Penn cohorts, including European Americans (n = 2,439) and African Americans (n = 3,881). The discovery GWAS identified one genome-wide significant signal in European Americans near LDHB (rs1677091) and three genome-wide significant associations in African Americans: near ARNTL2 (rs683813), near FAH (rs72740082), and on chromosome 18 (rs11876255). Limited replication in independent Army-STARRS cohorts supported several findings: the LDHB locus replicated in a Latino sample, and a variant in linkage disequilibrium with the FAH signal replicated in African Americans. A trans-population meta-analysis increased the total sample to over 20,000 individuals. Finally, polygenic risk score analysis showed a significant genetic overlap between suicide attempt severity and major depressive disorder, consistent with shared common-variant influences. The identified loci implicate pathways involved in anaerobic energy metabolism, circadian clock regulation, and tyrosine catabolism, providing new molecular insights into the biology underlying suicidal behavior.
This article summarizes published research findings. It does not provide medical advice. Clinical decisions should be made in consultation with qualified health professionals.