NEW YORK – With the help of a multitrait genome-wide association approach, a Peking University-led team has identified genetic loci with ties to non-suicidal self-injury (NSSI), providing a look at overlapping behaviors and brain structure features and potential strategies for reducing NSSI behaviors.
The behavior involves "deliberate, direct, self-inflicted harm to the body without suicidal intent," Peking University Sixth Hospital researchers Yaoyao Sun and Weihua Yue explained in an email, noting that NSSI is known to be a "complex behavior determined by genetic and environmental factors" that are most prevalent in adolescents and young adults.
Using genotyping and phenotyping data for more than 157,300 European ancestry UK Biobank participants with self-reported mental health questionnaire data, the team performed a GWAS for NSSI, combining the summary statistic data with that from GWAS of self-harm ideation, self-harm behavior, and suicide attempts for a subsequent multitrait analysis of GWAS.
Their work, published in Cell Reports Medicine on Friday, led to three NSSI-associated sites in or around the DCC or LCA5L/GET1/GET1-SH3BGR genes and the chromosome 7q31.2 locus that were subsequently analyzed in more detail and used to inform polygenic risk score (PRS) analyses.
Along with fine-mapping and expression quantitative trait locus analyses focused on variants influencing the expression of GET1 and SH3BGR in the hippocampus, the team validated their findings using data from the Adolescent Brain Cognitive Development (ABCD) study and went on to explore interaction networks for proteins encoded by NSSI-associated genes or variants.
In polygenic risk score (PRS) and brain magnetic resonance imaging analyses done using data for more than 5,300 European-ancestry children enrolled in the ABCD cohort at the ages of 9 or 10 years, meanwhile, the researchers found that a polygenic risk score for NSSI overlapped with the risk of suicidal ideation and suicidal attempt behavior in children as well as MRI-based cortical brain volume patterns found in the right temporal pole region.
"These findings highlight the potential utility of genetic tools (e.g., PRS) for early risk stratification in future preventive strategies," Sun and Yue explained, noting that "genetic predisposition to NSSI is partially mediated by neurodevelopmental alterations, particularly reduced volume in the right temporal pole — a brain region critical for integrating emotional and cognitive processes."
On the other hand, the team's Mendelian randomization analyses explored behavioral, dietary, or lifestyle factors that may ramp up or dial down individuals' risk of NSSI. For example, the analyses linked reduced NSSI risk to activities such as enjoyable exercise or walking for pleasure, while smoking coincided with a higher-than-usual risk of NSSI behavior.
Based on such findings, the investigators suggested that there may be opportunities to dial down the risk of such self-injury through programs and public health initiatives that help people quit smoking and promote forms of physical activity that are enjoyable for at-risk individuals.
"Engaging in enjoyable forms of exercise, such as walking for pleasure, swimming, cycling for fitness, and bowling, can significantly reduce the risk for NSSI," Sun and Yue noted.
Based on their current findings, the researchers pointed to the need for larger studies aimed at untangling NSSI mechanisms across development and in relation to environmental factors that include not only smoking habits, but also exposure to stressful events or situations, particularly for individuals who appear to be at elevated genetic risk of NSSI.
"Most importantly," Sun and Yue argued, "early identification, prevention, and intervention targeting NSSI should be prioritized as key public health initiatives."