Are polygenic risk scores (PRSs) for adult suicide associated with childhood suicidal thoughts and behaviors?
Suicide rates have been increasing among children and adolescents in the United States. Given this worrisome increase in the prevalence of youth suicide over the last decade, there is an urgent need for research focusing on suicide in children and adolescents.
Newly available genome-wide association studies (GWASs) carried out in adults have established that suicide attempts and death by suicide are heritable, determined by multiple genes, and share a genetic basis that is partially distinct from specific psychiatric disorders. However, we know far less about the contribution of genetic factors to suicidal thoughts and behaviors in children. More specifically, it is not known whether the risk factors and variables associated with suicidal ideation and behavior in adolescence and adulthood are the same as those determining risk in childhood.
A recent study from Phil H. Lee, PhD and colleagues from the Center for Genomic Medicine examines whether the genetic factors which determine susceptibility to suicide attempts (SAs) in adults are associated with suicidal thoughts and behaviors (STBs) in children. The study was designed to answer several important questions. First, are polygenic risk scores (PRSs) for SAs in adults associated with increased risk for STBs in children? If so, are the effects of SA PRSs independent of genetic risk for specific psychiatric disorders, such as major depressive disorder (MDD) and attention deficits hyperactivity disorder (ADHD)? Lastly, are the effects of SA PRSs on children’s STBs mediated by factors related to children’s temperament or psychopathology?
The current study tackled these questions by leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study. This population-based longitudinal study of 11,878 US children has enrolled participants between the ages of 9 and 10 years with a plan to follow them for 10 years. The current study analyzed youth reports of suicidal ideation (SI) and SAs obtained from the Kiddie Schedule for Affective Disorder and Schizophrenia at baseline and during two subsequent years of follow-up. PRSs for SAs were derived from an independent genome-wide association study of 550, 000 adults.
Polygenic Risk Scores Associated with Suicide Attempts in Children
The analysis focused on 4344 unrelated individuals of European ancestry. The lifetime prevalence of SAs among the participants increased approximately threefold from baseline (mean age 9.93 years, SD 0.62) to follow-up Year 2 (Baseline: 37 [0.85%] ; Year 1: 74 [1.7%]; Year 2, 102 [2.35%]). Over the same time period, reports of suicidal ideation nearly doubled (Baseline: 333 [7.67%]; Year 1: 488 [11.23%]; Year 2, 601 [13.84%]).
The researchers observed statistically significant associations between PRSs for SAs and children’s SAs. As the number of children with SAs increased each year, the association of SA PRSs with youth SAs became more pronounced. These associations remained significant after accounting for clinical, familial, and sociodemographic risk factors for suicide. There was not a significant association between PRSs for SAs and SI at any timepoint.
Next, they examined whether the associations between PRSs for suicide attempts and SAs in youth were independent of the genetic influences of MDD and ADHD. Consistent with the group’s previous analysis of the ABCD data published in Biological Psychiatry (2022), PRSs for these two psychiatric disorders were significantly associated with children’s SAs and SI; however, children’s SAs explained by SA PRSs were at least in part independent of the risk for MDD and ADHD.
They then examined whether the associations identified between SA PRSs and children’s SAs were mediated by known risk factors for suicide. Specifically, they hypothesized that genetic risk underlying SAs may increase children’s STBs through child psychopathology (e.g., depression, anxiety) or temperament issues (e.g., aggression, impulsivity). A significant proportion of SA genetic risk was mediated through children’s depressive mood and aggressive behaviors.
Can We Use Genetics to Estimate Suicide Risk in Children?
This study provides the first empirical evidence that common genetic variants associated with increased risk for SAs at the population level are associated with SAs in children. The associations between SA PRS and child SAs were independent of genetic risk for MDD and ADHD and significant even after accounting for clinical, sociodemographic, and family risk factors for suicide. These results extend prior epidemiological evidence indicating that suicide risk in this age group is influenced by genetic factors that modulate suicide risk across the lifespan.
The genetic association of adult SA risk was detected in children as early as 10 years of age and became more robust across the subsequent years. This finding is in line with the documented familial transmission of suicide risk, including evidence linking suicide in parents to SAs and death by suicide in their youth offspring.
Of note, while genetic factors may influence the risk of SAs among children, other familial and environmental factors play an important role. In this analysis, SA PRSs accounted for at most 1.5% of the variance in childhood SAs and thus would not have clinical utility on their own. Importantly, ethnical concerns for using genetic data for suicide risk prediction should be adequately addressed. However, this study finding suggests that combining genetic data with phenotypic, socioeconomic, and psychosocial risk factors that are stronger predictors of suicide risk in youth may help to improve risk stratification, especially in younger children. Considering the rapidly increasing rates of STBs in youth, further research is warranted to dissect the complex interplay of genetic and environmental risk factors and to set the stage for improved suicide prevention and intervention efforts.
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Lee PH, Doyle AE, Li X, Silberstein M, Jung JY, Gollub RL, Nierenberg AA, Liu RT, Kessler RC, Perlis RH, Fava M. Genetic Association of Attention-Deficit/Hyperactivity Disorder and Major Depression With Suicidal Ideation and Attempts in Children: The Adolescent Brain Cognitive Development Study. Biol Psychiatry. 2022 Aug 1; 92(3):236-245.
