The Role of Genetics in Suicidality Among Pediatric Patients

In recent years, there has been an unfortunate and steep increase in suicide among children and adolescents in the United States.1 Suicidal behavior is a complex phenotype, with intricate interplay of environment and genetic predisposition. Catechol-o-methyltransferase (COMT) enzyme, encoded by COMT gene on chromosome 22q11.2, is critical for dopamine metabolism. Polymorphisms in COMT, especially the substitution of methionine (Met) for valine (Val) at codon 158 leads to one-fourth less enzymatic activity compared to the Val allele. Studies show that individuals homozygous for the Val allele have significantly lower synaptic dopamine levels.2

The role of COMT alleles

Previously, the role of COMT alleles in suicidal behavior has produced conflicting results. While some studies show that COMT polymorphism is associated with increased suicidal behavior,3-5 a meta-analysis of several studies did not find such correlation.6 Most studies thus far have analyzed adults with suicidal behavior.

Investigators at Cleveland Clinic Children’s recently conducted one of the largest studies in children and adolescents to investigate the role of COMT polymorphism (Val/Val, Val/Met, and Met/Met) in suicidal behavior. Led by Tatiana Falcone, MD, and Anjali Dagar, MD, the team analyzed 322 children and adolescents attending outpatient psychiatry clinics who underwent Genesight® testing, a pharmacogenomic test that analyzes clinically important genetic variations, as part of their clinical care. Close to 9% (n = 28) of participants reported at least one suicidal attempt, including 10 with multiple attempts. The researchers found a statistically significant difference in the mean number of suicide attempts between individuals with COMT Met/Met and COMT Val/Val alleles (P = 0.02; Figure 1).

These initial results in children and adolescents show the promise of early identification of individuals who may be more vulnerable to self-harm and suicidality. The investigators hope this ongoing study will shed more light on the role of genetics in suicidality among children and adolescents.

Figure 1: Number of suicide attempt in children and adolescents with various COMT alleles.

References

1. Curtin SC, Heron M. Death rates due to suicide and homicide among persons aged 10–24: United States, 2000–2007. NHCS Data Brief No. 352, October 2019. https://www.cdc.gov/nchs/products/databriefs/db352.htm (Accessed 8/17/20).
2. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain [published correction appears in Am J Hum Genet. 2005 Jun;76(6):1089. Am J Hum Genet. 2004;75(5):807-821.
3. Kia-Keating BM, Glatt SJ, Tsuang MT. Meta-analyses suggest association between COMT, but not HTR1B, alleles, and suicidal behavior. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(8):1048-1053.
4. Baud P, Courtet P, Perroud N, Jollant F, Buresi C, Malafosse A. Catechol-O-methyltransferase polymorphism (COMT) in suicide attempters: a possible gender effect on anger traits. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(8):1042-1047.
5. Bernegger A, Kienesberger K, Carlberg L, et al. The Impact of COMT and Childhood Maltreatment on Suicidal Behaviour in Affective Disorders. Sci Rep. 2018;8(1):692.
6. Calati R, Porcelli S, Giegling I, et al. Catechol-o-methyltransferase gene modulation on suicidal behavior and personality traits: review, meta-analysis and association study. J Psychiatr Res. 2011;45(3):309-321.