Despite the challenges associated with conducting large scale genetic studies of suicide, researchers have used twin and family studies to identify heritability estimates ranging from 17-55% for suicide-related phenotypes (e.g., attempts, ideation, behavior, etc.). These studies are often conducted in adult samples and findings are fragmented across a wide range of operational definitions of suicide, including ideation with or without a plan, non-fatal attempts with low or high lethality, and death by suicide. Several researchers have promoted the adoption of endophenotypes in an effort to focus genetic research on traits that are more proximal to genes and the underlying biology of disease. Mann et al. (2009) proposed several endophenotypes for studying suicidal behavior, including neurocognitive function. The present study investigated: (1) the heritability of suicide phenotypes within a sample of adolescents and (2) the genetic correlation of suicide across four domains of neurocognitive functioning (memory, executive, social cognition, and complex cognition) phenotypes among adolescents.
Genome-wide data (N=3,564 unrelated individuals of European Ancestry, aged 8-21, 49.7% male) were drawn from the Philadelphia Neurodevelopment Cohort and imputed (5,360,405 biallelic single nucleotide polymorphisms [SNPs] after imputation and quality control). Participants completed a clinical assessment of psychopathology symptoms based on the Kiddie-Schedule for Affective Disorders and Schizophrenia as well as a computerized neurocognitive battery (CNB) that assessed speed and accuracy across several domains. Factor analysis of the CNB items yielded four domains (i.e., memory, executive, social cognition, and complex cognition). Suicidal Ideation (SI) was operationalized as having endorsed one or more questions involving current or lifetime thoughts about death/dying or killing self. Genomic-relatedness-matrix restricted maximum likelihood estimation was used to determine the proportion of variance in suicide and neurocognitive phenotypes attributable to additive genetic variance (h2SNP) and bivariate models were used to estimate the genetic correlation between traits (rG). Genome-wide association (GWA) analyses were performed with adjustments for multiple testing to identify significant markers associated with each phenotype. All traits were adjusted for gender and age.
Nearly 17% of adolescents in the sample reported SI, including current (3.21%) and lifetime thoughts about death or dying (13.83%) and thoughts about killing themselves (7.54%). The SNP-heritability estimate for SI was 11% (SE=8%) and was nominally significant (p=0.086). SNP-heritability estimates for the neurocognitive domains were all significant and ranged from 13-25%, with 13% (SE=8%, p=0.032) for social cognition, 17% (SE=8%, p=0.013) for memory, 24% (SE=8%, p<0.001) for complex cognition, and 25% (SE=8%, p<0.001) for executive. Bivariate analyses indicated a nominally significant rG between SI and memory (rG=0.68, SE=0.57, p=0.07). No single marker for any phenotype was significant at the GWA level of p < 10-8.
Consistent with previous genetic research, neurocognitive phenotypes were heritable. Endorsement of SI had a small, nominally significant SNP-heritability estimate that was genetically correlated with memory. Implications and future directions for genetic studies of SI are discussed.
References: Mann, J. J., Arango, V. A., Avenevoli, S., Brent, D. A., Champagne, F. A., Clayton, P., ... & Kleinman, J. (2009). Candidate endophenotypes for genetic studies of suicidal behavior. Biological Psychiatry, 65(7), 556-563.
Cognition: Education, Intelligence, Memory, Attention , Psychopathology (e.g., Internalizing, Externalizing, Psychosis)
