Citation
Brick, Leslie; Benca-Bachman, Chelsie; & Palmer, Rohan (2019). M96. GENETIC SOURCES OF VARIATION UNDERLYING CANNABIS USE AND THE TRANSMISSIBLE LIABILITY INDEX FOR SUBSTANCE USE DISORDERS. European Neuropsychopharmacology.Abstract
Background: Cannabis is the most widely used illicit drug across the globe, with an estimated 3.9% prevalence of use, despite adverse effects on physical and mental health. Molecular genetic studies have estimated that common single nucleotide polymorphisms (SNPs) explain between 6-20% of the liability for lifetime cannabis use (CU) and may represent risk factors for development of substance use and other psychiatric disorders. A plausible strategy to identify risk genes/loci is to leverage indices of risk. The Transmissible Liability Index (TLI), a latent construct indicated by a breadth of childhood/adolescent characteristics, has been found to be heritable and genetically correlated with substance use disorder (SUD). Thus, TLI scores may also reflect the genetic and environmental mechanisms related to an adolescent's liability for SUD based on behaviors assessed during early adolescence, including mood and socialization, property damage, stealing, fighting, and weapon use. Our goals were to: (1) characterize the sources of SNP-based heritability (h2SNP) across several CU phenotypes in a longitudinal sample of youth and (2) examine the phenotypic and genetic covariance between CU and TLI using GCTA-GREML. Methods: Data were from the National Longitudinal Study of Adolescent to Adult Health (N>20,000 youth, of which 9,974 have genetic data). Factor analysis was used to construct and validate TLI. After genetic imputation and quality control, there were 4,953 unrelated individuals of European Ancestry and 7,493,644 autosomal SNPs (minor allele frequency>1%). Of these individuals, 2,697 (µage=28.62 [SD=1.59]; 46.4% male) had viable phenotypic data. Analyses controlled for sex and age. Results: Logistic regression analyses indicated a 71% increase in odds of ever using cannabis per standard deviation increase in TLI. Univariate GREML indicated a lifetime CU (use 5+ times) h2SNP-LD=0.28 (SE=0.16) when stratified across linkage disequilibrium (LD) quartiles. Contrary to our hypotheses and prior work, h2SNP for TLI (0.05, SE= 0.15) was negligible, possibly due to poor representation of internalizing traits. Within a subset of individuals who had been exposed to cannabis, frequency of use in the past year (h2SNP-LD=0.10, SE=0.29), and age of onset were modest (h2SNP-LD=0.68, SE=0.33), though sample sizes were quite small (N=1309 and N=1631, respectively). Discussion: Overall, our results indicated consistent support for the heritability of lifetime CU, with the majority of genetic variance attributable to SNPs in low LD with other variants. However, while phenotypically associated with the CU, the h2SNP of TLI was negligible and CU phenotypes were not genetically correlated with TLI. The small sample size and narrow operationalization of the TLI potentially limits the generalizability of this work to prior literature. Future research should continue to examine the genetic architecture of TLI, include diverse ancestral populations, and seek to identify regions of genome that confer risk for CU.URL
https://doi.org/10.1016/j.euroneuro.2019.08.196Reference Type
Conference proceedingBook Title
European NeuropsychopharmacologyAuthor(s)
Brick, LeslieBenca-Bachman, Chelsie
Palmer, Rohan