Genetic Heritability of Substance Use and Behavioral Traits

The SNP heritability of the 19 GWAS mentioned above (Supplementary Table S2) was estimated using linkage disequilibrium score regression (LDSC) (44 (link)) (Supplementary Table S3).⁶ In the case of cocaine dependence, alcohol dependence, cannabis dependence, cannabis use disorder, opioids dependence, opioids use disorder, ever addicted phenotype, and anxiety, heritability was reported on the liability scale considering the sample and population prevalence of each of them. For the other GWAS, a liability scale could not be used due to the absence of a population prevalence estimate or the use of a continuous scale to define the traits.
A total of 7 GWAS were discarded with a SNP-based heritability estimates h²_SNP < 0.05, indicating a low genetic contribution (Supplementary Table S3). In the case of opioids addiction, both summary statistics of opioids dependence and opioids use disorder showed a heritability higher than 5%, but opioids use disorder summary statistics was selected for subsequent analyses given the higher number of individuals included in this study (Supplementary Table S2).
In total, 11 summary statistics from GWAS were selected for subsequent analyses, including 5 studies on SUD [alcohol dependence (45 (link)), cannabis use disorder (CUD) (46 (link)), cocaine dependence (47 (link)), opioids use disorder (OUD) (48 (link)) and a multivariate analysis of three substance use disorders (SUD) (49 (link))], two on aggressive behavior [antisocial behavior (AB) (50 (link)) and disruptive behavior disorders comorbid with attention-deficit/hyperactivity disorder (ADHD-DBD) (51 (link))] and four on related behavioral traits (anxiety, irritability, neuroticism and risk taking behavior) (Table 1).
Genetic variants from most of the summary statistics used were filtered out by MAF ≤ 0.01 and info-score for imputation quality ≤0.8. There were three exceptions in which variants with a lower imputation quality could not be filtered out because the specific info-score values were missing: antisocial behavior (info-score > 0.6), risk taking (info-score > 0.4), and SUD.