Participants in the Yale-Penn study were from small nuclear families and unrelated individuals recruited in the eastern United States in the course of studies of the genetics of alcohol, cocaine or opioid dependence. Nicotine dependence had no role in subject selection. Yale-Penn participants were administered the Semi-Structured Assessment for Drug Dependence and Alcoholism and were genotyped on the Illumina HumanOmni1-Quad v1.0 microarray. Participants with missing rate >2% were excluded. SNPs with missing rate >2%, HWE P<1 × 10−4 and with significantly different minor allele frequency across genotyping labs (Yale or CIDR) were set to missing before imputation. SNP genotype imputation was performed with IMPUTE2 (ref. 25) using genotyped SNPs and the March 2012 1000 Genomes ALL reference panel. Genetic relationships were examined by calculating pairwise identity-by-state estimates using PLINK.17 Sample duplicates (identity-by-state >90%) were removed, pairs of individuals whose identity-by-state proportions did not match their reported genetic relationship were assigned to two different families and pairs of individuals who shared >25% of their alleles identity-by-state were assigned to the same family. Participants with gender discordance (FST<0.2 for chromosome X SNPs
