We used the n = 4733 sibling GWAS sample to calculate the EduYears-GPS-mean (for each sibling group) and EduYears-GPS-deviation scores (for each individual within that sibling group). We then filtered the sample based on participants’ age at last interview to retain those who were 25 years of age or older (age cutoff selected to ensure that participants had passed through the period of highest risk for onset of the SUDs) for our primary sibling comparisons sample; additional information regarding this process can be found in Supporting Information section 3. Using all available GWAS data from a sibling group to calculate the EduYears-GPS-mean and EduYears-GPS-deviation scores has the advantage of providing a more precise estimate for these variables (since genotype does not change with age), versus limiting calculation of EduYears-GPS-mean to those siblings who also met the phenotypic age threshold. In separate linear mixed models, we then examined whether EduYears-GPS-deviation predicted SUDs after controlling for EduYears-GPS-mean. The sibling comparison is captured by the EduYears-GPS-deviation parameter, and indicates whether sibling differences in EduYears-GPS predict SUDs; this parameter captures the within-family effect. The EduYears-GPS-mean parameter captures whether family-level differences in EduYears-GPS predict SUDs, reflecting the between-family effect.
