Exploring the genetic overlap between substance use disorder and educational attainment.

Abstract

Substance use disorder (SUD) is a polygenic psychiatric condition characterized by persistent drug use despite negative consequences. Several studies support that higher cognitive performance and educational attainment (EA) are associated with a reduced risk for SUD. Here, we aimed to understand better the genetic relationship between EA and SUD, using a general addiction risk-factor (addiction) as a proxy of SUD. We used GWAS summary statistics on EA (n = 766 345) and addiction (n = 647 703) and applied a multistep approach to: (i) examinate the genetic overlap between EA and addiction; (ii) test the polygenic contribution of addiction and EA on SUD diagnosis and its clinical heterogeneity in an independent in-house clinical sample (1427 individuals with SUD and 2309 controls); and (iii) dissect the genetic liability of addiction according to its role in EA and assessing its genetic overlap with SUD-related traits, other mental disorders and behavioral traits. We confirmed a negative genetic correlation between addiction and EA [r_g = -0.33, standard error (SE) = 0.02, P = 1.14e-57]. When we dissected the genetic liability of addiction by its relationship with EA we found that the discordant overlapping variation between addiction and EA, highly enriched for the genetic background of addiction (h² _SNP = 2.42%, P = 6.37e-21), showed the strongest effect on SUD (OR = 1.66, 95% confidence interval = 1.54-1.79, P = 2.01e-40) and was associated with worse sociodemographic, health and SUD-related outcomes in individuals with SUD compared with the other genomic partitions studied. Our results provide new evidence on the shared genetic basis between addiction and educational attainment. By separating the genetic liability of addiction according to its relationship with educational attainment, we were able to clarify its polygenic effects on substance use disorder diagnosis and related outcomes, providing novel insights into the shared genetic signatures between addiction and other comorbid traits.