Obtaining a large enough sample size to effectively identify risk loci has been a common obstacle for OUD GWAS [43]. Our study represents a new and qualitatively different way of characterizing individuals at high risk for OUD. Our approach is stimulated by the idea of fractionating OUD and looking at POU as an early stage of misuse [44]. In particular, we were motivated to characterize the common mechanism of taking opioids not as prescribed, which can lead to abuse. Sometimes referred to as minimal phenotyping, where a complex trait is reduced to a single (yes or no) question [44], the polygenic signal of POU is nevertheless informative for aspects of OUD risk that is not intended to be a ‘noisy’ measurement of the true underlying disease.
