History and Philosophy of Science and Medicine: “Genotype-Phenotype Predictors Will Never Be Fully Portable”

"Genotype-Phenotype Predictors Will Never Be Fully Portable” 

Enthusiasm for the potential of DNA-based genomic predictors—particularly polygenic scores (PGS)—to transform science and medicine has been tempered by a persistent challenge: limited portability. In general, the more a target population differs from the population in which a predictor was developed, the less accurately it predicts phenotypic outcomes. This limitation raises serious concerns about whether genomic prediction technologies will alleviate or exacerbate existing health disparities. Efforts to understand and address the portability problem have largely emphasized two approaches: (1) assembling larger and more diverse genomic datasets and (2) developing increasingly sophisticated statistical models to account for the complex relationships among genotypes, phenotypes, and environments. Although these approaches can substantially improve predictive performance across populations, we argue that limited portability is not merely a temporary consequence of unrepresentative datasets or inadequate statistical methods. Rather, it reflects fundamental properties of genotype–phenotype relationships that impose enduring constraints on genomic prediction. We argue that genomic predictors capture statistical relationships contingent on the genetic, environmental, and developmental contexts in which they are derived. These relationships are not fixed or universal: they emerge from complex interactions among factors whose distributions, effects, and interactions vary across populations and change over time. Consequently, even increasingly comprehensive datasets and sophisticated models cannot establish a universally stable, context-independent mapping from genotype to complex phenotype. We conclude that the portability problem is not simply an unresolved technical challenge, but an inherent and ineliminable feature of genotype-phenotype prediction. Although the boundaries of portability can be continually expanded, the problem itself can never be fully resolved. In this sense, the portability problem is not temporary but permanent—not merely difficult to solve, but impossible to eliminate in principle. Paper by Lucas J. Matthews and Eric Turkheimer

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