The False Dawn of Polygenic Risk Scores for Human Disease Prediction

Abstract

Polygenic risk scores (PRSs) are being constructed for many diseases and are presented today as a promising avenue in the field of human genetics. These scores aim at predicting the risk of developing a disease by leveraging the many genome-wide association studies (GWAS) conducted during the two last decades. Important investments are being made to improve score estimates by increasing GWAS sample sizes, by developing more sophisticated methods, and by proposing different corrections for potential biases. PRSs have entered the market with direct-to-consumer companies proposing to compute them from saliva samples and even recently to help parents select the healthiest embryos. In this paper, we recall how PRSs arose and question the credit they are given by revisiting underlying assumptions in light of the history of human genetics and by comparing them with estimated breeding values (EBVs) used for selection in livestock.

De la salud colectiva a la medicina “personalizada”: desafíos bioéticos de la evaluación genética preimplantatoria desde la perspectiva norte-sur

“…Estos cambios en la forma de decir tienen efectos concretos en las prácticas, por ejemplo, al no tratarse ya de un "diagnóstico" es preciso conocer cómo se realizará la evaluación del riesgo, y qué supone en cada caso presentar un riesgo genético. Esta situación resulta especialmente problemática al haberse expandido los PGT a las condiciones poligénicas, aquellas patologías multifactoriales, en muchos casos de comienzo adulto (como diabetes, hipercolesterolemia o trastornos de salud mental) en las que resulta debatible el peso relativo de los factores genéticos y ambientales, así como la posibilidad concreta de encontrar variantes genéticas causales (17,18) . Este tipo de PGT se asocia a una creciente preocupación por la optimización de la salud y extiende la vigilancia genética a casos en que no existen antecedentes familiares de enfermedad (19) .…”

'Dysgenic fertility' is an ideological, not a scientific, concept. A Comment on: ‘Stability and change in male fertility patterns by cognitive ability across 32 birth cohorts’ (2023), by Bratsberg & Rogeberg

“…Belief (3) has the appearance of a scientific hypothesis but would require a great deal more evidence to function in this way than Bratsberg & Rogeberg [7] provide. Bratsberg & Rogeberg do cite research claiming to find an association between polygenic scores for cognitive ability and fertility [11,12], but polygenic scores do not necessarily capture a causal relationship between genes and a complex trait such as cognitive ability, due to confounding factors such as cultural inheritance, assortative mating, dynastic effects and population stratification, [13][14][15][16]. Genetic and environmental entanglement has plagued behavioural genetic research on intelligence since long before the era of polygenic scores [13,[17][18][19].…”