Do individuals with low polygenic risk scores have disadvantages?

A news article in this week’s Nature suggests that it is urgent to determine if very LOW polygenic risk scores for some diseases might be associated with disadvantages. The article reports that three companies now offer pre-implantation genetic testing using polygenic scores (PGT-P) to test embryos conceived by in-vitro fertilization. One cell from each of several  embryos is removed at the 8 cell stage and sequenced. The embryo with the lowest polygenic score for multiple diseases, including schizophrenia and diabetes, is implanted. This arouses many practical, scientific, and ethical issues, but an evolutionary medicine perspective suggests another reason to proceed with caution and a needed study.

Many have suggested that alleles associated with schizophrenia and other highly heritable diseases might somehow give advantages. The overall evidence seems to me to indicate that they are just deleterious variations that disrupt the delicate process of brain development. However, it remains possible that selection for mental performance has set the system at a performance peak that is intrinsically vulnerable to failure. If that is the case, then individuals with the lowest polygenic scores could have deficits. If they are just fine or better than fine, as I expect, that should put the kibosh on the idea that there is anything beneficial about alleles that increase the risk of schizophrenia. I have been encouraging geneticist friends who know how to use the UK BioBank data to do the study.

A related preprint posted on medRxiv June 23, 2022, uses UK BioBank data to estimate the potential benefits enjoyed by the individual with the lowest polygenic risk of 20 diseases in a group of five randomly selected individuals. They estimate that the fortunate individual will enjoy an additional three disability-adjusted-lost-years of life (DALY). More important, they report no evidence that the individuals with the lowest risk scores have increase risks of other diseases. “We found no statistical evidence for strong antagonistic trade-offs in risk reduction across these diseases. Correlations between disease risks are found to be mostly positive, and generally mild.”

However, these global correlations do not answer the question of whether individuals with the lowest polygenic risk for specific diseases, such as schizophrenia, have advantages or disadvantages related to other traits such as intelligence or other abilities. I hope someone will carry out the study soon. If the results match my expectations–no disadvantages associated with low polygenic risk scores–that will provide strong disconfirmation for hypotheses that have circulated for years. However if there are any associated disadvantages, that would be profoundly important.

Illustration by Paweł Jońca

Kozlov, M. (2022, September 22). The controverisal embryo tests that promise a healthy baby. Nature, 609, 668–671.

Widen, E., Lello, L., Raben, T. G., Tellier, L. C. A. M., & Hsu, S. D. H. (2022). Polygenic Health Index, General Health, Pleiotropy, Embryo Selection and Disease Risk (p. 2022.06.15.22276102). medRxiv. https://doi.org/10.1101/2022.06.15.22276102