Screening Human Embryos for Polygenic Traits Has Limited Utility

Abstract

The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.

Keywords: cognitive ability; complex traits; embryo screening; embryo selection; height; polygenic scores; pre-implantation genetic testing; quantitative genetics.

Figure 1.. The mean gain vs the proportion of the variance explained by the PS.

Blue dots and the 95% confidence intervals (light blue bands) represent simulations with 10 embryos per couple. To generate scores with increasing proportions of variance explained, we gradually added chromosomes 1 to 22 to the computed PS. The orange line corresponds to the theoretical model derived in Methods S1 and described in Eq. (1). For each value of $r_{\text{ps}}^2$, dots are averages and 95% confidence intervals are based on ±1.96 the standard error of the mean over the simulated families. (A) Gain in height for random couples: 500 simulated pairings drawn from the Longevity cohort. (B) Gain in height for actual couples: 102 couples from the Longevity cohort. (C) Gain in IQ for random couples: 500 simulated pairings drawn from the ASPIS cohort. See also Figure S3.

Figure 2.. The mean gain vs the number of embryos.

Blue dots are from simulations, and orange lines are for the theoretical prediction (Eq. (1)). All details are as in Figure 1. See also Figures S1 and S2.

Figure 3.. The distribution of the predicted gain from embryo selection with 10 embryos per couple.

(A) The gain in height by simulating 500 random couples from the Longevity cohort. (B) Same as (A), but with actual spouses (n = 102). (C) The gain in IQ by simulating 500 random couples from the ASPIS cohort. Lines are estimated densities.

Figure 4.. The prediction interval width as a function of the proportion of variance explained by the combination of parental phenotypes and the PS of the child.

If the proportion of variance explained is p, the half-interval width is $1.96{\sigma }_z\sqrt{1-p}$. (A) The prediction interval for height, assuming σ_z = 6cm. The proportion p is unknown, but cannot exceed the heritability, which we assume to be h² ≈ 0.8, and cannot fall under h⁴/2 ≈ 0.32, which is the theoretical variance explained by the mid-parental height. (B) The prediction interval for IQ, with σ_z = 15 points. We assume the heritability is in the range [0.6,0.8], with a minimal variance explained of 0.6²/2 = 0.18.

Figure 5.. An analysis of selection for height in 28 real families with up to 20 adult offspring each.

(A) The realized gain in each family, defined as the difference between the actual (age- and sex-corrected) height of the offspring with the highest PS and the average height of all offspring in the family. The theoretical prediction is based on Eq. (1). (B) The actual height (age- and sex-corrected) of all members of all families. The figure demonstrates the effect of the current low-accuracy prediction models, as the tallest-predicted sibling (red squares) is usually not the actual-tallest sibling (only 7/28 times). Siblings are depicted as grey dots, and the parents of each family as blue triangles. In some families only one parent was available.