Screening Human Embryos for Polygenic Traits Has Limited Utility

Ehud Karavani; Or Zuk; Danny Zeevi; Nir Barzilai; Nikos C Stefanis; Alex Hatzimanolis; Nikolaos Smyrnis; Dimitrios Avramopoulos; Leonid Kruglyak; Gil Atzmon; Max Lam; Todd Lencz; Shai Carmi

doi:10.1016/j.cell.2019.10.033

Screening Human Embryos for Polygenic Traits Has Limited Utility

Karavani E, Zuk O, Zeevi D, Barzilai N, Stefanis NC, Hatzimanolis A, Smyrnis N, Avramopoulos D, Kruglyak L, Atzmon G, Lam M, Lencz T, Carmi S

Published November 27, 2019 Cell

DOI 10.1016/j.cell.2019.10.033 PMID 31761530 PMC PMC6957074

RRM Academy Synopsis

Polygenic Screening of Five Embryos Is Predicted to Add About 2.5 cm

Average predicted height gain from choosing among five embryos is about 2.5 cm. The comparison is the average embryo, and the predicted IQ gain is about 2.5 points. The 2019 study combined a statistical model, simulated embryos, and 28 large families. Gains in individual families varied widely around the averages.

Key Findings

With five viable embryos, the predicted gain from selecting the top-scoring embryo is about 2.5 cm of height and about 2.5 IQ points.
Selecting among 10 embryos gives a mean gain of about 3 cm or 3 IQ points. With 1000 embryos the gain would be only about 1.7 times higher than with 10.
The polygenic scores explained 24.8% of height variance in the Longevity cohort and 4.3% of IQ variance in the ASPIS cohort of 919 young Greek men.
Among 28 large families, the offspring with the highest height score was the tallest sibling in 7 of 28 families and shorter than the family average in 5 of 28.
Even if scores and parental heights together explained the full heritability of height, the 95% prediction interval would remain about ±5 cm around any predicted gain.

Interpretation

The study used modeling and simulation. No embryos were screened and no children were born after selection. Height simulations drew on 102 couples, and IQ simulations paired 919 young Greek men at random. The family analysis treated adult siblings from 28 families as if they were embryos. The authors state that the model, which leaves out assortative mating, gives an upper bound. They add that polygenic scores can lose power across populations and predict less accurately within families. Because IQ is genetically positively correlated with autism and anorexia, they expect selection for higher predicted IQ to increase the risk of both.

RRM Context

The authors describe IVF as invasive, with substantial discomfort for the mother and significant financial cost. IVF goes around infertility and leaves the reason conception fails unsolved. Ranking embryos adds one more selection step. Restorative reproductive medicine evaluates both partners and treats the cause of infertility, so conception can proceed without ranking embryos.

Our editorial summary of this paper, not the article's abstract.

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.

Ehud Karavani, Or Zuk, Danny Zeevi, Nir Barzilai, Nikos C Stefanis, Alex Hatzimanolis, Nikolaos Smyrnis, Dimitrios Avramopoulos, Leonid Kruglyak, Gil Atzmon, Max Lam, Todd Lencz, Shai Carmi

E Karavani, O Zuk, Daniel Zeevi, D Zeevi, N Barzilai, N Stefanis, Alexander Hatzimanolis, Alexandra Hatzimanolis, A Hatzimanolis, N Smyrnis, D Avramopoulos, L Kruglyak, G Atzmon, M Lam, T Lencz, S Carmi

PMID 31761530 31761530 DOI 10.1016/j.cell.2019.10.033 10.1016/j.cell.2019.10.033 Karavani et al. 2019, Karavani 2019

Screening Human Embryos for Polygenic Traits Has Limited Utility

Polygenic Screening of Five Embryos Is Predicted to Add About 2.5 cm

Key Findings

Interpretation

RRM Context

Abstract

By this author

Promises and pitfalls of preimplantation genetic testing for polygenic disorders: a narrative review

Utility of polygenic embryo screening for disease depends on the selection strategy

Finding the missing heritability of complex diseases

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