Problems with Using Polygenic Scores to Select Embryos

Patrick Turley; Michelle N Meyer; Nancy Wang; David Cesarini; Evelynn Hammonds; Alicia R Martin; Benjamin M Neale; Heidi L Rehm; Louise Wilkins-Haug; Daniel J Benjamin; Steven Hyman; David Laibson; Peter M Visscher

doi:10.1056/NEJMsr2105065

Research Methods · Evidence Synthesis

Problems with Using Polygenic Scores to Select Embryos

Turley P, Meyer MN, Wang N, Cesarini D, Hammonds E, Martin AR, Neale BM, Rehm HL, Wilkins-Haug L, Benjamin DJ, Hyman S, Laibson D, Visscher PM

Published July 2021 N Engl J Med

DOI 10.1056/NEJMsr2105065 PMID 34192436 PMC PMC8387884

RRM Academy Synopsis

Embryo polygenic scores predict modest gains with wide uncertainty

Picking the top-scoring of 10 same-parent embryos over a random pick is expected to add 0.53 years of education for European ancestry, a 2021 NEJM simulation analysis finds. The authors say this may be a best-case estimate. For those embryos, the 95% prediction interval of the actual gain spans +4.2 years to −3.2 years.

Key Findings

Choosing the highest-scoring of 10 embryos from the same parents is expected to add 0.53 years of education for European ancestries and 0.23 to 0.40 years for the other groups.
The between-family estimate of 1.55 years of education falls to 1.36 years after adjusting for environmental differences, and to 0.53 years for European-ancestry embryos from the same two parents.
For European-ancestry parents, the 95% prediction interval of the actual gain in educational score runs from +4.2 years to −3.2 years of education.
For type 1 diabetes, simulations imply a 35% lower relative risk for European ancestries, which is 0.12 percentage points against a lifetime risk of 0.34%.
With selection on the educational-attainment score, bipolar disorder risk rises 16% in relative terms, from 1.0% to 1.16% in absolute risk.

Interpretation

The paper pairs simulation calculations with an ethical and regulatory argument. The authors built the estimates from data on adults in genome-wide studies. The paper reports no outcomes from children born after embryo selection. For educational attainment, the authors say the values may be considered best-case-scenario estimates because the assumptions favor larger gains. Most scores come from people of European ancestry, and prediction was weaker in other ancestry groups. The authors say the same limits apply to clinical outcomes. They call the service unproved and experimental.

RRM Context

Companies offer embryo selection by polygenic score to patients considering IVF. IVF bypasses the reproductive problem without resolving why conception fails. Restorative reproductive medicine evaluates both partners and treats the cause of infertility. The paper notes that the Federal Trade Commission curbed IVF clinics that gave misleading pregnancy rates in the 1990s and 2000s.

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

Abstract

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).

Topics

Research Methods › Evidence Synthesis › Systematic Reviews · Ethics and Policy › Reproductive Ethics › Embryo Status · Assisted Reproduction › Add-Ons and Adjuncts › Preimplantation Genetic Testing

Patrick Turley, Michelle N Meyer, Nancy Wang, David Cesarini, Evelynn Hammonds, Alicia R Martin, Benjamin M Neale, Heidi L Rehm, Louise Wilkins-Haug, Daniel J Benjamin, Steven Hyman, David Laibson, Peter M Visscher

Pat Turley, P Turley, M Meyer, N Wang, Dave Cesarini, D Cesarini, E Hammonds, A Martin, Ben Neale, B Neale, H Rehm, L Wilkins-Haug, Dan Benjamin, Danny Benjamin, D Benjamin, Steve Hyman, S Hyman, Dave Laibson, D Laibson, Pete Visscher, P Visscher

PMID 34192436 34192436 DOI 10.1056/NEJMsr2105065 10.1056/NEJMsr2105065 Turley et al. 2021, Turley 2021

Problems with Using Polygenic Scores to Select Embryos

Embryo polygenic scores predict modest gains with wide uncertainty

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

Clinical utility of polygenic risk scores for embryo selection: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)

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Finding the missing heritability of complex diseases

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