Polygenic risk score for embryo selection—not ready for prime time

Abstract

Numerous chronic diseases have a substantial hereditary component. Recent advances in human genetics have allowed the extent of this to be quantified via genome-wide association studies, producing polygenic risk scores (PRS), which can then be applied to individuals to estimate their risk of developing a disease in question. This technology has recently been applied to embryo selection in the setting of IVF and preimplantation genetic testing, with limited data to support its utility. Furthermore, there are concerns that the inherent limitations of PRS makes it ill-suited for use as a screening test in this setting. There are also serious ethical and moral questions associated with this technology that are yet to be addressed. We conclude that further research and ethical reflection are required before embryo selection based on PRS is offered to patients outside of the research setting.

Sibling variation in polygenic traits and DNA recombination mapping with UK Biobank and IVF family data

“…A surprising objection to the use of PGS in the context of IVF is that the variation within families (specifically between siblings) is negligible and therefore it has little utility as a screening mechanism 41 , 42 . For example, in 42 the authors write “It is also important to note that all embryos produced by a couple are genetically related and share on average 50% of SNPs [single nucleotide polymorphism].…”

“…A surprising objection to the use of PGS in the context of IVF is that the variation within families (specifically between siblings) is negligible and therefore it has little utility as a screening mechanism 41 , 42 . For example, in 42 the authors write “It is also important to note that all embryos produced by a couple are genetically related and share on average 50% of SNPs [single nucleotide polymorphism]. One must conclude that owing to inherent limitations of the PRS-ES [polygenic risk score for embryo screening] models and limited variation in the genetic makeup of embryos produced by a couple, the clinical utility of PRS-ES is almost certainly diminutively small”.…”

Sibling Variation in Phenotype and Genotype: Polygenic Trait Distributions and DNA Recombination Mapping with UK Biobank and IVF Family Data

“…A surprising objection to the use of PGS in the context of IVF is that the variation within families (specifically between siblings) is negligible and therefore it has little utility as a screening mechanism [41, 42]. For example, in [42] the authors write…”

“…A surprising objection to the use of PGS in the context of IVF is that the variation within families (specifically between siblings) is negligible and therefore it has little utility as a screening mechanism [41,42]. For example, in [42] the authors write "It is also important to note that all embryos produced by a couple are genetically related and share on average 50% of SNPs [single nucleotide polymorphism].…”

“…A surprising objection to the use of PGS in the context of IVF is that the variation within families (specifically between siblings) is negligible and therefore it has little utility as a screening mechanism [41,42]. For example, in [42] the authors write "It is also important to note that all embryos produced by a couple are genetically related and share on average 50% of SNPs [single nucleotide polymorphism]. One must conclude that owing to inherent limitations of the PRS-ES [polygenic risk score for embryo screening] models and limited variation in the genetic makeup of embryos Siblings Unrelated (a) A trait example: not all siblings are equally tall and can be both taller or shorter than their parents, with typical variance V S = 1 2 V U .…”