Introduction

Genetics predispose people to many common but serious diseases.  While the cause of most diseases is a combination of genetics and environment, research has found high heritability estimates for many high-impact diseases (a disease’s heritability is the proportion of observed variation in disease susceptibility that  can be attributed to genetics):

• Coronary Artery Disease, at 40-60% heritability
• Schizophrenia, at around 80% heritability
• Breast Cancer, at 31% heritability

The biggest concern for many prospective parents is that they will pass to their child a disease that they have suffered or have seen close relatives suffer.  Embryo screening — including Orchid’s polygenic  screening —  gives parents the ability to reduce disease risk in their children.  By testing embryos for their disease risk while conceiving via IVF, parents can choose to implant embryos with a low genetic predisposition to certain diseases.

However, most prospective parents do not know:

• The extent to which certain diseases, including those that run in their family, are genetic,
• What embryo screening is, or how to estimate the disease reduction possible via embryo screening,
• How to combine their family history with their genetics to ask “How much can embryo screening reduce disease risk for children with my family history?”

We want to provide parents with the tools to answer these questions. This post walks through a risk calculator we built to help families understand what is (and isn’t) possible when using Orchid embryo screening to reduce the risk of polygenic inherited diseases.  You can use it here.

An example: a family history of Schizophrenia

Let’s talk about Schizophrenia.

A family history of significant mental health disease is one of the top concerns we hear from prospective families; parents who have a mental health disorder themselves, or have seen family members be impacted, often want to do anything possible to reduce the risk of passing the same disease to their children.  

One of the most common questions is how much Orchid can reduce Schizophrenia risk.  Orchid’s polygenic genetic predisposition screening allows families to screen for Schizophrenia risk, and our risk calculator allows famlies to visualize how embryo screening can aid in reducing the risk of schizophrenia in children:

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The lifetime risk of Schizophrenia is around 1% for the average person in the US — 0.9% in our reference data.  Without any knowledge of family history, a child conceived naturally will have around a .9% lifetime risk of developing Schizophrenia – what you see here as “Random Chance”.

On the right, we show the impact of selecting the embryo with the lowest genetic risk of developing Schizophrenia, by default from a cohort of 5 embryos.  In this case, you can achieve around a 32% relative risk reduction (an absolute risk reduction of about 0.3%).

However, families are usually not worried about reducing the risk of genetic disease in a vacuum. They are worried that their children will inherit a disease that runs in the family — that the parents themselves have or that their parents or siblings were impacted by.  

Let’s walk through an example.  In my family, the maternal grandmother was diagnosed with Schizophrenia, which I would indicate in the family tree:

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Based on my family history, random chance (natural conception) has moved from 0.9% to 3.1%.  This is because schizophrenia is a highly heritable disease (estimated at 70-80%); a single grandparent with Schizophrenia triples the baseline chance. However, with embryo screening, I can reduce my future child's risk of schizophrenia by 29%.   The absolute risk reduction possible from choosing among 5 embryos also roughly tripled, to 0.9%.

Risk reduction changes with the number of viable embryos available. The number of embryos available during an IVF cycle varies significantly with age and health, primarily of the mother. The default is 5 euploid embryos per cycle; however, a healthy young couple undergoing IVF for the purpose of fertility preservation may have significantly more, while an older couple undergoing IVF due to infertility may have significantly fewer.

With embryo screening and prioritizing from 8 embryos instead of 5, I can reduce my future child's risk of schizophrenia by 35% (see below).

In this example, but also in general, couples will see meaningful polygenic risk reduction when prioritizing up to 5 embryos, and can still see increased risk reduction when prioritizing among larger numbers of embryos.

Next steps

• Our risk calculator is available here.  If there are additional diseases or complex family histories you’d like to understand better, please let us know.
• If you’re ready to learn how to use Orchid for embryo screening, or just have questions, get started with a free consultation with one of our board-certified genetic counselors.
• Remember that this simulation does not factor in your personal genetics.  This models the average outcomes we expect for a couple undergoing PGT-P, but the genetics of you and your partner dictate the outcomes on a complex polygenic disease.  If you’d like to learn more about how embryo screening would work for a couple with your genetics, you can get started with our couple report.

Going deeper

How to interpret the average risk reduction

The risk reduction here is an estimate of the risk reduction possible without knowing the genetic risk for specific embryos or parents.  As an example, let’s say we predict that given a specific family history of Coronary Artery Disease, a family can achieve a 35% reduction in risk across 5 embryos.  That means:

• We simulate thousands of families with 5 embryos
• For each family, we take the embryo with the lowest risk, and compare it to the average risk you'd expect from those parents
• The predicted risk reduction is the average reduction, averaging those comparisons across all those families.

The risk reduction each individual family can achieve, after evaluating the genetic risk for their embryos, will differ.  Some families may have a lowest-risk embryo with a 50% risk reduction.  For some families, it may be 20%.  Some families may not see any meaningful reduction.  But on average, the lowest-risk embryo will be 35% below the parents’ baseline risk for Coronary Artery Disease

Whitepaper

These estimates were produced using data from the UK Biobank, an anonymous national database which links individual disease history and their genetic sequences.  You can read about how we modeled disease status and family histories in this whitepaper.

Polygenic vs monogenic disease

It’s important to distinguish monogenic conditions from polygenic disease risk identified during embryo screening.  Orchid’s whole-genome embryo screening performs both, but the results should be interpreted very differently.

Polygenic screening identifies predispositions, which may indicate an embryo carries an elevated or lowered risk compared to the population baseline — the embryo for example may have 1/2 of the baseline population risk, or 2x if it is elevated.  But most children with elevated predispositions will still not experience disease — for example, a child of a parent with Schizophrenia has a highly elevated risk at 8.8%, but that leaves the majority of similar children without a diagnosis.

Orchid’s monogenic screening, on the other hand, identifies specific genetic variants strongly linked to genetic disease by external panels of experts.  Most embryos will not be identified as inheriting monogenic disease; however, when a pathogenic monogenic variant is identified in an embryo, the expectation is that the variant will generally result in disease.

This calculator models only the risk reduction possible via polygenic screening, and does not attempt to capture the disease risk reduction achievable via monogenic screening.  

If your family carries a known monogenic variant linked to disease, you can speak to a genetic counselor about targeted monogenic preimplantation testing (PGT-M) options.

Diseases not modeled

Three diseases included on Orchid’s embryo screening panel are not (yet) modeled here: 

• Type 1 diabetes
• Alzheimer's disease
• Celiac disease

These diseases exhibit what is called Oligogenic inheritance, where the disease is influenced by small numbers of genes — you can think of them as falling somewhere between monogenic disease and polygenic disease.

We don’t model the impact of embryo screening on these diseases here, not because embryo screening is ineffective (it’s actually quite effective compared to highly polygenic diseases) — but because the family history would need to be modeled differently.   We’ll be adding those soon, but in the meantime you can read our whitepapers on our GRS modeling for those diseases:

• Alzheimer’s disease
• Type 1 diabetes
• Celiac disease

What’s possible, and what’s not possible

The goal of embryo prioritization is to reduce absolute disease risk in a child, as compared to natural conception.  In general, when the family history of disease is more severe, the absolute risk reduction achievable via embryo screening is higher.  However, because the absolute risk is significantly elevated, the relative risk reduction possible is generally not higher in these cases.

So it’s important to note that in our example above, prioritizing embryos to reduce the risk of Schizophrenia still ends up with an elevated risk compared to the overall population.  For a family with a highly heritable rare disease like Schizophrenia, embryo screening will often not reduce the average risk for a child to below the population baseline.

In contrast, when prioritizing to reduce the risk of a disease like breast cancer, which (unfortunately) afflicts a large fraction of the general population, it’s plausible for prioritization to outweigh the risk incurred from a family history of disease:

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And last, always remember that polygenic disease screening can lower risk, but is never a promise— an embryo with high genetic risk may manifest a disease, and an embryo at low risk may end up with disease.  If you ever have questions about what this means for your family, reach out to one of our genetic counselors to talk through it. 

Genetic risk and the future

Genetic risk scores are a new science, and are improving every year.  

Genetic risk scores are built from large national databases which combine genetic and health information.  The size and diversity of these databases is increasing rapidly; as a result, the precision of genetic risk scores, and the number of diseases measured by these models, is likewise increasing.

If you are undergoing IVF for the purposes of fertility preservation and retain the raw sequencing data from your embryos, you can prioritize using the genetic risk scores available when you are ready to implant, instead of the ones available today.

When Orchid screens your embryos for disease, we generate raw sequencing data which represents the genetic sequence of each embryo, and on request, you can download this data.  In the future, this data can be used with updated genetic risk models to produce updated genetic risk scores, without re-biopsying your embryos.

Genetic risk scores — today, or in ten years — will always be a tool, not a promise.  To talk through your family plans with a genetic counselor, reach out for a free consultation here.