Complex Disease and Polygenic Risk Scores ~Direct-to-Consumer Genetic Testing~ (23andMe)

Summary

This video explores the role of genetics in determining health, focusing on monogenic and polygenic conditions. Monogenic conditions, like cystic fibrosis, have clear genetic causes, while polygenic conditions, such as heart disease and cancer, are influenced by many genetic variants and environmental factors. Polygenic risk scores, developed through genome-wide association studies, estimate the genetic risk for complex conditions. The video also discusses how these scores can aid in risk assessment, diagnosis, and treatment, and highlights their limitations, particularly regarding diverse populations and incomplete genetic data.

Takeaways

• 😀 Genetic testing can identify monogenic conditions caused by a single genetic variant, such as cystic fibrosis and Huntington's disease.
• 😀 Complex health conditions, like heart disease and cancer, are influenced by multiple factors, including genetics, environment, and lifestyle.
• 😀 Polygenic conditions are caused by the combined effect of many genetic variants, each contributing a small effect but collectively influencing risk.
• 😀 Heritability measures the proportion of variation in a health condition due to genetic factors, usually determined through twin studies.
• 😀 Genetic liability refers to the cumulative effect of genetic factors on a person's risk for a condition, with higher liability indicating higher risk.
• 😀 Polygenic risk scores (PRS) combine genetic variants to estimate a person’s risk for complex conditions, offering a more personalized approach to risk assessment.
• 😀 PRS are calculated using data from genome-wide association studies (GWAS), which identify variants linked to specific conditions.
• 😀 PRS can be used for population screening, personalized prevention strategies, and guiding treatment decisions, such as recommending statins for heart disease.
• 😀 Polygenic risk scores can be reported as relative risk, absolute risk, or percentile rank, each offering a different way to understand genetic risk.
• 😀 Limitations of PRS include their focus on European ancestry in GWAS and the fact that they measure only part of a person’s genetic risk, not all contributing variants.
• 😀 Despite limitations, polygenic risk scores represent an evolving tool in precision medicine and can help tailor healthcare strategies when used with other factors, like lifestyle and family history.

Q & A

What are monogenic conditions and can genetic testing give a clear answer for them?

Monogenic conditions, such as cystic fibrosis, sickle cell anemia, and Huntington disease, are caused by a single genetic variant in a single gene. Genetic testing for these conditions often provides a clear answer, indicating whether a disease-causing variant is present or not.

How are complex or multifactorial health conditions different from monogenic conditions?

Complex or multifactorial conditions, like heart disease, cancers, and mental illnesses, have more complicated causes. They are influenced by multiple genetic factors, environmental influences, lifestyle choices, and demographics, unlike monogenic conditions which are caused by a single genetic variant.

What does 'polygenic' mean, and how does it relate to complex conditions?

'Polygenic' refers to conditions that are influenced by multiple genetic variants. These variants, while individually having small effects, can combine to significantly impact a person's chances of developing a health condition, making these conditions polygenic in nature.

What is heritability and how does it measure the genetic influence on a health condition?

Heritability is a measure of how much the variability in a health condition within a population can be attributed to genetic factors. It is derived from twin studies that compare identical twins, who share all their DNA, to fraternal twins, who share half of their DNA, to estimate genetic influence.

What is genetic liability, and how does it relate to disease risk?

Genetic liability, also known as genetic load, refers to the cumulative effect of genetic factors on a person's risk for a health condition. A higher genetic liability increases the likelihood that an individual will develop a particular condition.

How are polygenic risk scores calculated and what do they represent?

Polygenic risk scores are calculated using data from genome-wide association studies (GWAS), which identify genetic variants associated with specific health conditions. These scores combine the effects of hundreds to thousands of variants, providing a personalized estimate of an individual's risk for complex conditions.

What role do polygenic risk scores play in healthcare?

Polygenic risk scores can be used for population screening to identify individuals at higher risk for conditions like coronary artery disease and prostate cancer. They also help clinicians make decisions about prevention, diagnosis, treatment, and prognosis for patients, enhancing precision medicine.

What is the difference between relative risk, absolute risk, and percentile rank in reporting polygenic risk scores?

Relative risk compares the risk between two groups, showing how much greater or smaller a person’s likelihood of developing a condition is compared to the average. Absolute risk reflects the actual likelihood of developing a condition over a specified time. Percentile rank compares a person's score to the distribution within a population, indicating where they stand relative to others.

What are the limitations of polygenic risk scores?

Polygenic risk scores have limitations, including the fact that they do not capture all genetic variants contributing to complex conditions. They also primarily reflect data from European ancestry populations, which can limit their accuracy for people of other ancestries. Ongoing research aims to improve these scores' applicability to diverse populations.

How do polygenic risk scores complement other risk assessments like family health history?

Polygenic risk scores are just one part of the risk assessment picture. They should be considered alongside family health history, lifestyle factors, and other clinical information to get a more complete understanding of a person’s health risk. While genetics can provide valuable insights, lifestyle changes can still reduce the risk of developing a condition.