38 Questions
What is the primary organ affected by the Mendelian disease cystic fibrosis?
Lungs
Which of the following complex diseases is NOT mentioned in the learning objectives?
Diabetes
What is the expected life expectancy of an individual with cystic fibrosis?
40 years
What is the term for a disease that is influenced by a single gene?
Monogenic disease
What is the pattern of segregation in families that indicates a Mendelian disease?
Autosomal recessive
What is the primary cause of lung disease in cystic fibrosis?
All of the above
What does the higher concordance of disease in monozygotic twins compared to dizygotic twins imply?
The contribution of a genetic component to disease risk
What type of disorders are characterized by rare variants and a single gene?
Mendelian disorders
What is the approximate frequency of BRCA1 mutation carriers in European populations?
1 in 1,000 people
What is the P-value threshold for significance in the study of BRCA1 and BRCA2?
5e-08
What type of study dominated early genetic studies of complex diseases?
Candidate gene association studies
What is the estimated penetrance of BRCA1 by age 70?
65%
What is the characteristic of the genetic effects involved in polygenic disorders?
Multiple genes, low penetrance
What is the estimated frequency of BRCA2 mutation carriers in European populations?
1 in 800 people
What is the primary characteristic of complex diseases in terms of their inheritance pattern?
No clear mode of inheritance
What is the purpose of twin studies in assessing the genetic contribution to a disorder?
To compare disease concordance in monozygotic and dizygotic twins
What is the estimate of heritability of schizophrenia?
Around 80%
What is the primary goal of family studies in understanding the genetic contribution to a disorder?
To assess the increased risk to first-degree relatives of cases
What is true about most diseases with a considerable public health impact?
They have a genetic component
What is the characteristic of complex diseases in terms of the number of genes that contribute to disease risk?
Multiple genes contribute to disease risk
What was the requirement for genome-wide association studies to emerge?
Knowledge of millions of SNP markers
What is the primary advantage of next-generation sequencing studies?
The ability to test each causal variant directly
What was the outcome of the genome-wide association study by Nikpay et al. in 2015?
Identified 58 SNPs associated with coronary artery disease
What is the threshold p-value used to determine significance in genome-wide association studies?
P = 5 x 10^-8
What is the effect of each SNP associated with coronary artery disease?
A small effect on disease risk
What is the current understanding of the genetic component of coronary artery disease?
Many SNPs have a small effect on disease risk
What is the current limitation of genome-wide association studies?
They are not able to detect rare variants in genes
What is the goal of combining information across SNPs?
To estimate disease risk
What is the primary limitation of polygenic risk scores?
They are not able to explain all the heritability of complex traits
What is the purpose of examining genetic and environmental factors in epidemiological studies?
To examine how genetic and environmental factors contribute to the risk of coronary disease
What is the definition of 'low genetic risk' in the context of coronary artery disease?
Lowest 20% of the genetic risk score
What is the effect of a high genetic risk score on the risk of coronary artery disease?
It increases the risk of coronary artery disease
What is the benefit of a healthy lifestyle in individuals with high genetic risk?
It can protect against coronary artery disease
What is the relationship between genetic and environmental risk factors in predicting coronary disease?
They work together to predict coronary disease
What is a limitation of using genetic and environmental risk factors to predict coronary disease?
They are not predictive enough for an individual's risk
What is a characteristic of complex diseases?
They involve many genetic loci and the environment
What is the significance of 'penetrance' in the context of complex diseases?
It is the probability of developing a disease given a certain genotype
What is the pattern of inheritance of complex diseases?
Complex
Study Notes
Complex Disease Genetics
- Complex diseases are influenced by many genetic and environmental factors
- Examples of complex diseases: Alzheimer's disease, breast cancer, coronary disease, inflammatory bowel disease, depression, schizophrenia, multiple sclerosis, asthma, rheumatoid arthritis, diabetes, SLE(Lupus), and heart disease
Defining Complex Disease
- Complex diseases have a raised risk in families, but the increase in risk may be slight compared to the population risk
- No clear mode of inheritance
- Multiple genes contribute to disease risk
- Environmental effects may also contribute
- Gene-gene and gene-environment interactions are involved
Assessment of Genetic Contribution to a Disorder
- Twin studies: comparing disease concordance in monozygotic (MZ) and dizygotic (DZ) twins
- Heritability: the proportion of the total variance of a trait caused by additive genetic factors
- Family studies: assessing the increased risk to first-degree relatives of cases compared to the population risk
Spectrum of Genetic Effects
- Rare variants: Mendelian disorders, single-gene disorders (e.g., Cystic Fibrosis, Huntington's disease)
- Common variants: polygenic susceptibility to most disorders (e.g., breast cancer, Alzheimer's disease, coronary disease)
- Mix of common and rare variants: some complex diseases (e.g., schizophrenia, rheumatoid arthritis)
Breast Cancer
- Major genes: BRCA1, BRCA2
- High penetrance: 65% penetrance by age 70 for BRCA1, 45% for BRCA2
- Approximately 1 in 1000 people are carriers of a BRCA1 mutation, and 1 in 800 people are carriers of a BRCA2 mutation
A Brief History of Complex Disease Mapping
- Candidate gene association studies (1950s-1980s)
- Linkage studies (1980s-1990s)
- Genome-wide association studies (2005 onwards)
- Next Generation Sequencing studies (2010 onwards)
Example: Coronary Artery Disease (CAD)
- Genome-wide association study: 60,801 CAD cases and 123,504 controls
- Identified 58 SNPs associated with CAD
- Each SNP increases risk only slightly
- CAD risk is the cumulative effect across SNPs
Polygenic Risk Scores (PRS)
- Combining information across SNPs to estimate disease risk
- Not yet showing clinical utility due to incomplete explanation of heritability and incomplete understanding of environmental risk
Coronary Artery Disease (CAD) Risk Factors
- Genetic and environmental risk factors work together to predict CAD risk
- Cumulative effect across both sources
- Genes: polygenic risk scores from 52 variants associated with heart disease
- Environment: score 1 for each factor: current smoking, obesity, unhealthy diet, physical activity less than once weekly
This quiz covers the concept of complex genetic disorders, including genetic and environmental factors that contribute to common diseases.
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