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Questions and Answers
What is the primary organ affected by the Mendelian disease cystic fibrosis?
What is the primary organ affected by the Mendelian disease cystic fibrosis?
Which of the following complex diseases is NOT mentioned in the learning objectives?
Which of the following complex diseases is NOT mentioned in the learning objectives?
What is the expected life expectancy of an individual with cystic fibrosis?
What is the expected life expectancy of an individual with cystic fibrosis?
What is the term for a disease that is influenced by a single gene?
What is the term for a disease that is influenced by a single gene?
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What is the pattern of segregation in families that indicates a Mendelian disease?
What is the pattern of segregation in families that indicates a Mendelian disease?
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What is the primary cause of lung disease in cystic fibrosis?
What is the primary cause of lung disease in cystic fibrosis?
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What does the higher concordance of disease in monozygotic twins compared to dizygotic twins imply?
What does the higher concordance of disease in monozygotic twins compared to dizygotic twins imply?
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What type of disorders are characterized by rare variants and a single gene?
What type of disorders are characterized by rare variants and a single gene?
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What is the approximate frequency of BRCA1 mutation carriers in European populations?
What is the approximate frequency of BRCA1 mutation carriers in European populations?
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What is the P-value threshold for significance in the study of BRCA1 and BRCA2?
What is the P-value threshold for significance in the study of BRCA1 and BRCA2?
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What type of study dominated early genetic studies of complex diseases?
What type of study dominated early genetic studies of complex diseases?
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What is the estimated penetrance of BRCA1 by age 70?
What is the estimated penetrance of BRCA1 by age 70?
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What is the characteristic of the genetic effects involved in polygenic disorders?
What is the characteristic of the genetic effects involved in polygenic disorders?
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What is the estimated frequency of BRCA2 mutation carriers in European populations?
What is the estimated frequency of BRCA2 mutation carriers in European populations?
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What is the primary characteristic of complex diseases in terms of their inheritance pattern?
What is the primary characteristic of complex diseases in terms of their inheritance pattern?
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What is the purpose of twin studies in assessing the genetic contribution to a disorder?
What is the purpose of twin studies in assessing the genetic contribution to a disorder?
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What is the estimate of heritability of schizophrenia?
What is the estimate of heritability of schizophrenia?
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What is the primary goal of family studies in understanding the genetic contribution to a disorder?
What is the primary goal of family studies in understanding the genetic contribution to a disorder?
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What is true about most diseases with a considerable public health impact?
What is true about most diseases with a considerable public health impact?
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What is the characteristic of complex diseases in terms of the number of genes that contribute to disease risk?
What is the characteristic of complex diseases in terms of the number of genes that contribute to disease risk?
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What was the requirement for genome-wide association studies to emerge?
What was the requirement for genome-wide association studies to emerge?
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What is the primary advantage of next-generation sequencing studies?
What is the primary advantage of next-generation sequencing studies?
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What was the outcome of the genome-wide association study by Nikpay et al. in 2015?
What was the outcome of the genome-wide association study by Nikpay et al. in 2015?
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What is the threshold p-value used to determine significance in genome-wide association studies?
What is the threshold p-value used to determine significance in genome-wide association studies?
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What is the effect of each SNP associated with coronary artery disease?
What is the effect of each SNP associated with coronary artery disease?
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What is the current understanding of the genetic component of coronary artery disease?
What is the current understanding of the genetic component of coronary artery disease?
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What is the current limitation of genome-wide association studies?
What is the current limitation of genome-wide association studies?
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What is the goal of combining information across SNPs?
What is the goal of combining information across SNPs?
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What is the primary limitation of polygenic risk scores?
What is the primary limitation of polygenic risk scores?
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What is the purpose of examining genetic and environmental factors in epidemiological studies?
What is the purpose of examining genetic and environmental factors in epidemiological studies?
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What is the definition of 'low genetic risk' in the context of coronary artery disease?
What is the definition of 'low genetic risk' in the context of coronary artery disease?
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What is the effect of a high genetic risk score on the risk of coronary artery disease?
What is the effect of a high genetic risk score on the risk of coronary artery disease?
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What is the benefit of a healthy lifestyle in individuals with high genetic risk?
What is the benefit of a healthy lifestyle in individuals with high genetic risk?
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What is the relationship between genetic and environmental risk factors in predicting coronary disease?
What is the relationship between genetic and environmental risk factors in predicting coronary disease?
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What is a limitation of using genetic and environmental risk factors to predict coronary disease?
What is a limitation of using genetic and environmental risk factors to predict coronary disease?
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What is a characteristic of complex diseases?
What is a characteristic of complex diseases?
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What is the significance of 'penetrance' in the context of complex diseases?
What is the significance of 'penetrance' in the context of complex diseases?
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What is the pattern of inheritance of complex diseases?
What is the pattern of inheritance of complex diseases?
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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
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Description
This quiz covers the concept of complex genetic disorders, including genetic and environmental factors that contribute to common diseases.
