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Genetics L1 > Lecture 15 - complex diseases > Flashcards

Lecture 15 - complex diseases Flashcards

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1
Q

What is a complex disease?

A
  • complex diseases are common (66% lifetime risk)
  • multifactorial
  • i. polygenic
  • ii. environmental

Identified risk alleles susceptibility - are NOT deterministic

Are familial

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2
Q

What are examples of complex diseases?

A
  • Obesity
  • Rheumatoid arthritis
  • Insulin dependent diabetes (Type 1)
  • Insulin independent diabetes (Type 2)
  • multiple sclerosis
  • premature cardio-vascular disease
  • epilepsy
  • peptic ulcer
  • hyperthyroidism
  • certain cancers
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3
Q

What are complex psychiatric conditions?

A
  • Alzheimer’s
  • Bipolar affected disorder
  • Depression
  • Tourette’s syndrome
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4
Q

What are complex congenial disorders?

A
  • cleft lip & palate
  • neural tube defects
  • pyloric stenosis
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5
Q

Why identify genetic components of complex diseases?

A
  • early diagnosis and treatment
  • will allow lifestyle changes to lower risk
  • help understand the molecular basis to develop therapeutics
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6
Q

Describe how we identify susceptibility or risk alleles

A
  • 11-15 million common variants - single nucleotide polymorphisms (SNPs)
  • SNPs found in both coding and non-coding regions of genome
  • Minor allele frequency (MAF) is the second most common allele in a population
  • Common SNP’s MAF >5%
  • Rare SNPs MAF <5%
  • the risk conferred by each SNP can be small
  • correlation between genotype and disease phenotype can be weak
  • identifying alleles which increase risk requires large number of individuals
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7
Q

What are 2 methods to find risk alleles in complex disease?

A
  • Family based Linkage analysis
  • Genome-wide association studies (GWAS)
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8
Q

What is family based linkage analysis as a method to find risk alleles in complex disease?

A

looks for linkage between mapping markers and occurrence of disease in families

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9
Q

What is a negative about family based linkage analysis?

A

usually has a small sample size

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10
Q

What is genome-wide association studies (GWAS)?

A
  • search for alleles in a population that occur more frequently in disease cases then in matched controls
  • more powerful at identify rare risk alleles and those that contribute a small increase in risk
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11
Q

What is phenotypic variation?

A

the sum of genetic and environmental variation

phenotypic variance = genetic variance + environmental variance

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12
Q

What is heritability?

A

the degree of variation within a population that is due to genetic variance

Heritability = Genetic variance/Phenotypic variance

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13
Q

Is heritability of a disease a fixed number?

A

no, as it can change depending on population assessed and the environment they are in

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14
Q

What does a higher heritability score mean?

A

a higher heritability score - the greater the genetic contribution. However, environmental factors can still influence likelihood of disease

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15
Q

How can heritability be experimentally determined?

A

Twin studies allow the effect of genetics (heritability) and environment on phenotypic variance

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16
Q

What are the 2 types of twin studies?

A
  • monozygotic twins (MZ)
  • dizygotic twins (DZ)
17
Q

Describe monozygotic twins

A
  • identical twins
  • share - 100% of genes
  • shared environment
18
Q

Describe dizygotic twins

A
  • non-identical twins
  • share - 50% of alleles
  • shared environment

Assume equal environment influence for identical & non-identical twins

19
Q

Describe twin studies

A

ACE model of phenotypic variance - what proportion of variance is genetic & environmental
- Genetic variance of heritability (A)
- Common environment variance (C)
- Specific environmental variance (E)

20
Q

What is concordance in twin studies?

A

the % of identical or non-identical twins that share phenotype/disease

21
Q

What is the correlation of Monozygotic twins?

A

Genetic (100%) + C (common environment)

22
Q

What is the correlation of Dizygotic twins?

A

Genetic (50%) + C (common environment)

23
Q

What is concordance a measure of?

A

Difference in concordance between indelicate and non-identical is a measure of the effect of 50% of genes on variation in the population

  • the greater the difference in concordance between mono and dizygotic twins, the greater the heritability of the trait
24
Q

Describe phenotypic variation in complex disease

A
  • most phenotypes show a continuous variation (e.g. height)
  • threshold for developing disease
25
Q

How do most phenotypes show a continuous variation (e.g. height)?

A
  • some complex disease also show a spectrum of variation
  • disease is controlled by multiple polygenes
  • each allele segregates according to Mendelian laws
  • Many polygenes + environment –> continuous phenotypic variation
26
Q

How is there a threshold for developing disease?

A
  • most diseases are discontinuous
  • an individual either has or doesn’t have the condition
27
Q

How can polygenic diseases show a continuous phenotype?

A
  • continuous phenotype variation can arise
  • in complex diseases many loci may contribute to this variation, leading to broad range of phenotypic variation
  • environmental factors will also affect phenotype; the same genotype will display different phenotypes
  • not all alleles will contribute the same risk
  • an increase in the number of loci, the greater the distribution of variation
28
Q

Do all alleles contribute the same amount of risk?

A

No - environmental factors can affect phenotype

29
Q

How can complex diseases show a continuous phenotype?

A
  • identified 44 significant risk loci for major depression
  • all humans carry greater or lesser numbers of genetic risk factors
  • associated with clinical features and included drug targets
30
Q

What is the hypothesis for disease susceptibility?

A
  • most diseases phenotypes are discontinuous
  • polygenes and environment produce a distribution of liability
  • the disease occurs when liability produce a distribution of liability
  • the disease occurs when liability exceeds threshold
  • relatives of affected individuals have an increased risk
31
Q

What is evidence of threshold hypothesis?

A

Pyloric stenosis
- projectile vomiting after feeding in infants
- 5 times more common in male infants
- females have a higher liability threshold than males
- affected females carry more risk alleles
- relatives of affected females have greater risk than relatives of affected males

32
Q

What are different possible architecture of complex diseases?

A
  • small number of dominant alleles confer a larger risk - Parkinson’s
  • common disease, common variant model (CDCV) - many alleles confer a small increase in risk - Type 2 diabetes
  • intermediate - one major allele exerts a large effect, numerous lower risk alleles - breast cancer

Genetics L1 (19 decks)

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