4 Multifactorial Inheritance

  1. Multifactorial Inheritance
    many factors are involved in causing a birth defect

    • combined contribution of genes & environmental factors in the causation of a disease or trait
  2. Trait
    distinct variant of a phenotypic characteristic that may be inherited
  3. Single Gene Trait
    Mendelian or monogenic; results from the influence only one gene
  4. Polygenic Trait
    results from the combined influence of multiple genes
  5. Multifactorial Trait
    results from the combined influence of multiple genes & environmental factors
  6. Quantitative Traits
    • • have a continuous range of measurement, are measured on a numerical scale
    • • result from the additive effect of multiple genetic & environmental factors
    • • follows a normal bell-shaped distribution in populations

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  7. What are examples or Quantitative Traits?
    height, weight, blood pressure, intelligence
  8. Threshold Traits
    • • trait is either present or absent
    • • bell-shaped distribution of liability
    • • individuals exceeding the threshold on the liability scale will express the trait
  9. What are examples or Quantitative Traits?
    • PYLORIC STENOSIS, club foot, diabetes, cleft lip & palate
    • • person either will or won’t express a trait; if they exceed a particular threshold he or she WILL develop the trait
  10. Liability
    • total combined genetic & environmental factors that influence the development of a multifactoral disorder or trait

    • observed rather than measured

    • determined from the incidence of the disease in a group
  11. What are signs of multifactorial inheritance?
    1. familial concentration of a disease or trait without a clear Mendelian pattern of inheritance

    2. no clear biochemical defects resulting from a single abnormal gene

    3. significant variation in severity & expression of the phenotype

    4. gender differences in the frequency with which the trait or disease occurs
  12. Pyloric Stenosis (PS)
    more likely to be seen in males

    • for a male to cross the threshold, they need a lower number of genetic and/or environmental factors to have this trait

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  13. Cleft Lip & Palate
    more likely to be seen in males

    • cleft lip: opening in the lip

    • cleft palate: opening in the roof of the mouth
  14. Congenital Hip Dysplasia
    more likely to be seen in females

    eg. females may only take 6 factors to develop hip dysplasia; a male might need 8 to develop the trait
  15. X-linked Recurrence Risk
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  16. Multifactorial Inheritance Recurrence Risk Rules
    • • the greater the severity, the higher the recurrence risk
    • - if something looks worse, it’s likely that there are more genes contributing to that disease

    • recurrence risk is higher if more than 1 family member is affected

    • recurrence risk decreases rapidly in more remotely related individuals

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    • recurrence risk is greater if the proband is of the LESS commonly affected sex
  17. For a disease that follows a multifactorial inheritance pattern, what is the recurrence risk for a 1st degree relative?
    the square root of the population incidence of the trait

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  18. What is the recurrence risk for most isolated birth defects?

    however if the birth defect is part of an underlying genetic syndrome, the recurrence risk would be much higher (autosomal dominant) or lower (Down Syndrome)
  19. Heritability
    • can estimate heritability by measuring the frequency of a trait in related individuals

    • essentially seeing how much genetics contributes to a disorder by observing familial aggregation
  20. Twin Studies & Heritability
    • monozygotic twins share 100% of their genetic information; dizygotic twins share 50% of genetic information (siblings born at the same time)

    • concordance rates in monozygotic twins can be compared to those in dizygotic twins to estimate the Heritability of a trait

    • the greater the percentage of concordance within monozygotic twins, the more a multifactorial trait is based on genetics
  21. What can you infer if monozygotic twins share a trait MORE often than dizygotic twins?
    that the trait is influenced by genetic factors
  22. What is the value of heritability always between?
    0 & 1

    • multifactorial traits have <100% concordance in MZ twins, however MZ concordance will be greater than DZ concordance

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    ~ highly unlikely Measles is caused by a genetic factor (concordance rates are so close)

    ~ h2 of BMI suggests genetics play a role
  23. How to Calculate Heritability (h2)
    h2 = (MZ condord - DZ condord) * 2
  24. How to Calculate Concordance
    # of all concordant pairs / total # of twin pairs
  25. What are MZ & DZ concordance values if a condition is 100% genetic?
    • MZ concordance = 1
    • DZ concordance = 0.5

    • to calculate heritability, h2 = (1 - .5)*2 = 1
  26. Linkage Analysis
    determines whether the inheritance of a genetic marker predisposes to a particular disease/trait in a family

    • goal is to identify a region of the genome where a candidate disease allele could be found
  27. Recombination Frequency
    by calculating you can determine how far apart loci are
  28. LOD Score
    used to assess the strength of evidence for linkage

    • LOD > 3 → linked

    • LOD < -2 → not linked
  29. Association Studies
    • used to identify specific alleles for a particular disease/trait within an already designated gene region

    • operates based on the hypothesis that a particular allele occurs more frequently in individuals with the disease than in controls
  30. What are the limitations of Association Studies?
    • association of an allele with a phenotype does not prove that one causes the other

    • multiple SNPs are needed because the marker allele needs to be closely linked to the disease locus

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    • extract DNA from a group of people with a disorder & run it on an array; do the same thing with a control population & hope the resulting patterns differ (this is only going to work if the only difference between people is the disease or trait!)
  31. Breast Cancer as a Multifactorial Disease
    • majority of breast cancer is sporadic

    • only 5-10% of breast cancer is due to an inherited mutation (eg. BRCA, p53, PTEN)
  32. What percent of breast cancer is familial?

    • there can be a strong family history of cancer but no identifiable genetic change

    • risk doubles with 1 affected family member

    • risk increases further with more affected relatives OR earlier age of onset
  33. What are environmental factors that can increase a woman’s risk of getting breast cancer?
    • • nulliparity (no children)
    • • delivering 1st child after 30 yrs
    • • high fat diet
    • • EtOH
    • • estrogen replacement therapy
  34. Alzheimer’s Disease
    • risk of developing Alzheimer’s doubles in individuals with an affected first-degree relative
  35. What protein has been studied extensively as a risk factor for Alzheimer’s?
    Apolipoprotein E

    • • 3 major alleles: ε2, ε3, ε4 (ε4 has the strongest association with Alzheimer’s)
    • • 1 copy of ε4 allele increases risk 2-5x
    • • 2 copies increases risk 5-10x
Card Set
4 Multifactorial Inheritance
Genetics Exam 1