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Lecture 63 (Human Genetics IV): Multifactorial & Complex Disorders -…

- - - - Polygenic
        quantitative trait loci
      - even monogenic height disorders have variability!
        
        ex: Marfan syndrome
        (taller than avg. pop.); but height varies
      - Environmental Influences
        
        occupation, diet, personal behaviors
        (smoking, ETOH, exercise, etc.)
  - - - Male bias
        
        Sons have the GREATER chance of risk!
      - Male w/malformation
        
        Son: 5.5% risk
        Daughter: 2.4% risk
        
        due to higher threshold for Females!
      - Female w/Malformation
        
        Son: 19.4%
        Daughter: 7.3%
    - - Systolic >130 mmHg
        Diastolic >80 mmHg
      - Guassian distribution
      - Heritability for BP b/w 30-50%
      - Small % of hypertension due to single-gene mutations (Liddle syndrome)
      - Increases risk of organ damage (kidney, cardiac disease)
      - Heritability Penetrance <100% so other factors involved
    - - Insulin resistance
      - 90% of ALL diabetic cases!
      - 2 Major Risk Factors:
        
        Family history
        
        Obesity- increases insulin resistance
      - 70 loci contribute to susceptibility
        
        Variants of TCF7L2 identified in all populations studied
  - - - Factors that can Increase Cancer Risk:
        -age, genetics
        -existence of infectious diseases
        -SES factors (expore/susceptibility)
- - - - Folic Acid (FA) intake
        
        moms w/FA deficiency =/= NTD
        
        moms taking FA can still result in NTD
    - - 1 child with NTD: 5%
      - 2 children with NTD: 10%
      - 3 children with NTD: 21%
      - Rest of the population: 1/1000 (0.1%)
- - - - mutated proto-oncogene
      - increased activity --> increased proliferation
  - - - oncogenes work in dominant fashion
      - Tumor suppressors need different mechanism! --> loss of heterozygosity
        
        "If patient inherits or develops mutation in tumor supp gene, the complementary allele must be deleted/mutated BEFORE cancer develops. This is NOT true of oncogenes
    - - 1:20,000 births
      - Example of tumor suppressor and first to support two-hit hypothesis :!:
      - RB1 gene
      - Retinoblasts normally stop dividing after embryogenesis
      - Results in retinal tumors (intraocular)
      - 90% penetrance
  - - - Rare dominant inherited mutation of p53 - Li-Fraumeni syndrome
      - 50% sporadic cancer include mutations in p53
      - p53 expression induced by DNA damage
      - Can induce apoptosis to stop proliferation of damaged cells
      - Specific nucleotide alterations in p53 shown with benzopyrene
      - Mutagen in cigarette smoke, direct link to lung cancer