Multifactorial Inheritance

Question 1

What is the threshold model conditions?

What is an example?

Answer 1

• Some disease are only present or absent, liability distribution, creation of a threshold of liability (Limit the separates normal from affected, may differ by sex or other factor)
• Ex. Pyloric stenosis (seen in 1/200 males and 1/1,000 females)

Question 2

What are some relative recurrence risks?

Answer 2

• Higher if more than one affected family member
• Higher if proband is more severely affected
• Decreases rapidly with more distant relationship
• Risk to siblings and offspring is square root of population risk (Rough estimate)

Question 3

What is locus heterogeneity?

Answer 3

• Mutation in different genes have similar phenotype.
• Different families have different mutations
• In any one family a single mutation in single gene.

Question 4

What are twin studies used for?

• Concordant vs. Discordant?
• When do you use the concordance rate?
• When do you use the intraclass correlation?

Answer 4

• Determine relative recurrence rate of trait
• Concordant - both affected, Discordant- one affected, one not.
• Concordance rate - for qualitative traits
• Intraclass correlation (how strongly people in the same group resemble each other) - for quantitative traits

Question 5

What do you use to find genes in multifactorial inheritance and what is the process?

Answer 5

• Quantitative Trait Loci (QTLs) -
  1) Use a pop. with affected and unaffected
  2) Perform a genome scan (VNTR, SNP,etc)
  3) Compare alleles at each locus with trait
  4) Locate regions which correlate with trait
  5) Screen region for candidate genes

Question 6

What Alternative method can be used to look for a gene?

Answer 6

• Affected sib-pair method:
  1) 2 sib affected
  2) Share 50% of genes causing effect
  3) Must share genes causing effect
  4) Use pairs from many families
  5) Compare to each other, unaffected sibs
  6) Find regions in common

Question 7

What are three main diseases with multifactorial genetics?

Answer 7

Heart disease, Hypertension, Diabetes

Question 8

What are the risk factors for more severe heart disease?

What is the genetic factor in heart disease?

Answer 8

• More affected relatives
• Affected relative is female (less affected sex)
• Early age of onset for affected relative
• Familial hypercholesterolemia

Question 9

What type of inheritance is familial hypercholesterolemia?
- What symptoms does it produce?
-

Answer 9

• Autosomal Dominant
• double serum cholesterol levels
• accelerates atherosclerosis and produces xanthomas.

Question 10

What are the five classes of LDL mutations?

Answer 10

Class I - no protein found
Class II - Cannot leave ER, degraded
Class III - Cannot bind LDL
Class IV - Do not migrate to coated pits (rare)
Class V - Cannot dissociate from LDL, not recycled to cell surface

Question 11

What are 3 types of therapies for hypercholesterolemia?

Answer 11

1) Decrease intake of cholesterol and fats
2) Bile-acid binding resins (liver increases synthesis of LDLR and cholesterol, limits recycling from intestine)
3) Statins block cholesterol synthesis by targeting HMG CoA reductase activity.
* **Combination therapy is best so far.

Question 12

What are the genetic factors in hypertrophic heart problems?

Answer 12

• autosomal dominant mutations in 10 genes for sarcomere. beta-myosin heavy chain (35%)

Question 13

What are the genetic factors of Dilated heart problems?

Answer 13

• 1/3 familial, autosomal dominant, X-linked and mitochondrial mutations,

Question 14

What are the genetic factors of Long QT?

Answer 14

• potassium and sodium channels screwed up.

Question 15

What are the genetic factors creating a possible risk factor for Stroke?

Answer 15

• MELAS, mutations in NOTCH3, Protein C and S mutations, Factor V Leiden.

Question 16

What does Liddle Syndrome cause and what are its genetic defects?

Answer 16

• Liddle Syndrome causes hypertension, defective epithelial sodium channel (ENaC)

Question 17

What does Gordon syndrome cause and what are its genetic defects?

Answer 17

Gordon syndrome- increased renal salt reabsorption (WNK2 or WNK4 kinases)

Question 18

What is the percentage genetic component of Diabetes Type I.

Answer 18

• 30 to 50% concordant in MZ twins

Question 19

Type I genetic mutations?

Answer 19

Caucasian Type I (95%) HLA, DR3 or DR4
50% of gen pop. DR3 or DR4
No aspartate at position 57 in DQ- 100% risk
-VNTR polymorphism 5’ to insulin gene (may affect insulin transcription

Question 20

Type II genetic mutations?

Answer 20

• Recurrence in first degree relative 10-15%
• diet and lack of exercise implicated
• Mutation in calpain-10
• Mutation in PPAR-y transcription factor gene (increases risk by 25%)

Question 21

What is the only purely genetic form of diabetes?

Answer 21

MODY (Maturity Onset Diabetes of the Young)

Question 22

What percentage of diabetes is autosomal dominant?

What is the mutation in 50% of cases?

Answer 22

• 1-5%

- Glucokinase mutation

Question 23

What are the transcription factors responsible for pancreatic development or insulin regulation?

Answer 23

1) hepatocyte nuclear factor 1-alpha (HNF1a)
2) Hepatic nuclear factor 1-Beta (HNF1B)
3) Hepatocyte nuclear factor 4-alpha (HNF4a)
4)Insulin promoter factor 1 (IPF1)
Neurogenic differentiation I (NEUROD1)

Question 24

What genes are implicated in obesity

Answer 24

• Leptin resistance

- Neuropeptide Y and MCR4 (for appetite control)

Question 25

What genes are suspected to have influence in gaining Alzheimers Disease?

Answer 25

• Presenilin 1 or 2 part of cleavage of APP precursor, gain of function mutants.