Multifactorial

Question 1

The majority of human genetic disorders are…

Answer 1

Multifactorial

Within the first few months of his life, a newborn exhibits progressively worsening projectile vomiting, slow growth due to poor absorption of nutrients, and dehydration

Age is the most important risk factor in the development of Alzheimer’s disease

Surgical correction of a developmental abnormality allows a child to lead a more normal life

Most forms of heart disease, cancer, autism, asthma, type-2 diabetes, etc. result from interactions of multiple genes and the environment

Question 2

What are the general types of genetic disorders?

Answer 2

Single gene

• Determined by the alleles at a single locus
• characterized by their patterns of transmission in families
  
  • autosomal dominant
  • autosomal recesssive
  • X-linked dominant or recessive

Chromosomal abnormalities
Mitochondrial

Complex or multifactorial (gene+ environmental)

Question 3

Explain genetic liability

Answer 3

• A curious thing about multifactorial inheritance and disease, it produces a discontinuous phenotype:
  
  • (ie. Affected versus not affected)

-But that is in the context of continuous variation; how?
=liability/ threshold model

-This model attempts to describe a population’s genetic and environmental susceptibility(I.e. likelihood of getting the disease)

Question 4

All factors that contribute to the disease=

Answer 4

= liability produces a normal distribution

At some point there is enough contribution to some underlying quantitative variable to cause expression of abnormal phenotype = threshold

Where an individual sits in this distribution will be a result Of genes AND environment

Question 5

Explain liability in multifactorial diseases

Answer 5

Disease state is determined by both genes and environment

If: you have only “good genes you can have a lot of bad environment and still. Be okay

But- If you start out with some bad genes, it doesn’t take much bad environment to tip you over the edge

Question 6

Explain liability threshold model and familial aggregation

Answer 6

A threshold point for the general population
-But for families with “bad” genes that curve is moved to the right (more of that population is above the threshold point)

• Same thing would be to say the ‘threshold’ line moves to the left
• In effect same thing happens, increased probability of recurrent affected family members

Question 7

The more closely related you are to someone with a multifactorial disorder, the more likely you are to have some of the same alleles…

Answer 7

= familial relative risk

But that risk drops by half fir every degree distance from affected person

Question 8

Explain familial aggregation and relative risk

Answer 8

Familial aggregation of a disease may be estimated by comparing the frequency (prevalence) of the disease in the relatives of an affected pro and with its frequency in the general population

This is the relative risk ratio= (lambda r)

Lambda r= (prevalence of disease in relatives of affected person)/ (prevalence of disease in general population)

Lambda r-sib= relative risk ratio for siblings

Lambda r-parents= relative risk ratio for parent / child tc.

Question 9

What are the characteristics of multifactorial inheritance?

Answer 9

• trait doesn’t demonstrate a simple Mendelian pattern of inheritance
• familial aggregation
• More common among the close relatives of the pro band and less common in relatives who are less closely related
• Environment also interacts with genotype to produce the final phenotype

All consistent with liability/threshold model

Therefore, this model can be used to determine /provide information about recurrence risk in families

Question 10

How does liability threshold model explain pattern of recurrence risk in families?

Answer 10

1. Risk of recurrence is higher in relatives of severely affected individuals
   Overall incidence is 1:1000

(Severely affected patients are likely to have more contributing genes, I.e. at that high end of the liability curve)

2. Recurrence risk in high in close relatives and decreases rapidly in more distant relations (e.g. risk in 1st degree relatives = about 4%, 2nd= 1%, 3rd= about 0.5%) all of these are approximations
3. Greater risk of more than one close relative is affected (multiple affected individuals implies more contributing genes in the family)

This is unlike Mendelian genetics where doesn’t change, e.g.m for autosomal recessive, all offspring of heterozygous parents have 1/4 risk

4. Sex bias May exist (fir example, pyloric stenosis is more frequent in males)

Question 11

Explain the sex bias in pyloric stenosis

Answer 11

Pyloric stenosis= hypertrophy of the muscle (the pylorus ) between stomach and intestines, causing it to narrow (stenosis) impeding gastric emptying

• can cause severe vomitting in babies
• palpitation of the abdomen may reveal a mass in the epigastrium
• May cause other problems such as dehydration and salt and fluid imbalances

Pyloric stenosis is more common in make babies than in females babies (1/200 for males, 1/1000 for females )

Question 12

What is pyloric stenosis?

Answer 12

The threshold for pyloric stenosis, is lower in males than vs females (more males are affected; or, it is easier fir a make to be affected)

• males are more prone to get the condition (I.e. have a lower liability threshold)
• therefore, for a female to be affected, she must be at the high end of the curve (has more ‘contributing’ genes)
• and her sons (or brothers) are more at risk than her daughters. (Or sisters)

Question 13

How can we separate the genetic and environmental factors of the multifactorial diseases?

Answer 13

The probability of developing most common genetic diseases is based on an interplay between genetics and environment

Diseases that you can’t do much about- are mostly genetic like PKU, and galactosemia

But consider PKU: people with pku are fine if they adhere to dietary restriction

Diseases due to environment, can be. Moderated by lifestyle

Question 14

Identifying the genetic component of a complex diseases=

Answer 14

= determining the heretibaility of a disease

Question 15

What are the tools for determining the effects of genetics vs environment?

Answer 15

• population/migration studies
• family studies
• twin studies
• adoption studies
• Association studies

Question 16

How can population/migration factors be indicative of environmental effects?

Answer 16

Disease incidence differences between populations suggest a genetic basis for that disease

However could also be due to cultural/lifestyle differences
E.g. incidence of breast cancer is lowest in Asian women

However…

After immigration to the U.S., the increased to near American levels within one to two generations

Therefore, genetic condition is the same, but lifestyle (environment) is different

Question 17

How can cancer incidence vary by geography?

Answer 17

Australia is very sunny, and the population is very fair skinned, increased risk of skin cancer

People in Japan eat a loaf of fish, increases risk of stomach cancer (involves chemistry of nitrogen compounds)

Question 18

Contrast the types of twins

Answer 18

Monozygotic twins= derived from a single ovum

-genetically identical

Identical twins, same genome

Dizygotic twins=(controls)= derived from two separate ova but share intrauterine environment
-just siblings (about 50% identical)

Fraternal twins, genome same as siblings (50%)

Question 19

Explain The disease concordance for monozygotic twins

Answer 19

Concordance means both twins have the same disease

Discordance means one has it but the other does not

In MZ twins if concordance = 100%, genetically determined; concordance less than 100%, non-genetic factors involved

The greater the difference in concordance rate between MZ and DZ twins= the greater genetic input

Question 20

What are the limitations of twin studies ?

Answer 20

1. May underestimate heritability (only addresses differences between 100% and 50% identical genomes)
2. MZs do have some different genes (e.g. mitochondrial genes) and epigenetic differences, also different accumulation of somatic mutations due to errors in mitosis
3. Different environmental exposures (in utero and development after being born)
4. Different genes in different twin pairs (studies between different sets of twins may point to different contributors for same phenotype)
5. Ascertain ment bias
6. Most studies do NOT specify the loci and alleles but how genotype and environment interact
   - but still a very useful loci

Question 21

What other what are the alternative to twin studies?

Answer 21

Family studies

• similar to twin studies but not as precise
  
  • more genetic variability

Adoption studies

• separation of identical twins= same genes but different environment
  - Can yield good idea, but logistically very difficult

Question 22

Explain association analysis

Answer 22

To test the co-occurrence of a specific allele at a marker locus and a trait in a population by comparing the frequency of an allele in patients and controls

• These association studies compare populations of “cases” to “controls” in attempt to find genetic markers that are more commonly found in an individual with the disorder
• They do not concern familial inheritance patterns; the term used to describe them is called “case-control studies “

Question 23

Explain genome-wide association studies (GWAs)

Answer 23

Association studies meet microarrays

• Hapmap project identified about 500,000 common SNPs, which is a small enough number to fit on a microarray
• GWAS compare the genomes of people with an illness to unaffected people to identify associations between SNPs and phenotype

Question 24

What are the types of neural tubes defect?

Answer 24

Anencephaly

Spina bifida

Both show multifactorial inheritance

Question 25

What is anencephaly ?

Answer 25

- Most severe of the neural tube defects - Rare and it is lethal - Underdeveloped brains and incomplete skulls - May have brain stem function - Most do not survive more than a few hours after birth

Question 26

What is spina bifida?

Answer 26

- Incomplete closure of the spine - Can be quite variable in severity - Repair May sometimes be done in utero or postnatally, but successful outcomes are variable

Question 27

What is evidence of spina bifida (for genetics)?

Answer 27

- Varying prevalence in different human populations - A woman who has had one child with a neural tube such as spina bifida has about 3% risk of having another (much higher than population risk) - Mutations in genes coding enzymes for folate metabolism

Question 28

What are the evidence of spina bifida (for environment)?

Answer 28

- Supplementation of the mother’s diet with folate can reduce the incidence of neural tube defects by about 70% - So, the 3% risk that a woman will have a second child with an NTD can be reduced to 1% with high doses of folic acid