Multifactorial Flashcards
The majority of human genetic disorders are…
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
What are the general types of genetic disorders?
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)
Explain genetic liability
- 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)
All factors that contribute to the disease=
= 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
Explain liability in multifactorial diseases
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
Explain liability threshold model and familial aggregation
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
The more closely related you are to someone with a multifactorial disorder, the more likely you are to have some of the same alleles…
= familial relative risk
But that risk drops by half fir every degree distance from affected person
Explain familial aggregation and relative risk
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.
What are the characteristics of multifactorial inheritance?
- 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
How does liability threshold model explain pattern of recurrence risk in families?
- 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)
- 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
- 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
- Sex bias May exist (fir example, pyloric stenosis is more frequent in males)
Explain the sex bias in pyloric stenosis
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 )
What is pyloric stenosis?
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)
How can we separate the genetic and environmental factors of the multifactorial diseases?
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
Identifying the genetic component of a complex diseases=
= determining the heretibaility of a disease
What are the tools for determining the effects of genetics vs environment?
- population/migration studies
- family studies
- twin studies
- adoption studies
- Association studies
How can population/migration factors be indicative of environmental effects?
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
How can cancer incidence vary by geography?
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)
Contrast the types of twins
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%)
Explain The disease concordance for monozygotic twins
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
What are the limitations of twin studies ?
- May underestimate heritability (only addresses differences between 100% and 50% identical genomes)
- MZs do have some different genes (e.g. mitochondrial genes) and epigenetic differences, also different accumulation of somatic mutations due to errors in mitosis
- Different environmental exposures (in utero and development after being born)
- Different genes in different twin pairs (studies between different sets of twins may point to different contributors for same phenotype)
- Ascertain ment bias
- Most studies do NOT specify the loci and alleles but how genotype and environment interact
- but still a very useful loci
What other what are the alternative to twin studies?
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
Explain association analysis
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 “
Explain genome-wide association studies (GWAs)
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
What are the types of neural tubes defect?
Anencephaly
Spina bifida
Both show multifactorial inheritance
What is anencephaly ?
- 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
What is spina bifida?
- 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
What is evidence of spina bifida (for genetics)?
- 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
What are the evidence of spina bifida (for environment)?
- 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
