Multifactorial Inheritance Flashcards
When is multifactorial inheritance indicated?
When there is an increased risk to relatives, but there is no consistent pattern of inheritance within families
What contributes to susceptibility in multifactorial inheritance?
possibly multiple genes and/or environmental factors
What are simple mendelian diseases, usually?
single gene disorders characterized by inheritance patterns that follow Mendelian expectations and are discernable by examining pedigrees with multiple effected individuals
One to one relationship between whether you have the variant and whether you have the trait - means likely what kind of trait?
Simple Mendelian
What is a classic example of a simiple Mendelian trait?
Sickle Cell
Complex traits
Characteristics of diseases that demonstrate multifactorial inheritance (4)
Incomplete penetrance
Variable expressivity
Heterogeneity - allele and locus
Presence of phenocopies
Do complex traits aggregate in families?
Yes, complex traits tend to aggregate in families but they do not show the typical Mendelian inheritance patterns
What is a major obstacle when trying to determine genetics of complex traits?
Distinguishing between clustering in families due to genetic factors and due to shared environment
One of the major obstacle in studying complex traits and multifactorial inheritance is distinguishing between clustering due to genetic vs. environmental factors… what kind of studies are done to overcome this? (3)
Epidemiologic Twin
Adoption
Immigration
Twin studies…
MZ vs. DZ
MZ - 100% genetic similarity
DZ - 50% genetic similarity
Both share X% environment
If twins raised together and assume same degree of similar environment, then differences in concordance between MZ and DZ likely due to genetic factors
For studies comparing MZ and DZ twins, what is the key assumption?
That the X% shared environment is the same for mono and dizygotic twins
What is concordance rate?
How often both twins are either diseased or not diseased
Twin Studies…what can we clean from monozygotic twins raised apart?
If twins raised apart and assume had different environments, then similarities in trait (high concordance rates) are likely due to genetic factors
What is the key assumption for twin studies comparing monozygotic twins raised apart?
That their environment were different
What information can we glean from adoption studies?
If biological siblings raised apart are more similar than adopted siblings raised together (higher concordance rate) - then have evidence for genetic component as opposed to environmental
How do we compare frequency of disease in relative of patients to see if higher than in general population?
lambda S =
Risk of disease in siblings of affected /
Risk of disease in general population
What would be the Lamba S score (risk of disease in relative calculation) if the risk in the general population for type I diabetes is 0.4% and the risk to sibling of type I diabetes patient is 6%?
Lambda S = 6/0.4 = 15
What is the heritability of a trait?
The proportion of total variance in a trait that is due to variation in genes
What does a high heritability imply?
That differences among individuals with respect to a trait in a population can be attributed to differences in genetic make-up (As opposed to environmental differences)
What is the key thing to remember when evaluating heritability estimates?
We are describing variation in BOTH genetic factors AND non-genetic factors. If one (alleles or environment) doesn’t demonstrate much variability, then it doesn’t have much potential to explain variability in a trait
It heritability about whether or not there is a genetic component
No! You can have a lot of variability due to environmental variation that dilutes the variation due to genetics - Thus, even if the genetic component has the same impact, if there is a lot of variation in the environment it can appear to have lower heritability even though genetic factors variation is the same
Does a high heritability imply that non-genetic factors are not important?
NO!
Does a low-heritability imply that genetic factors are not important?
NO!
Complex traits demonstrate one or more of the following (4)
Incomplete penetrance
Variable expressivity
Heterogeneity (allele and locus)
Presence of phenocopies
Incomplete penetrance: not everyone with predisposing variant develops disease
What is an example
Type I diabetes and MHC
What is the penetrance of a genotype?
The probability that an individual will develop the trait if they have the genotype
Up to 20% of the general population has one of two high risk haplotypes for diabetes, but incidence of disease is only 0.4%
This is exemplifying____ which is charactistic of _____
incomplete penetrance
complex trait
Variable expressivity
individuals with the same variant do not show precisely the same disease or quantitative phenotype characteristics
What disease was exemplared as having variable expressivity?
MODY
Mature onset diabetes of the young
Looking at the age of diagnosis in mutations causing mature onset diabetes of the young, we see that it is highly variable for both different mutated codons and the same mutated codon. This is illustrative of?
Which is characteristic of?
Variable epxressivity
Complex trait
What is allelic heterogeneity?
The same disease can be caused by different alleles in one location
OR
Different alleles in the same gene result in different traits
What is an example of allelic heterogeneity?
Cystic Fibrosis Many alleles (Affecting same gene) appear to have a very similar clinical progression of disease
HOWEVER
Alleles can also be grouped into classes - severity of lung and pancreatic involvement depends on allele class
How does cystic fibrosis exemplify allelic heterogeneity?
Different alleles of the same gene give the same trait (diagnosis of CF)
Different alleles of the same gene result in different trait (organ involvement in CF)
CF example of different allele mutants of CFTR causing different pancreatic traits?
DeltaF508 mutation (F508/F508) is a more severe variant and causes pancreatic insufficiency in 85%
R117H mutation (R117H/R117H of R117H/F508) is a less severe mutant and only causes pancreatic insufficiency 15%
This is example of allelic heterogeneity with different alleles of the same gene manifesting different phenotypes / risks
CF example of different allele mutants of CFTR causing different pulmonary function
Mild mutations have slightly better lung function than those carrying severe mutations, but when we deal with partcular patient form both groups it is very difficult to predict if they will have a severe or mild lung disease
Thus, unlike pancreas, which seemed relatively determined by genotype, lung involvement likely is influenced by other factors
What is locus heterogeneity?
Variants in different genes result in very similar clinical presentation
Which disorder exemplified locus heterogeneity?
Early onset AD
Mutations in 3 different genes all result in identical presentation of early AD
What does locus heterogeneity present a challenge to?
Mapping for locus, because same phenotype results from differing genotype
Increased noise
Phenocopy
Environmentally caused phenotype that mimics the genetic version of trait
What is an example of a phenocopy?
Thalidomide induced limb malformation
vs.
Genetically induced
Which disease was given as an exemplar of mutifactorial inheritance?
Type 2 diabetes
Type 2 diabetes Evidence for genetic component? 1) early studies 2) relative studies 3) intermediate trait studies
- early studies showed type 2 aggregates in families
- Concordance rate for MZ twin is about 2x DZ (35-100%)
Risk to 1st degree relative 3-4x general population - intermeidate traits of blood glucose and insulin levels have heritability estimates as high as 50%
Genetic risk for type 2 diabetes, what do the odds ratios associated with increasing # of at risk alleles tell us?
The odds ratio never gets above 2, and is highly variable, even for those with upwards of 30 at risk alleles…
Thus, something more than genetics is at play here and our ability to predict using gene variants is low
Predicting risk for type 2 diabetes… ROC (recievier operator characteristic) curve for prediction of type 2 diabetes based on 18 genetic polymorphisms and clinical characteristics (age, sex, BMI)… do genes help?
They only slightly help bump up our sensitivity per specificity / not much
Which genetic diseases are we more likely to be able to predict?
Severe ones
If we can’t directly correlate genes to type 2 diabetes susceptibility, what second best thing could we do?
We can use genetic predisposition for factors leading to the development of Type II diabetes, such as insulin resistance and insulin deficiency, which may be more related to genetic effects
What is the distinguishing factor between simple mendelian and complex?
one major gene with high penetrance is relevant for simplest Mendelian (e.g. sickle cell)
But it is really more of a continuum between simple and complex
