Multifactorial Inheritance

Question 1

When is multifactorial inheritance indicated?

Answer 1

When there is an increased risk to relatives, but there is no consistent pattern of inheritance within families

Question 2

What contributes to susceptibility in multifactorial inheritance?

Answer 2

possibly multiple genes and/or environmental factors

Question 3

What are simple mendelian diseases, usually?

Answer 3

single gene disorders characterized by inheritance patterns that follow Mendelian expectations and are discernable by examining pedigrees with multiple effected individuals

Question 4

One to one relationship between whether you have the variant and whether you have the trait - means likely what kind of trait?

Answer 4

Simple Mendelian

Question 5

What is a classic example of a simiple Mendelian trait?

Answer 5

Sickle Cell

Question 6

Complex traits

Characteristics of diseases that demonstrate multifactorial inheritance (4)

Answer 6

Incomplete penetrance
Variable expressivity
Heterogeneity - allele and locus
Presence of phenocopies

Question 7

Do complex traits aggregate in families?

Answer 7

Yes, complex traits tend to aggregate in families but they do not show the typical Mendelian inheritance patterns

Question 8

What is a major obstacle when trying to determine genetics of complex traits?

Answer 8

Distinguishing between clustering in families due to genetic factors and due to shared environment

Question 9

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)

Answer 9

Epidemiologic Twin
Adoption
Immigration

Question 10

Twin studies…

MZ vs. DZ

Answer 10

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

Question 11

For studies comparing MZ and DZ twins, what is the key assumption?

Answer 11

That the X% shared environment is the same for mono and dizygotic twins

Question 12

What is concordance rate?

Answer 12

How often both twins are either diseased or not diseased

Question 13

Twin Studies…what can we clean from monozygotic twins raised apart?

Answer 13

If twins raised apart and assume had different environments, then similarities in trait (high concordance rates) are likely due to genetic factors

Question 14

What is the key assumption for twin studies comparing monozygotic twins raised apart?

Answer 14

That their environment were different

Question 15

What information can we glean from adoption studies?

Answer 15

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

Question 16

How do we compare frequency of disease in relative of patients to see if higher than in general population?

Answer 16

lambda S =

Risk of disease in siblings of affected /
Risk of disease in general population

Question 17

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%?

Answer 17

Lambda S = 6/0.4 = 15

Question 18

What is the heritability of a trait?

Answer 18

The proportion of total variance in a trait that is due to variation in genes

Question 19

What does a high heritability imply?

Answer 19

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)

Question 20

What is the key thing to remember when evaluating heritability estimates?

Answer 20

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

Question 21

It heritability about whether or not there is a genetic component

Answer 21

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

Question 22

Does a high heritability imply that non-genetic factors are not important?

Answer 22

NO!

Question 23

Does a low-heritability imply that genetic factors are not important?

Answer 23

NO!

Question 24

Complex traits demonstrate one or more of the following (4)

Answer 24

Incomplete penetrance
Variable expressivity
Heterogeneity (allele and locus)
Presence of phenocopies

Question 25

Incomplete penetrance: not everyone with predisposing variant develops disease What is an example

Answer 25

Type I diabetes and MHC

Question 26

What is the penetrance of a genotype?

Answer 26

The probability that an individual will develop the trait if they have the genotype

Question 27

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 _____

Answer 27

incomplete penetrance complex trait

Question 28

Variable expressivity

Answer 28

individuals with the same variant do not show precisely the same disease or quantitative phenotype characteristics

Question 29

What disease was exemplared as having variable expressivity?

Answer 29

MODY | Mature onset diabetes of the young

Question 30

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?

Answer 30

Variable epxressivity Complex trait

Question 31

What is allelic heterogeneity?

Answer 31

The same disease can be caused by different alleles in one location OR Different alleles in the same gene result in different traits

Question 32

What is an example of allelic heterogeneity?

Answer 32

``` 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

Question 33

How does cystic fibrosis exemplify allelic heterogeneity?

Answer 33

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)

Question 34

CF example of different allele mutants of CFTR causing different pancreatic traits?

Answer 34

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

Question 35

CF example of different allele mutants of CFTR causing different pulmonary function

Answer 35

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

Question 36

What is locus heterogeneity?

Answer 36

Variants in different genes result in very similar clinical presentation

Question 37

Which disorder exemplified locus heterogeneity?

Answer 37

Early onset AD | Mutations in 3 different genes all result in identical presentation of early AD

Question 38

What does locus heterogeneity present a challenge to?

Answer 38

Mapping for locus, because same phenotype results from differing genotype Increased noise

Question 39

Phenocopy

Answer 39

Environmentally caused phenotype that mimics the genetic version of trait

Question 40

What is an example of a phenocopy?

Answer 40

Thalidomide induced limb malformation vs. Genetically induced

Question 41

Which disease was given as an exemplar of mutifactorial inheritance?

Answer 41

Type 2 diabetes

Question 42

``` Type 2 diabetes Evidence for genetic component? 1) early studies 2) relative studies 3) intermediate trait studies ```

Answer 42

1. early studies showed type 2 aggregates in families 2. Concordance rate for MZ twin is about 2x DZ (35-100%) Risk to 1st degree relative 3-4x general population 3. intermeidate traits of blood glucose and insulin levels have heritability estimates as high as 50%

Question 43

Genetic risk for type 2 diabetes, what do the odds ratios associated with increasing # of at risk alleles tell us?

Answer 43

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

Question 44

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?

Answer 44

They only slightly help bump up our sensitivity per specificity / not much

Question 45

Which genetic diseases are we more likely to be able to predict?

Answer 45

Severe ones

Question 46

If we can't directly correlate genes to type 2 diabetes susceptibility, what second best thing could we do?

Answer 46

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

Question 47

What is the distinguishing factor between simple mendelian and complex?

Answer 47

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