Genetics of Complex Disorders and Inheritance Patterns Flashcards
complex disorders
-also called multifactorial conditions
+combination of environment and genetics
-includes most isolated birth defects (clefts, ONTDs, CHDs)
-many common diseases (diabetes, psychiatric disorders, heart disease, dementia, arthritis)
-aggregate, but don’t segregate-diagnosis comes from ruling out other etiologies
family studies
comparing frequency among close biological family members in that of an affected and non-affected individual to establish possible increased genetic risk, but can’t parse out the significance
multifactorial condition research pipeline
- establish condition runs in family
- use twin studies to find out genetic involvement
- use traditional studies to define which genetic factors play a role
- establish why these factors play a role
twin studies
- based on assumption MZ twins share nearly 100%, DZ share 50%, but share same in-utero environment
- allow us to generate estimates of heritability
concordance
chance that another twin is affected, when one is
-expect it to be higher in MZ than DZ, but not 100%
heritability
statistical measure of variance in a phenotype across a population
-like census data-average across a population
linkage studies
useful for identifying genetic differences that play a large role in phenotype
-tend to generate more equivocal results between different studies
association studies
more useful for identifying underlying genetic associations that have smaller effects
- often study SNPs and comparing frequency of these in population of people with and without phenotype
- difficulties in replication again
GWAS
thought to be even more advanced-like doing thousands or millions of association studies at once
-requires very large sample sizes and a stringent threshold for statistical significance (p<5x10^-8)
jar model
-in order to experience effects of a complex condition jar has to be filled to the top
+combo of purely genetic factors and environmental ones
-we all start out with a certain varying baseline vulnerability (DNA sequence based)
-environmental vulnerability factors can accumulate on top of the genetic factors (ex: even obstetric complications, childhood head injury)
-additional environmental factors from stressful life events, then leads to active episodes of illness
*can also explain variability in phenotype
estimating chance for recurrence
does not equal risk, it is a probability
chance of recurrence in absence of family history
- approximately square root of frequency of condition in the general population for first degree relative
- by third degree relative it is approximately general population level
limits of empiric data
average probability that’s influenced by many factors including characteristics of an affected individual, characteristics of the individual for whom probability is being calculated, characteristics of family history
affected individual risk factors
- earlier age of onset increases probability
- if they are of the less typically affected sex
- experienced more severe illness onset (this can be challenging to quantify though)
characteristics affecting person whose probability is being calculated
- age
- sex
- medical history
characteristics of family history that effect probability
- greater number of affected family members increases chance of recurrence
- consanguinity-greater sharing of vulnerability alleles
heritability calculation
h^2=Ve/(Ve+Vg) or h^2=(Vdz-Vmz)/Vdz
- Ve=Vmz
- Vdz=Ve+Vg=Vmz+Vg
- Vg=Vdz-Vmz
reduced penetrance
- individual with a disease-genotype may not show the phenotype
- offspring are still at risk
- ex: heritable PAH
- all or nothing
age-dependent penetrance
- symptom onset delay
- individual could have children before knowing they are affected
- individuals could also die prior to symptom onset
- ex: HBOC and HD
variable expressivity
phenotype severity varies significantly
- some individuals may be unaware they are affected and pass on a condition to their children
- can be influenced by environmental effects and/or modifier genes
- ex: NF1
- level of affectedness
anticipation
more severe expression or earlier age of onset in younger generations
- sometimes caused by DNA repeat expansions; may be more likely when inherited in mom v. dad, depending on condition
- ex: HD or myotonic dystrophy
de novo/new mutation
- affected proband with no history of disease in family (especially if AD)
- if genes in other germ cells (gonadal mosaicism) do not have the mutation risk to siblings is not increased over gen pop and risk to offspring depends on condition
germline or gonadal mosaicism
-rare phenomenon of two or more offspring being affected in the absence of family history
+due to the presence of more than one distinct reproductive cell line
-poses increased risk to siblings of an affected proband
-ex: DMD, Hem A, achondroplasia, NF1, OI2
sex-influenced transmission
-phenotype can be limited to or severity influenced by mutation presence in a male or female
+due to tissues or hormonal differences
male lethality
- type of sex-influenced/limited transmission
- often with XLD conditions
- ex: incontinentia pigmenti
incontinentia pigmenti
- XLD IKBKG mutation leads to only affected females (male lethality); often mosaic
- skin abnormalities include a blistering rash in childhood, followed by wart-like skin growths and eventual swirls and lines of hyper and hypo pigmentation
- alopecia, pitted or lined nails, dental and vision abnormalities and sometimes neurological effects may be seen
skewed X-inactivation
- seen in XLR conditions
- the majority of active X chromosomes carry the mutation, causing heterozygote females to manifest condition symptoms
- ex: FRAX, DMD
phenocopies
individual in family displays a similar phenotype, but does not have a disease-causing allele
-ex: HBOC
small families
pattern of inheritance is less evident in a family
-ex: Lynch syndrome
