Complex diseases
- Diseases resulting from complex interactions
between genes (major genes, polygenes) and
environmental exposures. - Disease transmission in families does not fit a simple Mendelian pattern.
- Commonly exhibit variable expressivity,
incomplete penetrance, or age-dependent effects.
Variable expressivity
- The same trait/disorder is expressed differently in different people - mild and severe forms. Example: Neurofibromatosis.
- Different/many phenotypes associated with the same disease gene/mutation. Example: The same gene can cause OCD in one individual and motor tics in a different individual.
Incomplete penetrance
When a person carries a gene, but there is no observable expression or phenotype.
Age-dependent effects
Certain disorders have particular ages of onset; psychiatric disorders tend to have a later age of onset.
Multifactorial
Phenotype determined by more than one gene, gene-gene interactions, and/or gene-environment interplay.
Heterogeneity
Same phenotype caused by different genes or different interactions or variations in the same gene that is associated with differences in disease risk.
Penetrance
How often a phenotype appears in an individual with a mutation.
_ can be a marker of the severity of the index disorder.
Comorbidity.
Assortative mating
- People tend to prefer similar individuals when choosing a partner, which also includes their health problems.
- Example: Among people with bipolar disorder, the likelihood their partner will have a history of mood disorder is 70%.
Heritability
- The degree to which genetics contributes to the overall variability of a disorder within a population.
- A population statistic that expresses the proportion of the total phenotypic variation of a trait that is due to genetics.
Heritability can be assessed through _
Familial aggregation studies, twin studies, and adoption studies.
Copy number variants (CNVs)
- Variations in stretches of DNA found throughout the genome. These are often deletions or duplications.
- Most are benign, but rare large or de novo duplications or deletions have been associated with autism, epilepsy, learning disabilities, and schizophrenia.
- These can be tested for, although the testing is very expensive.
The easiest way to measure heritability is through _
Twin studies - compare the concordance of monozygotic (identical) twins versus dizygotic (fraternal) twins.
Epigenome/epigenetics
- Biochemical factors that alter gene expression but do not involve changes in the underlying DNA sequence.
- Examples: Alterations in methylation patterns or histone proteins.
- Epigenetic mechanisms have been suggested as possibly important in the onset of schizophrenia.
For a given trait, a heritability of 0.5 means that _
50% of the variability in the population can be said to be related to genes.
Increased susceptibility for developing Alzheimer’s disease is primarily associated with mutations on the _ gene on chromosome 19.
APOE.
_ syndrome has been associated with schizophrenia.
Velocardiofacial.
Candidate genes
- Identify genes involved in a biochemical process and then evaluate them for functional changes in affected individuals.
- Examples: Dopamine transmitters, serotonin receptors.
Susceptibility genes are often looked for by _
Association studies.
Genome Wide Association Studies (GWAS)
- Tests that look for areas of the genome associated with a certain disease by comparing the genomes of affected and unaffected populations.
- Can help to identify susceptibilty genes of small effect. Disadvantage: Hard to replicate.
Pleiotropy
An effect in which a single-gene disorder results in problems expressed in many tissues and functions.
Features of _ are consistent with early life reprogramming of genes in response to environmental effects.
DNA methylation.
Psychiatric illness are often said to be _
Polygenic (many genes are involved, each of which as a small effect).
The DSM focuses on defining psychiatric disorders in terms of _
Symptoms or phenotype (defining by etiology is considered too complex at this time).
The association between bipolar disorder and schizophrenia is an example of a _
Cross-disorder overlap.
Empiric risk
- A risk figure for a person being affected with a (usually) multifactorial disorder, obtained by observation and experience of many families where people have that disorder - based on statistics for a population.
- Usually expressed as a range.
- Identifying and explaining empiric risks is what much of genetic counseling is based on.
Lithium, often administered to people with bipolar disorder, is associated with _ in fetuses.
Transposition of the great arteries.
Endophenotypes
- Phenotypes associated with psychiatric illness but are more quantifiable, more common, and seen in more widespread conditions.
- Example: p50 EEG wave in schizophrenia, low response to alcohol.
Behavioral phenotypes in genetic disorders
- Prader-Willi syndrome has an association with OCD, particularly compulsive eating.
- Neurofibromatosis has an association with ADHD.
- Down syndrome has an association with early-onset Alzheimer’s.
Which statement or condition best reflects multifactorial inheritance?
The susceptibility to a problem is an inherited trait but development of the problem is related to environmental conditions.