GEN: complex diseases Flashcards
what are complex diseases?
diseases involving multiple loci and environmental effects
what are the features of complex diseases?
- raised familial risk (can be slight in comparison to pop. risk)
- no clear inheritance mode
- multiple genes are contributors
- environmental effects contribute
- gene-gene and gene-environment interactions
what are some examples of complex diseases?
inflammatory bowel disease, depression, schizophrenia, multiple sclerosis, asthma, rheumatoid arthritis, diabetes and heart disease
what kind of disease is huntingtons
mendelian
what kind of disease is cycstic fibrosis
mendelian
what is heritability?
the proportion of population varied of a trait explained by genetics compared by both explained by genetics and environment
what are some Mendelian rare variants?
Huntington’s disease, cystic fibrosis, SMA
what are some common variants?
CVD, rheumatoid arthritis, schizophrenia, depression
what are some mix of common and rare variants?
autism, epilepsy, ALS, Alzheimer’s, breast cancer (BRCA1/2)
what are the two major breast cancer genes?
BRCA1 and BRCA2
what are the three rare high risk Alzheimer’s genes?
APP
PSENI
PSEN2
what can Alzheimers Disease risk be increased by 2 things/ what are the 2 moderate risk genes?
APOE allele e4
variants of TREM2
what are some low risk variants identified through association studies in Alzheimers Disease?
SNPS in genes:
CLU
CRU
PICALM
how many factors are involved in mendelian disease vs complex
mendelian = one factor (gene) involved
comple = multiple factors (both genetic and environment) involved
whats the difference in predictability in mendelian disease vs complex
mendelian = knowledge of the factor (genotype) is high predictive
complex = not very predictive
whats the difference in segregation patterns in mendelian disease vs complex
mendelian = clear segregation pattern, either dominant or recessive
complex = no clear segregation but can ‘run in families’
what does the genome wide association study GWAS do?
tests whether an allele of a specific genetic variant (SNPs) alters disease risk
how are GWAS tests done?
- case control studies with clear clinical criteria and random samples - both have similar genetic backgrounds
- SNP tests of two alleles - genotype frequencies or alleles
- statistical analysis: chi-square test
- chip tech used
- regression methods using covariants to account for confounding
- Manhattan plot: genomic position at x axis
what types of risk do we look at for Mendelian and polygenic diseases?
- Mendelian: absolute risk
penetrance → probability of developing disease
- Polygenic: relative risk
odds ratio (or relative risk) comparing disease risk for different genotypes
how many SNPs were found to be associated with coronary artery disease?
58 - each SNP increases risk slightly
what SNP was found to be significantly associated with CAD?
rs17087335 on chromosome 4
what are polygenic risk scores?
outcome measured using an individual’s genotype to construct a risk score focussed on associated risks
are genetic and environmental risk factors predicitive enough for an individual’s risk?
NO - these risk are not predictive enough for an individuals risk - but gives useful population level information
what are the 3 allelles of APO-E and risk relation to AD
e4 allele: increases risk of AD
e3 allele: baseline risk
e2 allele: protective against AD
