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Lect 2: Intro to CD (Complex disease (1 or more mutations (alleles at…
Lect 2: Intro to CD
Complex disease
- 1 or more mutations (alleles at locus)
- Environment strong
- Families are rare (maybe like HSPR -> familial)
- Low penetrance (mostly)
- Unknown pattern of inheritance
- Relatively common
- genetic variations -> common & x causative (x develop disease) -> more prone/at risk -> other factors influence instead
- Mostly late onset
Monogenic, oligogenic & poly genic disease -> dep on no. of risk alleles -> but x simple maths to det which disease belongs to which grp
Difficult to analyse
- Genotypes (alleles) at one or more loci neither necessary or sufficient for a trait expression
- Common genetic variants increase disease risk
Monogenic
- involves single risk allele
- Gray area bet Mendelian & CD
Oligogenic
- Less risk alleles & higher inheritable component -> familial clustering, early onset, risk alleles larger effect as measured by OR & LOD score
- More common than monogenic;
- E.g. Hirschsprung’s disease -> debilitating disease from early birth -> cause: toxic megacolon in new born -> failure of ganglia to move down into lower gut to variant levels in embryo devt
- when child born -> x contraction -> faeces build up in lower gut -> surgery reqd
- Phentoype -> determined by few genes
- Small number of genes involved in -> control of only one property, and it seems that even fewer features controlled by the alleles from only one locus.
Polygenic
- Sporadic cases, genetic susceptibility det by various risk alleles
- Crohn's Disease
- Phenotype -> determined by many genes
- Often the genes are large in quantity but small in effect.
- E.g. height, skin color, eye color and weight
- involves stronger environmental interactions than other diseases; no. of risk alleles -> very high with 1 allele or allele family having large impact & many others having small effects
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Mendelian disease
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- Environment weak but x always
- Familial clustering common
- High penetrance
- Known pattern of inheritance -> nickel allergy when you handle nickel coins
- Relatively uncommon
- Simple analysis
- 1 mutation (at a locus)
- Rare & causative
- Mostly early onset
(Haines & Pericak-Vance (1998)
- Complex disease defn: disease (disorder/trait) where one or more alleles (genetic variations/mutations) acting alone or in concert increase/decrease risk of developing CD
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Heritability -> proportion of variation in a phenotype in a popn that can be accounted for by our genes
Hardy-Weinberg Principle: main stats analysis in popn genetics
- tests how allele freq changed from gen to gen
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Pleiotrophy: mutations that hv multiple effects -> in CD -> final clinical outcome det by complement of risk alleles inherited & environmental risk -> CD x comply with simple mendelian inheritance patterns
Multi-factorial
- phenotypic outcome (physical characteristic or disease predisposition) -> determined by more than one gene.
- both genetic (combination of genes from parents) & environmental factors -> produce trait/condition