Define multifactorial disorders(or complex disorders) and the types of disease it gives rise to.
Multifactorial diseases are not confined to any specific pattern of single gene inheritance and are likely to be associated with multiple genes effects together with the effects of environmental factors. Multifactorial disorders include many congenital malformations and common disease of adults.
Define single gene disorders, polygenic disorders, and heterogeneity.
- Single gene disorders – may be minor effects from variants at other loci, but rare genetic variants at primary gene locus have great effect on the phenotype.
- Polygenic disorders – genetic susceptibility to disease risk not due to a primary locus with strong phenotypic effects.
- Heterogeneity can be an issue – some complex disease a collection of related phenotypes and in some, rare variants can have a strong effect.
Define polygenic traits.
A polygenic traits a characteristic such as heigh, skin color, etc… many of these traits show a normal distribution.
Explain polygenic disease.
Multifactorial disease can be defined in terms of
quantitative(e.g. high blood pressure) or qualitative traits(e.g. cleft lip).
List the approaches used to demonstrate genetic susceptibility.
Family and twin studies
Heritability
Population incidence and migration
Explain pop. Incidence and migration.
- Suppose a migrant group moves from a low incidence popn. to a high incidence popn.
- If incidence in the migrant group then rises to that of its new popn. group, that would suggest environmental factors more important than genetic ones.
- Maintenance of low incidence in new popn. would suggest genetic factors of greater importance(e.g. CVD and spina bifida)
Define dizygotic and monozygotic.
dizygotic; non-identical twin pairs.
monozygotic; identical twin pairs.
Define concordat and discordant.
concordat; when twins share a trait.
discordant; when only one of the pair shows the trait.
What are the limitations of twin studies?
- MZ twins may be treated more similarly by parents/teachers than DZ twins (especially if of different sex)
- Tends to inflate environmental variance for DZ twins
- Using twin data provides only approximations of heritability
Define heritability and narrow heritability.
Heritability; is the proportion of the total phenotypic
variance (VP) that can be attributed to genetic variance (VG).
Narrow Heritability; is the proportion of VP due solely to additive genetic variance (VA).
Family studies may suggest a genetic involvement, but cannot identify genes responsible for susceptibility so how are genes identified?
Association studies
Define association, give an example, detail the calculation.
Association is a statical statement about co-occurrence of alleles or phenotypes. (E.g. B27 is present in ~90% of patients with ankylosing spondylitis but only in 5% of controls.)
Can test for association with chi-squared test, and then calculate an odds ratio.
What is the typical range of OR?
For most markers associated with multifactorial disease, frequency difference between cases and controls is small leading to small ORs (typically between 1.1 and 1.5).
T/F - does the identification of a susceptible locus mean that the definitive disease gene has been found?
False
Define missing heritability.
- h2 proportion of variance in a trait within a population attributable to genetics (eg if h2 of a complex trait estimated at 70%, then 70% due to genetic factors, 30% environment.)
- Genetic associations discovered so far (eg SNP A, SNP B, SNP C, etc) might explain eg 25% of the 70% of the trait variance.
- The remaining 45% is the “missing heritability”
List and outline (at least 3) the various reasons that explain missing heritability.
- Large numbers common variants with very small effect; If only weak effect (eg OR < 1.2) would need larger numbers of cases and controls (individual or in meta-analyses).
- Rare variants with large effect; Susceptibility may be due to
heterogeneous set of rare variants each with strong effects. - Gene-environment interactions; Can lead to inconsistent disease associations.
Define NTDs and its consequences.
Neural tube defects; result from defective closure of the neural tube during the first month of embryonic life. Most NTDs have serious consequences and is
not compatible with life. Most isolated NTDs likely to show multifactorial inheritance.
Explain everything about spina bifida.
Spina bifida alone account for 55% of NTDs. Closed legions are less severe than open legions. Without surgery 20% survive to 2 years. With surgery 40% survive but are severely handicapped.
What are the causes of NTDs?
- Higher incidence in offspring of consanguineous marriages, ethnic variation, etc suggest a genetic basis.
- Concordance between MZ and DZ twins low, suggests that any genetic influences predispose to environmental factors.
Name one very important environmental factor relevant to NTDs.
Maternal levels of folic acid!
- Supplementation with folic acid can reduce recurrence risk
of NTDs in subsequent high risk pregnancies. - Currently the prevalence of NTD is 0.5/1,000 births (lower than previous decades) after FA fortification.
Define proteomics and how its used to study NTDs.
Proteomics is the large scale analysis of proteins in a cell/system under defined conditions.
- 2-D electrophoresis (separates proteins on basis of isoelectric point as well as MW) used to study NTDs.
Prenatal diagnosis of NTDs is a combination of what?
ultrasound scanning and amniotic fluid biochemistry.
Is screening for NTDs offered by the NHS?
Screening for NTDs offered by NHS as part of the 18-20 week foetal anomaly scan.
What is PRS?
Polygenic risk score
