Genetics of common diseases

Question 1

What is familial clustering?

Answer 1

• many phenotypes of traits and disorders (eg. diabetes, alzheimers, asthma) occur more often within families than between unrelated individuals.
• this familial clustering suggests there is genetic susceptibility,

Question 2

What is multifactorial inheritance?

Answer 2

• common familial disorders do not follow the same predicted patterns of inheritance seen in single gene/mendelian disorders (such as cystic fibrosis, muscular dystrophy, fragile X syndrome) instead they result from a complex interplay of gene and environment.

Question 3

Define penetrance.

Answer 3

• a measure of proportion of those who have trait genotype who show the trait phenotype.

Question 4

What are 2 variants that are unlikely to be associated with monogenic disease in early childhood?

Answer 4

• deletion in the DNA sequence that encodes protein

- common missense variation

Question 5

What is genetic susceptibility?

Answer 5

• also known as genetic predisposition is an increased likelihood of developing a particular disease based on a person’s genetic makeup, a variation often inherited from parents.

Question 6

What is heritability?

Answer 6

heritability:

- measure of how well differences in people’s genes account for differences in their traits.

Question 7

How do you measure genetic heritability?

Answer 7

• calculated using twin studies, measure concordance rate between MZ and DZ for each trait of interest.
• measured from 0- 1, closer to 1 indicates almost all the variability in a trait comes from genetic differences, with very little contribution from environmental factors.
• negative 1 = negative correlation
• over 0.4 is of interest and worth investigating, so you do GWAS.

Question 8

What is the equation for estimating heritability?

Answer 8

h^2= 2 x (MZ correlation – DZ correlation)

Question 9

Give an example of heritability study and its finding.

Answer 9

=> heart rhythm heritability

• uses ECG to measure heart function, conductivity and electrical activity of heart.
• heritability estimated using correlation study
• over 0.4 for heart rate, PR interval, QRS and QT so it is worth investigating.

Question 10

Why do dizygotic twins share a bit more of their genetic variation than normal siblings if their genome is 50% similar like normal siblings?

Answer 10

Dz twins have the same utero environment.

Question 11

What does heritability rate tell you about the influences of genetics and environment?

Answer 11

When HR is similar between M/z and D/Z the environmental influence > genetics
When HR is very different genetics > environmental

Question 12

What did HapMap project measure?

Answer 12

• gene variance across different ethnicities

- aimed to develop a resource describing the common patterns of human DNA sequence variation.

Question 13

What is genome wide association studies (GWAS)?

Answer 13

• used to associate specific genetic variations with particular phenotypes/trait/diseases
• method involves scanning the genomes from many different people and looking for genetic markers (SNPs) that can be used to predict presence of a disease/trait.

Question 14

What is the goal of GWAS?

Answer 14

• identify genetic regions that explain differences in phenotype among individuals in a study population.
• to identify genetic variants that can be measured to determine whether an individual is at higher risk of disease
• to identify potential drug targets to treat disease.

Question 15

How do genetic association study work?

Answer 15

• HapMap project measured gene variance across different ethnicities
  -NGS made it easier to measure variability for common traits which would require the sequencing of thousands of individuals.
• catalogue of SNPs produced, which was used to identify genes involved in complex disease in ‘GWAS’
• SNP chips contain thousands of SNPs across lanes. Target DNA is amplified, fragmented and captured on chip by binding to array. labelled probe bing to samples that have ligated to SNP probes and intensity of array is measured.
• graph produced and binary code for inheritance of SNP (easier for computer to analyse)
• can genotype or £25 now and some SNP chips contain 5 million SNPs.
  h2= 2 x (MZ correlation – DZ correlation)

Question 16

What is linkage disequilibrium(LD)?

Answer 16

=> difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association.

• only measure some SNPs as many are inherited together and can infer that the others will also be there.
• further away genes more likely to be involved in recombination event so cannot assume they will inherit together - only close together SNPS used.

=> LD between two SNPs decreases with physical distance as more likely to have recombination event between them
=> if LD strong, need fewer SNPs to capture and easier/quicker to analyse.

Question 17

Why are SNPs not always useful in establishing genomic association?

Answer 17

• most SNPs in non-coding regions which are unlikely to contain the causal variation, so many SNP chips not enough to identify causal variant(might be inherited with gene in coding region that it tags and affects, having the actual effect on disease/trait)
• statistical analysis can determine if association of SNP and trait is significant.

Question 18

What is an example of genetic association study?

Answer 18

• identify SNP of interest and phenotype of interest(heart rate)
• convert individuals results into dosage and plot against heart rates.
• copy G allele increases likelihood of increased heart rate.
• line of bestfit drawn. Gradient between change in single allele is P-value. indicates significance of the association - probability that allele is associated with trait.
• P- values plotted on Manharran plot with -log10(P- value) against position in genome.
• P value threshold 5x10 -1 (has to be less than this or false positive) is the standard for GWAS to correct for multiple testing.
  =>assumption is that every SNP is independent.

Question 19

What is the statistical result of genetic association?

Answer 19

• Boneferoni correction = number of tests is n, threshold is 0.05/n
• if SNP is associated : could be causal, marker(linkage disequilibrium with actual causal locus) false positive.