14. USING THE RESULTS OF GENETIC STUDIES

Question 1

What does GWAS show?

Answer 1

• Genome wide association studies (GWAS) identifies loci in the genome that are associated with a phenotype or disease

Question 2

What are three difficulties with using GWAS?

Answer 2

1. In large GWAS, many loci will be detected so it’s difficult to prioritise genes
2. 90% of the GWAS SNPs identified are located in non-coding regions so are likely to be involved in gene regulation rather than being a causal gene
3. Doesn’t identify the cell type/tissue/ developmental stage for the variant

Question 3

What are the issues with assuming loci & gene linkage?

Answer 3

• There can be linkage disequilibrium between the loci & the gen, making it difficult to identify a causal variant
• The identified loci may also act at a distance so the gene & loci aren’t linked

Question 4

**What are three applications of RNA sequencing?

Answer 4

1. Analyse the response of cell populations to treatment
2. Look at how gene expression changes with developmental stages or disease conditions
3. Single cell transcriptome analysis

Question 5

What are two difficulties with RNA sequencing?

Answer 5

• RNA sequencing identifies large numbers of differentially expressed genes which can make it difficult to see which are real/relevant
• Identification of differentially expressed genes doesn’t provide biological reasoning as it doesn’t consider complex interactions

Question 6

How can the results of genetic studies be used in the healthcare management of individuals?

Answer 6

1. Prevent & predict disease
2. Diagnosis
3. Personalised treatment

Question 7

What is fine mapping?

Answer 7

• Fine mapping is a high resolution study of loci associated with a disease or trait, which is then analysed to pinpoint individuals
• Focuses on identified loci & looks at the SNPs in that location to find a causal variant

Question 8

What is eQTL?

Answer 8

• Expression quantitative trait loci identifies genetic variants that affect the expression of one or more genes

Question 9

What is a co-localisation analysis?

Answer 9

• A method that compares GWAS to eQTL at a locus to determine whether they’re due to the same causal variant

Question 10

What are three reasons for overlap of GWAS & eQTL loci?

Answer 10

1. Linkage - there are two independent causal variants/SNPs
2. Causality - a single causal SNP
3. Pleiotropy - a single SNP has independent effects, it affects multiple phenotypes

Question 11

What are Transcriptome Wide Association studies (TWAS)?

Answer 11

• Transcriptome wide association studies integrates GWAS & RNA sequencing so it overcomes most of the issues with these two techniques
• Obtains all the possible cell types for each subject rather than comparing SNPs
• Directly tests for association between gene expression levels & phenotypes

Question 12

What is cell type SNP enrichment?

Answer 12

• SNP enrichment analysis is a method used to identify classes of genes or proteins that are overrepresented in a set of genes
• SNP enrichment is sued to determine the cell type by looking at gene expression, regulatory elements & open chromatin

Question 13

What are three ways of validating results from genetic studies?

Answer 13

1. Cell studies
2. Functional phenotyping
3. Reverse genetic screens

Question 14

Describe the principle of cell studies

Answer 14

• Once a gene is identified, the cell type can be determined
• Immunofluorescence can be used to locate where in the cell the gene is
• Knocking out the gene allows us to see whether the gene affects functional activity of the cell

Question 15

What is reverse genetics?

Answer 15

• Forward genetics involves identifying what gene causes a particular phenotype or disease
• Whereas reverse genetics involves looking at what phenotype arises from a gene by manipulating the gene. E.g knocking out the gene.