11 - Polygenic Disorders

Question 1

What are polygenic disorders (complex traits)?

Answer 1

Disorders that are affected by multiple genes as well as the environment.

Question 2

What are examples of polygenic disorders?

Answer 2

Diabetes, heart disease, kidney disease, and psychiatric disorders.

Question 3

What must occur for a person to have a polygenic disease? Do genes play a large role?

Answer 3

They must have a particular genetic make-up and be exposed to certain environments.

Genes usually play a small role.

Question 4

Why are alleles associated with complex traits difficult to identify using a linkage analysis? How are they identified instead?

Answer 4

Because they are relatively common and have a high freq in the pop.

Associated studies used for complex traits.

Question 5

What are associated studies/how do they work?

Answer 5

They test whether an allele of an SNP is correlated with the disease (ie whether it occurs more frequently in individuals who are affected by the disease).

Question 6

What was the Hapmap project?

Answer 6

Tan SNPs were identified throughout the genome, enabling researchers to genotype only a subset of SNPs within the genome and help identify genes involved in complex traits.

Question 7

What is the difference between a linkage analysis (family studies) and an association analysis(population studies)?

Answer 7

Linkage analysis: correlating inheritance of genotype with phenotype (identification of linked region on chromosome)

Association analysis: presence of genotype with phenotype (identification of associated alleles of SNPs)

Question 8

Define the characteristics of a linkage (family) study.

Answer 8

Single gene, mendelian inheritance

rare with high penetrance

~300 short tandem repeats.

Question 9

Define the characteristics of an association (population) study?

Answer 9

Polygenic (genes x environ)

Complex inheritance

Common

~30,000 to 500,000 or more polymorphic markers

Question 10

What are two ways that association analysis can be conducted?

Answer 10

Using cases and controls (ie diabetic and non) or populations(ie to measure fasting glucose).

Question 11

Explain the simplest way to do an association study? How do you analyze the data collected?

Answer 11

Biallelic SNP genotyped in a group of affected people and in a control group.

Chi-square test used to determine whether the observed allele distribution in the two groups is different than expected.

Question 12

What are gene candidate studies? How are candidate genes chosen?

Answer 12

Association studies that focus on SNPs in individual candidate genes.

Chosen based on their known role in disease physiology and a hypothesis that variants in the gene may impair the gene function enough to cause a pathology.

Question 13

What is the primary concern about candidate gene studies?

Answer 13

The study can only be as good as the initial guess about the appropriate candidate gene.

They prevent discovery of novel genes and pathways previously unknown to be involved in a particular disease.

Question 14

What are genome-wide association studies?

Answer 14

Observational study of a genome-wide set of genetic variants in different individuals to see if any variant (SNP) is associated with a trait.

Question 15

What did genome-wide association studies done for Type 2 diabetes in adults conclude?

Answer 15

That ~60% of genes recently identified explain <10% of the variation in the disease.

Both environment and genetics play a role in development of type 2 diabetes.

Question 16

What was a mistake being made when determining statistical significance in genome-wide association studies?

Answer 16

They needed to correct for the number of SNPs tested - Bonferroni Correction

Significant p <0.05/(# SNPs tested).

Question 17

What contributes to the limited success of GWAS?

Answer 17

Heterogeneity of populations

Larger than expected overall effect of rare variants rather than commonly shared variants affecting these traits

Epistasis (the interaction between genes)

Question 18

What is being done to improve GWAS to identify the missing heritability not previously explained?

Answer 18

1. Increase sample size
2. Looking at gene-gene and gene-environment interactions
3. Whole genome or exome sequencing for rare variants
4. Gene expression studies
5. Animal studies

Question 19

What is the benefit of gene expression analysis? How is this done?

Answer 19

Allows investigators to measure transcript abundance in a variety of tissues and cells.

Sequencing RNA using next-generation sequencing technology (RNA-seq).

Question 20

What does RNA-seq allow you to compare?

Answer 20

Healthy and diseases tissues to see which genes are up or down-regulated and therefore may play a role in disease.

Question 21

What is the purpose of mapping transcription abundance levels to the genome?

Answer 21

To identify DNA variants that regulate gene transcription.

Question 22

What do gene expression studies allow investigators to do?

Answer 22

Group genes whose expression levels are highly correlated (ie have high levels of expression under a certain condition) into a network.

They can then see if this network is correlated to a disease.