10: Complex Genetic Traits

Question 1

What are some monogenic (Mendelian) diseases?

Answer 1

• Sickle cell
• Cystic fibrosis
• Muscular dystrophy
• Huntington’s disease
• Friedrich’s ataxia
• PKU

Question 2

What is a polygenic disorder?

Answer 2

Genetic risk is depended upon mutations in multiple genes of varying importance from individual or family to family.

Question 3

What are the genetics behind T1DM?

Answer 3

Antigen presenting cell of MHC Class II presents a specific antigen via a surface protein. If the patient has surface protein DR3/4-DQ2/DQ8 (coded by a human leukocyte antigen [HLA] gene), they will have a high T1DM susceptibility.

Antigen-presenting cells load extracellular antigens onto the MHC class II cell surface proteins. Certain haplotypes will bind insulin especially well, and T-cells may recognize as non-self, thus mouting an immune attack.

HLA genes are associated with many different diseases (same gene/locus involved).

Question 4

What is an oligogenic disorder?

Answer 4

Genetic risk is dependent on mutations in a handful of genes. Many of the affected individuals have a specific genotype, but not all.

Question 5

What explains the “Dark Matter” in GWAS?

Answer 5

Even when statistically significant, many genetic factors picked up by GWAS only predict a small percentage of heritability of any particular phenotype. (E.g., height is 80% heritable, but 40 genetic loci only account for 5% of phenotypic variance).

• Rarer variants (below 5% threshold) have large, undetected impact
• Structural variants poorly captured (duplications/deletions)
• Low power for gene x gene interaction
• Over-estimation of heritability

Question 6

What are the implications of gene x environment interactions?

Answer 6

Two alleles that on their own confer only mild risk may confer a higher risk together.

Rat study: Within each allele, early feeding determines order, but all the homozygous rats are heavier than even the most obese heterozygous rat. Gene (Fa vs. fa fa) x environment (feeding time) interaction.

Question 7

What is linkage disequilibrium?

Answer 7

Correlation of neighboring alleles due to common haplotype ancestry.

Two genes segregate together at a higher-than-expected rate because they are located close together.

One SNP is use to “score” an entire region in genetic analysis (i.e., SNP is 5kb, but “score” region of LD covering 20kb).

Question 8

What is a phenocopy?

Answer 8

A phenotype without genetic basis; under certain environmental conditions, one genotype’s phenotype resembles another genotype’s phenotype.

Question 9

What is genetic heterogeneity?

Answer 9

Different genes resulting in the same phenotype.

• Early onset Alzheimer’s caused by different genes than late onset (but same phenotype)
• Bardet-Biedl Syndrome (obesity, polydactyly) has at least 18 genes causing the cilia defects responsible for the syndrome.