Normal Variation, GWAs

Rare vs. Common Diseases, Conditions and Traits

  • Rare Conditions/diseases: single gene, predictable

    • Achondroplasia, Cystic Fibrosis, Huntington, Hemophilia, Sickle Cell Anemia, etc.


  • Common diseases: more complex “run in families”, less predictable

    • Heart disease, diabetes, psychiatric disorders, cancers, asthma, high blood pressure, obesity, hypothyroidism, etc.


  • Common (NORMAL) traits: complex “run in families” less predictable

    • Height, personality, physical ability, appearance, cognition


Quantitative vs. Qualitative Traits

  • Quantitative trait: In genetics, quantitative traits fall on a continuum. Multiple genes are involved and often they are influenced by environmental factors — ex. height


  • Qualitative trait: A qualitative trait is one that is either/or, if you don’t have the right allele (s) of a gene, you don’t have the phenotype — ex: Mendelian traits: round or wrinkled pea seeds

  • Single Nucleotide Polymorphisms (SNPs): A SNP is a common type of genetic variation where a single nucleotide in the DNA sequence differs among individuals in a population. — a person can be homozygous or heterozygous for a SNP


  • GWS: An approach that rapidly scans SNPs across the complete genome of many people to find genetic variations (SNPs) associated with a particular trait or disease.

    • Extremely powerful tool for identifying genes that are associated with a specific disease, condition, or trait

    • GWAS study identifies regions of the genomes that appear to contribute to a conditions. They do not prove that an individual SNP contributes to the condition.

      • typically, several hundred thousand spanning every chromosome

COMMON DISEASES


  • Monogenic Trait - Mendelian: controlled by one gene — very few in humans

    • usually discontinuous phenotypes, qualitative traits


  • Multifactorial/Complex Trait: controlled by multiple genes AND environmental factors

    • usually continuous phenotypes, quantitative traits

    • Characteristics of Multifactorial Traits:

      • Multiple genes are involved

      • Each gene involved contributes a small amount to phenotype

      • Environmental factors interact with genes to produce the phenotype

      • Distributions form a bell-shaped curve

      • Trait not inherited in a recognizable Mendelian fashion

      • Trait “runs” in families vs. general population, with frequencies much lower than Mendelian predictions

    • The genetic component is responsible for disease susceptibility. The phenotype or disease occurs when a genetically susceptible individual is exposed to the adverse environmental factors. → some genetically susceptible individuals will not be affected because the environmental exposure was not present


  • ALL diseases are discontinuous — either you have the disease or you don’t, but severity can vary


  • General concept of Multifactorial (complex) Disease

    • Some variants can increase disease risk; others can decrease risk → together, defines susceptibility

    • Same goes to environmental factors


Monogenic/Mendelian vs. Environmental/Multifactorial

  • Monogenic: the risk of disease is almost all genetic, but variation in the environment may alter the severity


  • Environmental: the risk of disease is almost all environmental, but genetic variants may alter the severity

    • Most common human diseases and conditions are multifactorial: ex. high blood pressure, high cholesterol, bipolar disorder, arthritis, allergies, etc.


  • Neural tube defect: failure of neural tube completely closing before birth

    • Multifactorial birth defect: multiple genes + environment (mother’s diet)

      • FDA began requiring addition of folic acid to enriched breads, cereals, flours, pastas, and other grain products → this lead to drop in neural tube defects

Why are Multifactorial Diseases Difficult to Study?

  • Haploid genome has 3 billion base pairs

  • ~20,000 protein-coding genes + more non-coding genes

  • Many genes involved in each disease

  • Many environmental factors are also involved


Goals for Studying Complex Diseases?

  • Determine which genes cause disease or increase disease risk (or protect against disease and lower risk)

  • Determine which variants (alleles) in these genes are responsible

    • Use the data to identify individuals who are at risk and find interventions that can reduce their risk


Liability for a Multifactorial Disease: Individuals have a set of liabilities for a given condition - combination of a protective or pre-disposing genes and favorable or unfavorable environmental influences.

  • When the cumulative contributions exceed a certain threshold, the capacity of the individual to buffer against the liabilities is overcome, and the trait is seen