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HMB321H1 Study Guide - Final Guide: Allele Frequency, National Institutes Of Health, Genotyping

Human Biology
Course Code
Dr. Maria Papaconstantinou
Study Guide

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How to Interpret a GWAS - Pearson and Manolo(answer GWAS short answer ques)
A GWA study is defined by the NIH as a study of common genetic variation across the
entire human genome designed to identify genetic associations with observable
The present discussion focuses on studies attempting to assay at least 100,000
SNPS selected to serve as proxies for the largest possible number of SNPs.
The typical GWAS study has 4 parts:
1) Selection of a large number of individuals with the disease or trait of interest and a
suitable comparison group`
2) DNA isolation, genotyping and data review to ensure high genotyping quality
3) Statistical tests for associations between the SNPs passing quality thresholds and
the disease/trait.
4) Replication of identified associations in an independent population sample or
examination of functional implications experimentally.
While GWAS has been used to identify SNPs associated with common diseases, the
technique can be used to find genetic variants to quantitative traits such as height, and
to rank the relative importance of the previously identified susceptibility genes. GWAS
can also demonstrate gene-gene interactions or modification of the association of one
genetic variant by another and can detect high-risk haplotypes or combinations of
multiple SNPS within a single gene. These studies have been also used to identify SNPs
associated with gene expression, either as a confirmation of a phenotypic association or
more globally. Thus, GWAS have broader applications than those solely involving covery of
individual SNPs associated with discrete disease end points.
The most frequently used GWAS design to date has been the case-control design, in which
allele frequencies in patients with the disease were compared to those in a disease-
free comparison group. These studies are often easier and less expensive to conduct
than studies using other designs, especially if sufficient number of case and control
participants can be assembled rapidly. This design also carries the most assumption
s which if not met, can lead to substantial biases and false associations. The most
important of these biases involve the selected, often unrepresentative nature of the
study case participants, who are typically sampled from clinical sources and thus,
may not include fatal, mild or silent cases not coming to clinical attention; and the lack
of comparability of case and control participants, who may differ in important ways that
could be related to both genetic risk factors and to disease outcomes.
If the well-established principles of epidemiologic design are followed, case-control studies
can produce valid results, that for rare diseases, may not be obtained in any other way.
However GWAS using the case-control methodologies have not adhered to these principles.
The trio design includes the affected case participant and both of his/her parents.
Phenotypic assessment (classification of the affected status) is performed only in the
affected offspring, and only the affected offspring are included however the genotyping is
performed in all 3 trio members. The frequency with which an allele is transmitted to an

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affected offspring from heterozygous parents is then estimated. The trio design studies
allele transmission from parents to offspring, it is not susceptible to population
stratification or that genetic differences between the case and control participants unrelated
to disease but due to sampling them from population from different ancestry. A significant
challenge of the trio design in GWAS is its sensitivity to even small degrees of
genotyping error which can distort transmission proportions between parents and
offspring, especially for uncommon alles. Therefore, standard for genotyping quality in trio
sudies needs to be more strict than other designs.
Cohort studies involve collecting extensive baseline information in a large number of
individuals who are then observed to assess the incidence of disease in subgroups
defined by genetic variants. These studies are typically more expensive and take longer
to condct than case-control, they often include study participants who are more
representative than clinical series of the population from which they are drawn, and
they typially include a vast array of health-related characteristics and exposures for which
genetic associations can be sought.
Many GWAS use multistage designs to reduce the number of false-positive results
while minimizing the number of costly genome-wide scans performed and retaining
statistical power. Genome-wide scans are typically performed on an initial group of case
and control participants and then a smaller number of associated SNPs is replicated in
a second or third group of case and control paricipants. Some studies begin with small
numbers of particiapnts in the intial scans but carry forward large numbers of SNPs to
minimize false-negative reuslts.

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