MEDICAL GENETICS EXAM AND
ITS CORRECT ANSWERS
What are 3 ways to improve GWAS?
- more power -> increase sample size, increase effect
- better chip design or sequencing to detect rarer variants
- better case vs control definition -> e.g. some control may
have hypertension (ht) but not identified and the study
may be looking at genome for ht
What would it mean if HT had fewer risk alleles of
larger effect sizes than other complex phenotypes?
identification of susceptible variants for ht is likely to be
reliant on synthesis of findings from multiple large scale
studies
Why should you use diverse populations in GWAS?
Expanding studies to underrepresented populations can
uncover novel genetic associations and improve the
generalizability of finding
What is a LOD score?
logarithm of the odds score, is a statistical estimate of
how likely it is that two genetic loci are close together
on a chromosome. A LOD score of 3 or higher generally
indicates that two genes are close together and are likely
to be inherited together
Linkage was interpreted as significant if the logarithm of
odds (LOD) score was ≥ 3.0, “noteworthy” if the LOD
score was ≥ 2.6, and scores ≥ 2.0 were identified as
“interesting”.
,What is a GWAS?
any study that measures genetic variation over the entire
genome and looks for associations between the variation
and phenotype variability
What do association studies focus on?
the relationship between a specific allele and a disease
within a population
How does association and linkage studies differ?
association is associated with a disease in a similar
manner across a whole population whereas linkage allows
different alleles to be associated with the disease in
different families
How do GWAS asses significance of the association?
P-value
How does a linkage studies identify genes associated
with CVD?
through analysing DNA markers in families where multiple
members are affected
How do linkage studies asses the significance of
association?
using LOD score
What are 4 benefits of GWAS?
1. can pinpoint specific loci / SNPs associated with the
disease
2. can analyse hundred of thousands of individuals
capturing common variants with small effect sizes
3. unbiased approach and reflective of a wide population
rather then just one family
4. polygenic risk scores help predict individual risk based
on genetic variation
What are 2 limitations of GWAS?
, 1. population bias if study cohort is not diverse
2. rare variants with big impacts may be missed due to
limitations in chip design and sample size
What are 2 benefits of linkage studies?
1. effective for mendelian diseases where it is caused by a
mutation in a single gene
2. no need for large sample sizes
What are 3 limitations of linkage studies?
1. requires multigenerational families -> not always
available
2. ineffective for complex diseases like CVD as there are
several environmental and polygenic factors
3. linkage studies identify large regions within the genome,
therefore requires further mapping to pinpoint the
causative gene
What happens in SMA type 0?
- symptoms present before birth
- extremely severe
- decreased foetal movement
- difficulty swallowing
- respiratory failure after birth
- life expectancy 2 months
- very rare
What happens in SMA type 1?
- most common ~60%
- severe
- muscle weakness by 6 months
- never sit independently
- difficulties suckling or swallowing
- normal intelligence
ITS CORRECT ANSWERS
What are 3 ways to improve GWAS?
- more power -> increase sample size, increase effect
- better chip design or sequencing to detect rarer variants
- better case vs control definition -> e.g. some control may
have hypertension (ht) but not identified and the study
may be looking at genome for ht
What would it mean if HT had fewer risk alleles of
larger effect sizes than other complex phenotypes?
identification of susceptible variants for ht is likely to be
reliant on synthesis of findings from multiple large scale
studies
Why should you use diverse populations in GWAS?
Expanding studies to underrepresented populations can
uncover novel genetic associations and improve the
generalizability of finding
What is a LOD score?
logarithm of the odds score, is a statistical estimate of
how likely it is that two genetic loci are close together
on a chromosome. A LOD score of 3 or higher generally
indicates that two genes are close together and are likely
to be inherited together
Linkage was interpreted as significant if the logarithm of
odds (LOD) score was ≥ 3.0, “noteworthy” if the LOD
score was ≥ 2.6, and scores ≥ 2.0 were identified as
“interesting”.
,What is a GWAS?
any study that measures genetic variation over the entire
genome and looks for associations between the variation
and phenotype variability
What do association studies focus on?
the relationship between a specific allele and a disease
within a population
How does association and linkage studies differ?
association is associated with a disease in a similar
manner across a whole population whereas linkage allows
different alleles to be associated with the disease in
different families
How do GWAS asses significance of the association?
P-value
How does a linkage studies identify genes associated
with CVD?
through analysing DNA markers in families where multiple
members are affected
How do linkage studies asses the significance of
association?
using LOD score
What are 4 benefits of GWAS?
1. can pinpoint specific loci / SNPs associated with the
disease
2. can analyse hundred of thousands of individuals
capturing common variants with small effect sizes
3. unbiased approach and reflective of a wide population
rather then just one family
4. polygenic risk scores help predict individual risk based
on genetic variation
What are 2 limitations of GWAS?
, 1. population bias if study cohort is not diverse
2. rare variants with big impacts may be missed due to
limitations in chip design and sample size
What are 2 benefits of linkage studies?
1. effective for mendelian diseases where it is caused by a
mutation in a single gene
2. no need for large sample sizes
What are 3 limitations of linkage studies?
1. requires multigenerational families -> not always
available
2. ineffective for complex diseases like CVD as there are
several environmental and polygenic factors
3. linkage studies identify large regions within the genome,
therefore requires further mapping to pinpoint the
causative gene
What happens in SMA type 0?
- symptoms present before birth
- extremely severe
- decreased foetal movement
- difficulty swallowing
- respiratory failure after birth
- life expectancy 2 months
- very rare
What happens in SMA type 1?
- most common ~60%
- severe
- muscle weakness by 6 months
- never sit independently
- difficulties suckling or swallowing
- normal intelligence
