Week 4

Question 0

What do the QQ plots show?

Answer 0

Shows the expected vs observed p values

(This can help us see if there is a systematic inflation of p values due to poor quality control or population stratification)

Question 1

Why don’t candidate genes replicate?

Answer 1

False negatives

• replication samples were underpowered to replicate the initial effect
• replication samples have a different methodology or different inclusions/exclusion criteria than us
• there may be gene x environment interaction effects going on

False positives

• multiple testing and publication bias
• methodological limitations in our study
• the winners curse

Question 2

Why are GWAS studies not finding the heritability (missing heritability)

Answer 2

The effect sizes are too small

It’s just not that heritable

It’s too heterogenous

It’s due to gene-environment interactions

Question 3

Individually, variants have small effect sizes - what does this mean with regards to a GWAS study?

Answer 3

To find effect sizes this small requires a very large sample (n > 10 000)

Question 4

Using the QQ plots what was it possible to show with GWAS studies of intelligence?

Answer 4

That there was a “lifting off” of the observed p values from the predicted, this shows that the SNPs are there and they are each having a tiny effect, but the studies just not reaching genome-wide significance due to power issues from sample size.

Question 5

What is one (sort of) answer to the case of

Missing heritability in GWAS?

Answer 5

Looking at the cumulative effect of variants using polygenic approaches such as genome-wide complex trait analysis.

Question 6

Were the same findings found for depression as was found for intelligence?

Answer 6

No - even with a sample of 10 000 (Ripke et al., 2013)

• possibly due to heterogeneity of the disorder and diagnostic criteria

Question 7

Perhaps depression is not that heritable, how have studies shown that this is unlikely to be the case?

Answer 7

Depression heritability = .37

Parkinson’s = .30

Parkinson study with 5333 cases got several hits

Question 8

Is depression heterogenous?

Answer 8

Yes the differences between typical and atypical depression are large (e.g. Sleep: decreased or excessive| appetite reduced or increased respectively

Question 9

How can heterogeneity play a role in missing heritability? (With regards to depression)

Answer 9

Major depression includes several sub types

Typical/atypical
Post-natal
Catatonic
Seasonal affective disorder

GWAS studies limp all these subtypes together but they might have very distinct aetiologies

Question 10

Discuss the gxe interaction between stress and depression

Answer 10

Stress is an established risk factor for depression (80% of those with depression report stress)

However, it is not necessary (20% people don’t report stress) or sufficient to cause the disorder (not everyone who has stress develops depression)

Genes make some people resilient and others sensitive to stress -> depression

Question 11

Why is the 5-HTTLPR gene-environment interaction controversial?

Answer 11

Findings have not always replicated. A large meta-analysis found no significant interaction effects (risch et al.,)

However this paper left out quite a lot of studies, a more inclusive meta-analysis (n = > 40000) dos for a significant result.

Question 12

When are gene-environment interactions for the 5-HTTLPR gene strongest?

Answer 12

When the life event is childhood maltreatment and when considering chronic depression (brown, 2013)

Question 13

A diathesis is?

Answer 13

A genetic variant

Question 14

What does the diathesis stress model suggest?

Answer 14

A diathesis (genetic variant) makes an individual vulnerable to a stressor

Question 15

What did Eley et al (2004) study find?

Answer 15

Adolescents at high environmental risk (e.g. stressful life events) were consistent with Caspi et al., (2003) finding

(Depressive symptoms were highest in those with the ss genotype exposed to stress)

HOWEVER…
Those with the ss genotype not exposed to stress had the fewest symptoms

Suggesting differential susceptibility

Question 16

What did Hanklin et al (2011) study find?

Answer 16

Found the same results as Eley et al., (2004) but with an adult population of neuroticism:

Those with the ss genotype exposed to positive life events had the best outcomes.

And again the same results were found for a study on parenting and child outcomes

Question 17

What does differential susceptibility mean?

Answer 17

Genetic variants makes individuals more sensitive to their environment: for better or for worse.

Question 18

Are there genetic differences between those who report high and low stress levels?

Answer 18

Yes the total genetic effects are greatest for those reporting stress and for those reporting less stress genes play less of a role,

So there could be quantitative etiological differences between the high and low stress groups.

Question 19

Where should the future of depression research go next?

Answer 19

Depression is a polygenic disorder which results from multiple genetic variants of small effect sizes

But all out gxe studies have focused on a small selection of candidate genes which often fail to replicate

We clearly need to take a systematic genome- wide approach!