Genetics, coffee consumption, and Parkinson’s disease Answers

Question 1

Several case-control studies of PD have examined interactions of coffee consumption with candidate genes that were selected because of their associations with PD (e.g., SNCA), with caffeine metabolism (e.g., CYP1A2), or with caffeine’s CNS effects (e.g., ADORA2A). Although these studies have often confirmed previously observed main effects, they have not found statistically significant gene-environment interactions. Suggest two possible reasons why such studies have been unsuccessful in identifying interactions.

Answer 1

• Insufficient sample size/power to detect interactions
• Choice of non-involved candidate genes
• Selected statistical model of interaction doesn’t describe biological effects
• Imprecise or biased classification of coffee consumption

Question 2

From 2005 through mid-2012, 47 genome-wide association studies (GWAS) of PD reported 79 “hits” (highly significant associations) in 66 genes. Until 2011, none of these GWAS had examined any environmental risk factors (or protective factors). Comment on two challenges to studying gene-environment interactions in a GWAS.

Answer 2

• Most GWAS are composed of cases and controls assembled from multiple studies that either didn’t collect any environmental exposure information or collected it inconsistently.
• Even the large sample sizes assembled for GWAS may be insufficient to detect gene-environment interactions (proposed rule of thumb suggests that 4x as many participants are needed).
• Selected statistical models of interaction might not describe biological effects.

Question 3

Approximately how similar/different are the main effects of GRIN2A genotype and coffee intake?

Answer 3

• Heavy coffee intake and rs4998386 TC and TT genotypes are less frequent among cases than controls.
• Overall, heavy coffee intake is more prevalent (35% cases, 42% controls) than the TC genotype (15% cases, 22% controls). The TT genotype is very rare (0.8% cases, 1.1% controls).
• Both heavy coffee intake and the TC genotype have OR’s of approximately 0.65, suggesting they are “protective” against PD.
• The p-value for heavy coffee intake is smaller than that for the TC or TT genotypes.

Question 4

The authors stated that they tested models of “Dominant, Additive, and Recessive modes of inheritance” of the implicated GRIN2A allele. What does this statement mean?

Answer 4

It refers to analyses comparing different combinations of genotypes:

• TC/TT vs. CC (dominant)
• TT vs. TC vs. CC (additive, if TT is considered a “double dose”)
• TT vs. TC/CC (recessive)

Using data from the chart above, complete a 2×4 table for GRIN2A genotype, coffee intake, and PD case-control status. Combine data for the TC and TT genotype strata. Calculate odds ratios (OR), 95% confidence intervals, and p-values (based on Pearson chi-square). Use the largest stratum (CC genotype, Light coffee intake) as the reference group. Use the 2×2 chi-square calculator at http://statpages.org/ctab2x2.html or another similar program.

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Question 6

Use the case data from your table in 5. to perform a case-only analysis. Note that because coffee intake and the T allele have protective effects against PD, all the OR’s will be <1.0. In the absence of gene-environment interaction, the “synergy index,” which is calculated as ORge / (ORg * Ore) is expected to equal 1.0. Calculate the synergy index.

Is ORge / ( ORg * ORe ) equal to 1.0?

Answer 6

Is _0.376_ / (_0.794_ * _0.858_) equal to 1.0? No, it is 0.55

Question 7

Perhaps not, OR=1.43, 95% CI 1.04 – 1.97

Question 8

In the Abstract, the authors made three arguments for the importance of their findings. Based on your evaluation of the data presented in these questions (you are not required to review the entire article), how persuaded are you of each of their claims? Use the “smiling scale” to consider how you would rate each argument, then write 2 or 3 sentences to explain your ratings overall.

Example: This article makes me want to drink more coffee.

Argument 1
First, it is a proof of concept that studying genes and environment on the whole-genome scale is feasible, and this approach can identify important genes that are missed when environmental exposures are ignored.

Argument 2
Second, the knowledge of interaction between GRIN2A, which is involved in neurotransmission in the brain, and caffeine, which is an adenosine-A2A-receptor antagonist, will stimulate new research towards understanding the cause and progression of PD.

Argument 3
Third, the results may lead to personalized prevention of and treatment for PD.

Answer 8

This study is useful for drawing attention to the importance and potential feasibility of using gene-environment interactions to help interpret the results of GWAS studies. It should be considered hypothesis-generating and the first hypothesis to be tested should be the interaction of GRIN2A with coffee intake in PD. This finding requires replication in other studies before it can be considered a basis for further biological research and development of “personalized” interventions.