On 2016 Jun 10, Marcus Munafò commented:

Kim and colleagues highlight the role of genes on chromosome 12 in a range of cardio-metabolic traits, and argue that this reflects genetic pleiotropy. One prominent gene in this region is ALDH2, which has been shown to strongly influence alcohol consumption in East Asian samples, where the minor allele associated with reduced consumption is relatively common [1]. A more parsimonious explanation for the findings reported by Kim and colleagues, therefore, is simply that alcohol exerts a causal effect on cardio-metabolic traits.

Genetic studies can tell us about modifiable behavioural risk factors that contribute to disease [2], and results of genetic studies should therefore be interpreted with this in mind. In particular, the distinction between biological (or horizontal) and mediated (or vertical) pleiotropy is critical. The former refers to a genetic variant influencing multiple separate biological pathways, while the latter refers to the effects of a genetic variant on multiple outcomes via a single biological pathway. Effects of ALDH2 on cardio-metabolic traits most likely are due to the latter.

Marcus Munafò and George Davey Smith

1. Quertemont E. Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry, 2004. 9: p. 570-581.
2. Gage, S.H., et al. G = E: What GWAS Can Tell Us about the Environment. PLoS Genet, 2016. 12: e1005765.

On 2016 Jun 10, Marcus Munafò commented:

Kim and colleagues highlight the role of genes on chromosome 12 in a range of cardio-metabolic traits, and argue that this reflects genetic pleiotropy. One prominent gene in this region is ALDH2, which has been shown to strongly influence alcohol consumption in East Asian samples, where the minor allele associated with reduced consumption is relatively common [1]. A more parsimonious explanation for the findings reported by Kim and colleagues, therefore, is simply that alcohol exerts a causal effect on cardio-metabolic traits.

Genetic studies can tell us about modifiable behavioural risk factors that contribute to disease [2], and results of genetic studies should therefore be interpreted with this in mind. In particular, the distinction between biological (or horizontal) and mediated (or vertical) pleiotropy is critical. The former refers to a genetic variant influencing multiple separate biological pathways, while the latter refers to the effects of a genetic variant on multiple outcomes via a single biological pathway. Effects of ALDH2 on cardio-metabolic traits most likely are due to the latter.

Marcus Munafò and George Davey Smith

1. Quertemont E. Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry, 2004. 9: p. 570-581.
2. Gage, S.H., et al. G = E: What GWAS Can Tell Us about the Environment. PLoS Genet, 2016. 12: e1005765.