On 2016 May 03, Marcus Munafò commented:

Joshi and colleagues report that genetic variants in the CHRNA5-A3-B4 gene cluster and the APOE gene are associated with lifespan. This is not surprising – the former influences smoking behaviour, which in turn leads to a number of adverse health outcomes, while the latter influence Alzheimer disease risk. The critical insight here is that genetic studies can provide information about the role of modifiable, behavioural determinants of health and disease, such as smoking [1]. In many cases, this will be the most parsimonious explanation. For example, while we agree with Joshi and colleagues that the effects of CHRNA5-A3-B4 on lung cancer remain after adjustment for self-reported smoking intensity, this is most likely because self-report measures poorly capture actual tobacco exposure, given inter-individual differences in smoking topography (e.g., number of puffs taken per cigarette, depth of inhalation, etc.) [2]. When the association between and CHRNA5-A3-B4 smoking intensity is estimated using cotinine, a precise biomarker of exposure, this is sufficient to fully account for the observed association between CHRNA5-A3-B4 and lung cancer [3]. Joshi and colleagues describe the genes they identify as associated with lifespan as “very pleiotropic”, but the distinction between biological (or horizontal) and mediated (or vertical) pleiotropy is important here (4). 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. In our opinion, many effects of CHRNA5-A3-B4 on health outcomes are likely to be the result of mediated pleiotropy. In other words, smoking kills.

Marcus Munafò and George Davey Smith

1. Gage, S.H., et al. G = E: What GWAS Can Tell Us about the Environment. PLoS Genetics, 2016. 12(2): e1005765.

2. McNeill, A. and Munafò, M.R. Reducing harm from tobacco use. Journal of Psychopharmacology, 2013. 27(1): p. 13-8.

3. Munafò, M.R., et al. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute, 2012. 104(10): p. 740-8.

4. Davey Smith, G. and Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 2014. 23(R1): p. R89-98.

On 2016 May 03, Marcus Munafò commented:

Joshi and colleagues report that genetic variants in the CHRNA5-A3-B4 gene cluster and the APOE gene are associated with lifespan. This is not surprising – the former influences smoking behaviour, which in turn leads to a number of adverse health outcomes, while the latter influence Alzheimer disease risk. The critical insight here is that genetic studies can provide information about the role of modifiable, behavioural determinants of health and disease, such as smoking [1]. In many cases, this will be the most parsimonious explanation. For example, while we agree with Joshi and colleagues that the effects of CHRNA5-A3-B4 on lung cancer remain after adjustment for self-reported smoking intensity, this is most likely because self-report measures poorly capture actual tobacco exposure, given inter-individual differences in smoking topography (e.g., number of puffs taken per cigarette, depth of inhalation, etc.) [2]. When the association between and CHRNA5-A3-B4 smoking intensity is estimated using cotinine, a precise biomarker of exposure, this is sufficient to fully account for the observed association between CHRNA5-A3-B4 and lung cancer [3]. Joshi and colleagues describe the genes they identify as associated with lifespan as “very pleiotropic”, but the distinction between biological (or horizontal) and mediated (or vertical) pleiotropy is important here (4). 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. In our opinion, many effects of CHRNA5-A3-B4 on health outcomes are likely to be the result of mediated pleiotropy. In other words, smoking kills.

Marcus Munafò and George Davey Smith

1. Gage, S.H., et al. G = E: What GWAS Can Tell Us about the Environment. PLoS Genetics, 2016. 12(2): e1005765.

2. McNeill, A. and Munafò, M.R. Reducing harm from tobacco use. Journal of Psychopharmacology, 2013. 27(1): p. 13-8.

3. Munafò, M.R., et al. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute, 2012. 104(10): p. 740-8.

4. Davey Smith, G. and Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 2014. 23(R1): p. R89-98.