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Problems in interpreting and using GWAS of conditional phenotypes illustrated by 'alcohol GWAS'

Molecular Psychiatry volume 24, pages 167–168 (2019)Cite this article

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Dear Editor: We read with interest the findings of a genome-wide association study (GWAS) in the UK Biobank reported by Clarke et al. [1] in Molecular Psychiatry. The authors aimed to conduct a GWAS of alcohol consumption. Prior to conducting the GWAS, Clarke et al. regressed alcohol intake on body weight and age, and used the residuals from this regression analysis for the GWAS analysis. The authors identified 14 loci harbouring variants associated with the residuals at levels indicative of GWAS significance and took these forward to characterise the relationship of these SNPs with various phenotypes, such as adiposity.

By adjusting alcohol for body weight prior to the GWAS, Clarke et al. in effect generate a phenotype which is automatically associated with body weight and its correlates [2]. When the SNPs from the GWAS are combined (as the authors do), this would have the effect of generating a genetic instrument that has a positive association with alcohol and an inverse association with body weight. This can lead to spurious findings when the SNPs are then related to other traits. For example, in Fig. 3, the authors note a negative genetic correlation of alcohol consumption (indexed by SNPs associating with alcohol adjusted for body weight) with various markers of adiposity including waist circumference, body mass index, overweight and obesity. In Table 2, these relationships are more formally characterised: a polygenic risk score associating with 0.08 SD higher units of alcohol per week was associated with a 0.024 SD lower body mass index (BMI). A naive interpretation would be that more alcohol leads to less adiposity, however this would be incorrect. Large-scale Mendelian randomisation meta-analysis using rs1229984 in ADH1B has identified the genetic variant associated with more alcohol intake to be strongly associated with a higher (not lower) body mass index [3]. A recent instrumental variable study that used flushing as a proxy for ALDH2 genotype also suggested strong associations of more alcohol with higher BMI [4]. Thus, a large body of evidence using reliable Mendelian randomisation approaches indicates that consuming more alcohol, all things being equal, leads to higher BMI.

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References

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Authors and Affiliations

  1. Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK

    Michael V Holmes

  2. Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Big Data Institute Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK

    Michael V Holmes

  3. National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK

    Michael V Holmes

  4. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK

    Michael V Holmes & George Davey Smith

  5. Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK

    George Davey Smith

  6. National Institute for Health Research Bristol Biomedical Research Centre, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK

    George Davey Smith

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  1. Michael V Holmes
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Correspondence to Michael V Holmes or George Davey Smith.

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Holmes, M.V., Davey Smith, G. Problems in interpreting and using GWAS of conditional phenotypes illustrated by 'alcohol GWAS'. Mol Psychiatry 24, 167–168 (2019). https://doi.org/10.1038/s41380-018-0037-1

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