Acknowledgements: R.P. was supported by Rutherford Fund fellowship from the Medical Research Council (MR/R026505/1 and MR/R026505/2). B.A., X.J., and F.O. were supported by Rutherford Fund from Medical Research Council MR/R026505/2. R.M. was funded by the President’s PhD Scholarship from Imperial College London. PE is Director of the MRC Centre for Environment and Health and acknowledges support from the Medical Research Council (MR/S019669/1). PE also acknowledges support from the UK Dementia Research Institute, Imperial College London (UKDRI-5001), Health Data Research UK London (HDRUK-1004231) and the British Heart Foundation Imperial College London Centre for Research Excellence (BHF-RE/18/4/34215). The Airwave Health Monitoring Study was funded by the UK Home Office (780- TETRA, 2003-2018) and is currently funded by the MRC and ESRC (MR/R023484/1) with additional support from the NIHR Imperial College Biomedical Research Centre in collaboration with Imperial College NHS Healthcare Trust. R.C.P is supported by the UK Dementia Research Institute (UKDRI-5001), which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Work in LMM’s laboratory is supported by the UK Medical Research Council, intramural project MC_UU_00025/3 (RG94521). The views expressed are those of the authors and not necessarily those of the sponsors. We thank Prof. Ulrike Heberlein, (Janelia Research Campus, Virginia, USA) for generously providing us the hppy17-51 fly lines. This research was funded, in whole or in part, by the Medical Research Council (MR/R026505/1 and MR/R026505/2). A CC BY or equivalent licence is applied to the Author Accepted Manuscript (AAM) arising from this submission, in accordance with the grant’s open access conditions.Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD
