Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD. ; Yang-Lin Liu, Helen L. Reeves, Alastair D. Burt, Dina Tiniakos, Stuart McPherson, Julian B. S. Leathart, Michael E. D. Allison, Graeme J. Alexander, Anne-Christine Piguet, Rodolphe Anty, Peter Donaldson, Guruprasad P. Aithal, Sven Francque, Luc Van Gaal, Karine Clement, Vlad Ratziu, Jean-Francois Dufour, Christopher P. Day, Ann K. Daly, Quentin M. Anstee