Genome-wide association study of liver fat, iron, and extracellular fluid fraction in the UK Biobank

Colm T. O’Dushlaine; Mary Germino; Niek Verweij; Jonas Bille Nielsen; Ashish Kumar Yadav; Christian Benner; Joshua Backman; Nan Lin; Gonçalo R. Abecasis; Aris Baras; Manuel A. R. Ferreira; Luca Andrea Lotta; Johnathon R. Walls; Prodromos Parasoglou; Jonathan Marchini

doi:10.1101/2021.10.25.21265127

Genetic & Genomic MedicinemedRxivOct 25, 2021

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Genome-wide association study of liver fat, iron, and extracellular fluid fraction in the UK Biobank

Colm T. O’Dushlaine iD, Mary Germino iD, Niek Verweij iD, Jonas Bille Nielsen iD, Ashish Kumar Yadav iD, Christian Benner iD, Joshua Backman iD, Nan Lin iD, Gonçalo R. Abecasis iD, Aris Baras iD, Manuel A. R. Ferreira iD, Luca Andrea Lotta iD, Johnathon R. Walls, Prodromos Parasoglou iD, Jonathan Marchini iD

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Abstract

Abdominal magnetic resonance imaging (MRI) represents a non-invasive approach allowing the extraction of clinically informative phenotypes. We developed an automated pipeline to segment liver pixels from abdominal MRI images and apply published models to approximate fat fraction, extracellular fluid fraction and iron content in 40,058 MRIs from the UK Biobank. We then conducted a genome-wide association of these traits using imputed variants (N=37,250 individuals, 11,914,698 variants) and exome sequence data (N=35,274 individuals, 8,287,315 variants). For liver fat we identified 8 novel loci in or near genes MARC1, GCKR, ADH1B, MTTP, TRIB1, GPAM, PNPLA2 and APOH. For liver iron we identified 1 novel locus between the genes ASNSD1 and SLC40A1, an iron transporter involved in hemochromatosis. For extracellular fluid fraction we identified 6 novel loci in or near genes AGMAT, NAT2, MRPL4-S1PR2, FADS1, ABO and HFE, with almost all having prior associations to obesity, liver, iron, or lipid traits.