Antonio F Di'Narzo1, Sander M Houten2, Roman Kosoy2, Ruiqi Huang3, Frédéric M Vaz4, Ruixue Hou3, Gabrielle Wei2, Wenhui Wang2, Phillip H Comella2, Tetyana Dodatko2, Eduard Rogatsky2, Aleksandar Stojmirovic5, Carrie Brodmerkel5, Jacqueline Perrigoue5, Amy Hart5, Mark Curran5, Joshua R Friedman5, Jun Zhu6, Manasi Agrawal7, Judy Cho7, Ryan Ungaro7, Marla C Dubinsky7, Bruce E Sands7, Mayte Suárez-Fariñas8, Eric E Schadt6, Jean-Frédéric Colombel7, Andrew Kasarskis9, Ke Hao6, Carmen Argmann10. 1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Sema4, Stamford, Connecticut. 2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, New York, New York. 3. Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Department of Clinical Chemistry, Amsterdam Gastroenterology & Metabolism, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 5. Janssen R&D, LLC, Spring House, Pennsylvania. 6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Sema4, Stamford, Connecticut; Icahn Institute for Data Science and Genomic Technology, New York, New York. 7. The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 8. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Sema4, Stamford, Connecticut; Icahn Institute for Data Science and Genomic Technology, New York, New York; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. 10. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, New York, New York. Electronic address: carmen.argmann@mssm.edu.
Abstract
BACKGROUND & AIMS: Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. METHODS: We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. RESULTS: We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
BACKGROUND & AIMS: Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. METHODS: We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. RESULTS: We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
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