Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families

Arunabh Sharma; Olaf Junge; Silke Szymczak; Malte Christoph Rühlemann; Janna Enderle; Stefan Schreiber; Matthias Laudes; Andre Franke; Wolfgang Lieb; Michael Krawczak; Astrid Dempfle

doi:10.3389/fgene.2023.1048312

Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families

Front Genet. 2023 Jan 23:14:1048312. doi: 10.3389/fgene.2023.1048312. eCollection 2023.

Authors

Affiliations

¹ Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany.
² Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
³ Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
⁴ Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
⁵ Institute of Epidemiology, Kiel University, Kiel, Germany.
⁶ Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
⁷ Institute of Diabetology and Clinical Metabolic Research, Kiel University, Kiel, Germany.

Abstract

Introduction: Inflammatory bowel disease (IBD) is characterized by a dysbiosis of the gut microbiome that results from the interaction of the constituting taxa with one another, and with the host. At the same time, host genetic variation is associated with both IBD risk and microbiome composition. Methods: In the present study, we defined quantitative traits (QTs) from modules identified in microbial co-occurrence networks to measure the inter-individual consistency of microbial abundance and subjected these QTs to a genome-wide quantitative trait locus (QTL) linkage analysis. Results: Four microbial network modules were consistently identified in two cohorts of healthy individuals, but three of the corresponding QTs differed significantly between IBD patients and unaffected individuals. The QTL linkage analysis was performed in a sub-sample of the Kiel IBD family cohort (IBD-KC), an ongoing study of 256 German families comprising 455 IBD patients and 575 first- and second-degree, non-affected relatives. The analysis revealed five chromosomal regions linked to one of three microbial module QTs, namely on chromosomes 3 (spanning 10.79 cM) and 11 (6.69 cM) for the first module, chr9 (0.13 cM) and chr16 (1.20 cM) for the second module, and chr13 (19.98 cM) for the third module. None of these loci have been implicated in a microbial phenotype before. Discussion: Our study illustrates the benefit of combining network and family-based linkage analysis to identify novel genetic drivers of microbiome composition in a specific disease context.

Keywords: family-based study design; gut microbiome; inflammatory bowel disease; linkage analysis; microbiome co-occurrence network.

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft through Research Training Group 1743 “Genes, Environment and Inflammation” (grant numbers GRK 1743, GRK 1743/2), CRC1182 “Origin and Function of Metaorganisms” (grant number 261376515), DFG Research Unit FOR5042 “The microbiome as a therapeutic target in inflammatory bowel diseases” (grant number DE1614/4-1) and Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (grant number EXC2167) and the German Bundesministerium für Bildung und Forschung (grant number 0315540).