Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome

Abstract

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory neurologic and neoplastic diseases. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain. Nevertheless, twin-studies clearly suggest host-genetics as driver of microbiome composition. In a genome-wide association analysis of 8,956 German individuals, we identified 32 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics, and its associated microbial communities as a 'metaorganism' broadens our understanding of disease aetiology and emphasizes the potential for implementing microbiota in disease treatment and management.

Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

“…Our study confirms previous findings 5 that secretor status or blood types do not seem to globally affect gut microbial alpha- or beta-diversity. It also confirms reports from two very recent studies: the first of these studies, a meta-analysis across five German cohorts, using 16S rRNA sequencing to characterize the gut microbiota, linked Bacteroides and Faecalibacterium to ABO and FUT2 79 . The second study, taking a functional approach, intriguingly associated bacterial lactose and galactose degradation genes to ABO variation in a cohort of 3,432 Chinese individuals 80 .…”

Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

“…We did not detect any evidence of interaction with diet at this locus, although this could be due to limitations in available information as the recording of dietary information was done at different times than stool collection time. We did, however, confirm that association at this locus depends on secretor status determined by the FUT2 gene 28 and thus on the ability to incorporate antigens into bodily fluids that are released in the gut. Intriguingly, we observed that taxa associated with the ABO locus also showed evidence of association at the LCT locus, indicating a common action of these two loci in contributing to the growth of these bacteria.…”

“…The strongest association with the gut microbiome was found at the LCT locus, which remains the most robust genetic association with gut microbiome identified to date. Associations at this locus with Bifidobacteria have been consistently reported in studies of different ethnicities, across a range of sample sizes, and in studies using different technologies and protocols for gut microbiome characterization 6,8,13,14,28 . We also confirmed that the increase of Bifidobacterium was more evident in LI individuals who were consuming milk or milk-derived products 13,29 .…”

“…Associations with microbiome composition at the ABO locus have been reported previously for populations of different ethnicities and in nonhuman species. For example, associations with Bacteroides and Faecalibacterium were reported in a study of five German cohorts that used 16S rRNA sequencing for gut microbiome characterization 28 and with the microbial pathway of lactose and galactose degradation in a cohort of 3,432 Chinese individuals 31 . The importance of ABO in determining host-microbiome interaction has also been recently reported in pigs 32 .…”

Quantifying the Impact of Human Leukocyte Antigen on the Human Gut Microbiota

“…Moreover, an association with microbiota composition has been observed for the HLA-DQ gene in relation to celiac disease ( 33 , 34 ). However, other genome-wide association studies did not find associations between HLA and the microbiome among many associated genes ( 35 , 36 ).…”