Table 3.
Rare microbial quantitative trait loci identified by gene-based burden meta-analyses
| Chr | SNP* | Gene symbol | Annotation | Microbial taxonomy/pathway | Microbial change† | Meta P value‡ | Meta FDR | LifeLines-DEEP cohort | IBD cohort | ||
| P value§ | Beta¶ | P value§ | Beta¶ | ||||||||
| 3 | 3:156 570 689 rs200834448 3:156 710 862 | LEKR1 | Stop gain, frameshift variant, splice donor variant and intron variant |
Superpathway of hexitol degradation bacteria | Increase in IBD/CD/UC | 8.42×10–7 | 8.25×10–4 | 1.84×10–5 | 0.61 | 0.016 | 0.54 |
| 5 | rs114285050 rs140458264 | GPR151 | Stop gain, stop gain | Homolactic fermentation | Increase in IBD/CD | 4.78×10–6 | 0.0047 | 0.0032 | −1.17 | 0.00040 | −1.40 |
| 5 | rs114285050 rs140458264 | GPR151 | Stop gain, stop gain | Glycolysis I from glucose 6-phosphate | Increase in IBD/CD | 5.45×10–6 | 0.0053 | 0.0030 | −1.17 | 0.00048 | −1.38 |
| 5 | rs114285050 rs140458264 | GPR151 | Stop gain, stop gain | Glycolysis II from fructose 6-phosphate | Increase in IBD/CD/UC | 4.63×10–6 | 0.0045 | 0.0028 | −1.18 | 0.00044 | −1.38 |
| 5 | rs114285050 rs140458264 | GPR151 | Stop gain, stop gain | Superpathway of glucose and xylose degradation | Increase in IBD/CD | 3.05×10–6 | 0.0030 | 0.015 | −0.97 | 0.00041 | −1.39 |
| 13 | rs139121187 rs150812023 | TPTE2 | Stop gain, splice donor variant and intron variant | Glycolysis IV plant cytosol | – | 4.62×10–6 | 0.0045 | 0.015 | 1.19 | 0.00029 | 2.47 |
| 22 | rs35742686 rs5030655 |
CYP2D6 | Frameshift variant, frameshift variant | Superpathway of menaquinol-8 biosynthesis I | – | 1.45×10–5 | 0.014 | 0.00015 | −0.91 | 0.021 | −0.63 |
| 22 | rs35742686 rs5030655 | CYP2D6 | Frameshift variant, frameshift variant | Superpathway of demethylmenaquinol-8 biosynthesis | – | 1.50×10–5 | 0.015 | 0.00019 | −0.90 | 0.019 | −0.65 |
Eight associations were identified by the gene-based burden test. We collapsed exome-wide protein truncating variants (PTVs) with minor allele frequency <5% into 980 genes. Genetic scores were used instead of single variant dosage in the association analyses in each cohort. Meta-analyses were performed for those associations with discovery p<0.005 and replication p<0.05.
*Rare PTVs located within genes used in the burden test.
†Case-control analysis on microbial data. Significant (FDR<0.05) microbial change in IBD are shown (online supplementary table 7).
‡Meta p value cut-off determined based on the total number of genes (n=980, Bonferroni correction).
§P values from association analyses in each cohort.
¶Effect size in association analyses in each cohort.
CD, Crohn’s disease.