A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn’s Disease and Human Gut Microbiome Composition

Abstract

BACKGROUND & AIMS Genome-wide association studies (GWAS) have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn’s disease (CD) and ulcerative colitis (UC) remains incompletely defined. Here we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip. METHODS Genotyping was performed in 10,523 IBD cases and 5,726 non-IBD controls. 91,713 functional single nucleotide polymorphism (SNP) loci in coding regions were analyzed. A novel identified association was further replicated in two independent cohorts. We further examined the association of the identified SNP with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface (MLI) cohort measured using 16S sequencing. RESULTS We identified an association between CD and a missense variant encoding alanine (Ala) or threonine (Thr) at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 Ala391Thr, rs13107325) and replicated the association with CD in two replication cohorts (combined meta-analysis p=5.55×10−13). This variant has previously been associated with distinct phenotypes including obesity, lipid levels, blood pressure and schizophrenia. We subsequently determined that the CD-risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (p=0.009) and CD cases (p=0.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (p=9.24×10−16) and overweight individuals (p=6.73×10−16). CONCLUSIONS Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

“…SLC39A8 is required during cardiac development and regulates zinc transport in endothelium (49). Recent studies also highlight a role for the SLC39A8 common variant in regulation of the gut microbiome and metal homeostasis in Crohn's disease (4,50,51).…”

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

“…Top pleiotropic SNPs included (1) rs13107325, a non-synonymous SNP in the gene SLC39A8, which was fine-mapped for balding, BMI, diastolic blood pressure, forced vital capacity, height, red blood cell count, total cholesterol, and waist hip ratio (adjusted for BMI); (2) rs1229984, a nonsynonymous SNP in the gene ADH1B, which was fine-mapped for BMI, LDL, mean corpuscular hemoglobin, mean platelet volume, systolic blood pressure, total cholesterol, and Vitamin D; and (3) rs76895963, a conserved intronic SNP in a promoter of the gene CCND2, which was fine-mapped for bone mineral density, height, red blood cell count, systolic blood pressure and triglycerides. The gene SLC39A8 is a zinc transporter and is associated with congenital disorder of glycosylation 36,37 ; the gene ADH1B is an alcohol dehydrogenase gene and is associated with alcohol dependence 38 ; and the gene CCND2 participates in cell cycle regulation and is associated with delayed psychomotor development 39 . We note that previous studies have reported that genetically uncorrelated traits often share association signals at the same loci 40 , but did not fine-map those signals to individual SNPs as performed here.…”

Host genetics and microbiome associations from the lens of genome wide association studies

“…The first such studies in humans focused on specific genes and pathways, and have identified several significant microbiome-associated variants [41][42][43][44][45]. However, a potential shortcoming of the above studies is that they require previous knowledge of associated genes, and thus cannot discover new associations.…”