A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition

Li, Dalin, Achkar, Jean-Paul, Haritunians, Talin, Jacobs, Jonathan P., Hui, Ken Y., D'Amato, Mauro, Brand, Stephan, Radford-Smith, Graham, Halfvarson, Jonas, Niess, Jan-Hendrik, Kugathasan, Subra, Buening, Carsten, Schumm, L. Philip, Klei, Lambertus, Ananthakrishnan, Ashwin, Aumais, Guy, Baidoo, Leonard, Dubinsky, Marla, Fiocchi, Claudio, Glas, Juergen, Milgrom, Raquel, Proctor, Deborah D., Regueiro, Miguel, Simms, Lisa A., Stempak, Joanne M., Targan, Stephan R., Torkvist, Leif, Sharma, Yashoda, Devlin, Bernie, Borneman, James, Hakonarson, Hakon, Xavier, Ramnik J., Daly, Mark, Brant, Steven R., Rioux, John D., Silverberg, Mark S., Cho, Judy H., Braun, Jonathan, McGovern, Dermot P. B. and Duerr, Richard H. (2016) A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology, 151 4: 724-732. doi:10.1053/j.gastro.2016.06.051

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Author Li, Dalin
Achkar, Jean-Paul
Haritunians, Talin
Jacobs, Jonathan P.
Hui, Ken Y.
D'Amato, Mauro
Brand, Stephan
Radford-Smith, Graham
Halfvarson, Jonas
Niess, Jan-Hendrik
Kugathasan, Subra
Buening, Carsten
Schumm, L. Philip
Klei, Lambertus
Ananthakrishnan, Ashwin
Aumais, Guy
Baidoo, Leonard
Dubinsky, Marla
Fiocchi, Claudio
Glas, Juergen
Milgrom, Raquel
Proctor, Deborah D.
Regueiro, Miguel
Simms, Lisa A.
Stempak, Joanne M.
Targan, Stephan R.
Torkvist, Leif
Sharma, Yashoda
Devlin, Bernie
Borneman, James
Hakonarson, Hakon
Xavier, Ramnik J.
Daly, Mark
Brant, Steven R.
Rioux, John D.
Silverberg, Mark S.
Cho, Judy H.
Braun, Jonathan
McGovern, Dermot P. B.
Duerr, Richard H.
Title A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition
Journal name Gastroenterology   Check publisher's open access policy
ISSN 1528-0012
0016-5085
Publication date 2016-10-01
Sub-type Article (original research)
DOI 10.1053/j.gastro.2016.06.051
Open Access Status File (Author Post-print)
Volume 151
Issue 4
Start page 724
End page 732
Total pages 9
Place of publication Maryland Heights, MO, United States
Publisher W.B. Saunders
Language eng
Abstract Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).
Formatted abstract
Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).

Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.

Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10-13). This variant has been associated previously 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 =.009) and CD cases (P =.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.
Keyword Genetics
Inflammatory bowel diseases
Microbiota
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 CA141743
R01 DK098231
U01 DK062413
T32 DK007180
P30 DK043351
UL1 TR001863
P30 DK089502
U01 DK062432
UL1 TR000124
R01 HS021747
F30 DK098927
U01 DK062429
R01 AG023651
U54 DE023798
S10 OD016290
P30 CA016042
P30 AI028697
U01 DK062422
T32 GM007205
P50 AG005133
R01 AG030653
U01 DK062423
R01 AG041718
R01 DK061451
U01 AI067068
P01 DK046763
U01 DK062420
U01 DK062431
R01 DK087694
R01 DK092235
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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