Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.

Stittrich, AB; Ashworth, J; Shi, M; Robinson, M; Mauldin, D; Brunkow, ME; Biswas, S; Kim, J-M; Kwon, K-S; Jung, JU; Galas, D; Serikawa, K; Duerr, RH; Guthery, SL; Peschon, J; Hood, L; Roach, JC; Glusman, G

Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.

Stittrich, AB Ashworth, J

Shi, M Robinson, M Mauldin, D Brunkow, ME Biswas, S Kim, J-M Kwon, K-S Jung, JU Galas, D Serikawa, K Duerr, RH Guthery, SL Peschon, J Hood, L Roach, JC Glusman, G

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Publication Type:: Journal Article
Citation:: Hum Genome Var, 2016, 3 pp. 15060 - ?
Issue Date:: 2016

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Field	Value	Language
dc.contributor.author	Stittrich, AB	en_US
dc.contributor.author	Ashworth, J https://orcid.org/0000-0003-4835-6551	en_US
dc.contributor.author	Shi, M	en_US
dc.contributor.author	Robinson, M	en_US
dc.contributor.author	Mauldin, D	en_US
dc.contributor.author	Brunkow, ME	en_US
dc.contributor.author	Biswas, S	en_US
dc.contributor.author	Kim, J-M	en_US
dc.contributor.author	Kwon, K-S	en_US
dc.contributor.author	Jung, JU	en_US
dc.contributor.author	Galas, D	en_US
dc.contributor.author	Serikawa, K	en_US
dc.contributor.author	Duerr, RH	en_US
dc.contributor.author	Guthery, SL	en_US
dc.contributor.author	Peschon, J	en_US
dc.contributor.author	Hood, L	en_US
dc.contributor.author	Roach, JC	en_US
dc.contributor.author	Glusman, G	en_US
dc.date.available	2015-10-29	en_US
dc.date.issued	2016	en_US
dc.identifier.citation	Hum Genome Var, 2016, 3 pp. 15060 - ?	en_US
dc.identifier.issn	2054-345X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/117189
dc.description.abstract	Currently, the best clinical predictor for inflammatory bowel disease (IBD) is family history. Over 163 sequence variants have been associated with IBD in genome-wide association studies, but they have weak effects and explain only a fraction of the observed heritability. It is expected that additional variants contribute to the genomic architecture of IBD, possibly including rare variants with effect sizes larger than the identified common variants. Here we applied a family study design and sequenced 38 individuals from five families, under the hypothesis that families with multiple IBD-affected individuals harbor one or more risk variants that (i) are shared among affected family members, (ii) are rare and (iii) have substantial effect on disease development. Our analysis revealed not only novel candidate risk variants but also high polygenic risk scores for common known risk variants in four out of the five families. Functional analysis of our top novel variant in the remaining family, a rare missense mutation in the ubiquitin ligase TRIM11, suggests that it leads to increased nuclear factor of kappa light chain enhancer in B-cells (NF-κB) signaling. We conclude that an accumulation of common weak-effect variants accounts for the high incidence of IBD in most, but not all families we analyzed and that a family study design can identify novel rare variants conferring risk for IBD with potentially large effect size, such as the TRIM11 p.H414Y mutation.	en_US
dc.language	eng	en_US
dc.relation.ispartof	Hum Genome Var	en_US
dc.relation.isbasedon	10.1038/hgv.2015.60	en_US
dc.title	Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.location.activity	England	en_US
utslib.for	060408 Genomics	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - C3 - Climate Change Cluster
utslib.copyright.status	open_access
pubs.publication-status	Published online	en_US
pubs.volume	3	en_US

Abstract:

Currently, the best clinical predictor for inflammatory bowel disease (IBD) is family history. Over 163 sequence variants have been associated with IBD in genome-wide association studies, but they have weak effects and explain only a fraction of the observed heritability. It is expected that additional variants contribute to the genomic architecture of IBD, possibly including rare variants with effect sizes larger than the identified common variants. Here we applied a family study design and sequenced 38 individuals from five families, under the hypothesis that families with multiple IBD-affected individuals harbor one or more risk variants that (i) are shared among affected family members, (ii) are rare and (iii) have substantial effect on disease development. Our analysis revealed not only novel candidate risk variants but also high polygenic risk scores for common known risk variants in four out of the five families. Functional analysis of our top novel variant in the remaining family, a rare missense mutation in the ubiquitin ligase TRIM11, suggests that it leads to increased nuclear factor of kappa light chain enhancer in B-cells (NF-κB) signaling. We conclude that an accumulation of common weak-effect variants accounts for the high incidence of IBD in most, but not all families we analyzed and that a family study design can identify novel rare variants conferring risk for IBD with potentially large effect size, such as the TRIM11 p.H414Y mutation.

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http://hdl.handle.net/10453/117189