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

TitleGenomic architecture of inflammatory bowel disease in five families with multiple affected individuals.
Publication TypeJournal Article
Year of Publication2016
AuthorsStittrich 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
JournalHum Genome Var
Date Published2016
Abstract<p>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.</p>
Alternate JournalHum Genome Var
PubMed ID27081563
PubMed Central IDPMC4785573
Grant ListP50 GM076547 / GM / NIGMS NIH HHS / United States
R01 DK091374 / DK / NIDDK NIH HHS / United States
U01 DK062420 / DK / NIDDK NIH HHS / United States