title: Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.
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.
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Stittrich
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Ashworth
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA.
authors.forename: Mude
authors.initials: M
authors.lastname: Shi
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Robinson
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Mauldin
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Brunkow
authors.affiliation: Novo Nordisk Research Center , Seattle, WA, USA.
authors.forename: Shameek
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Pathology, Chungnam National University School of Medicine , Daejeon, Korea.
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB) , Daejeon, Korea.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, WA, USA; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: David
authors.initials: D
authors.lastname: Galas
authors.affiliation: Novo Nordisk Research Center , Seattle, WA, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Serikawa
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Utah , Salt Lake City, UT, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Guthery
authors.affiliation: Novo Nordisk Research Center , Seattle, WA, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Peschon
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Jared C
authors.initials: JC
authors.lastname: Roach
authors.affiliation: Institute for Systems Biology , Seattle, WA, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman