Targeted Gene Sequencing in Children with Crohn’s Disease and Their Parents: Implications for Missing Heritability

G3: Genes, Genomes, Genetics. 2018;8(9):2881-2888 DOI 10.1534/g3.118.200404


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Journal Title: G3: Genes, Genomes, Genetics

ISSN: 2160-1836 (Online)

Publisher: Genetics Society of America

Society/Institution: Genetics Society of America

LCC Subject Category: Science: Biology (General): Genetics

Country of publisher: United States

Language of fulltext: English

Full-text formats available: PDF, HTML



Jiun-Sheng Chen
Fulan Hu
Subra Kugathasan
Lynn B. Jorde
David Nix
Ann Rutherford
Lee Denson
W. Scott Watkins
Sampath Prahalad
Chad Huff
Stephen L. Guthery


Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 11 weeks


Abstract | Full Text

Crohn’s disease is a complex genetic trait characterized by chronic relapsing intestinal inflammation. Genome wide association studies (GWAS) have identified more than 170 loci associated with the disease, accounting for ∼14% of the disease variance. We hypothesized that rare genetic variation in GWAS positional candidates also contribute to disease pathogenesis. We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn’s disease, including 179 parent-child trios and 200 controls, both of European ancestry. We used the gene burden test implemented in VAAST and estimated effect sizes using logistic regression and meta-analyses. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn’s disease.