Systematic association mapping identifies NELL1 as a novel IBD disease gene.
Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi...
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Public Library of Science (PLoS)
2007-08-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000691&type=printable |
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| author | Andre Franke Jochen Hampe Philip Rosenstiel Christian Becker Florian Wagner Robert Häsler Randall D Little Klaus Huse Andreas Ruether Tobias Balschun Michael Wittig Abdou Elsharawy Gabriele Mayr Mario Albrecht Natalie J Prescott Clive M Onnie Hélène Fournier Tim Keith Uwe Radelof Matthias Platzer Christopher G Mathew Monika Stoll Michael Krawczak Peter Nürnberg Stefan Schreiber |
| author_facet | Andre Franke Jochen Hampe Philip Rosenstiel Christian Becker Florian Wagner Robert Häsler Randall D Little Klaus Huse Andreas Ruether Tobias Balschun Michael Wittig Abdou Elsharawy Gabriele Mayr Mario Albrecht Natalie J Prescott Clive M Onnie Hélène Fournier Tim Keith Uwe Radelof Matthias Platzer Christopher G Mathew Monika Stoll Michael Krawczak Peter Nürnberg Stefan Schreiber |
| author_sort | Andre Franke |
| collection | DOAJ |
| description | Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10(-6); OR = 1.66, 95% CI: 1.30-2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10(-6) for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron). |
| format | Article |
| id | doaj-art-bdae868ac4114d94b96552c5d60da968 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2007-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-bdae868ac4114d94b96552c5d60da9682025-08-20T03:55:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032007-08-0128e69110.1371/journal.pone.0000691Systematic association mapping identifies NELL1 as a novel IBD disease gene.Andre FrankeJochen HampePhilip RosenstielChristian BeckerFlorian WagnerRobert HäslerRandall D LittleKlaus HuseAndreas RuetherTobias BalschunMichael WittigAbdou ElsharawyGabriele MayrMario AlbrechtNatalie J PrescottClive M OnnieHélène FournierTim KeithUwe RadelofMatthias PlatzerChristopher G MathewMonika StollMichael KrawczakPeter NürnbergStefan SchreiberCrohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10(-6); OR = 1.66, 95% CI: 1.30-2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10(-6) for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron).https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000691&type=printable |
| spellingShingle | Andre Franke Jochen Hampe Philip Rosenstiel Christian Becker Florian Wagner Robert Häsler Randall D Little Klaus Huse Andreas Ruether Tobias Balschun Michael Wittig Abdou Elsharawy Gabriele Mayr Mario Albrecht Natalie J Prescott Clive M Onnie Hélène Fournier Tim Keith Uwe Radelof Matthias Platzer Christopher G Mathew Monika Stoll Michael Krawczak Peter Nürnberg Stefan Schreiber Systematic association mapping identifies NELL1 as a novel IBD disease gene. PLoS ONE |
| title | Systematic association mapping identifies NELL1 as a novel IBD disease gene. |
| title_full | Systematic association mapping identifies NELL1 as a novel IBD disease gene. |
| title_fullStr | Systematic association mapping identifies NELL1 as a novel IBD disease gene. |
| title_full_unstemmed | Systematic association mapping identifies NELL1 as a novel IBD disease gene. |
| title_short | Systematic association mapping identifies NELL1 as a novel IBD disease gene. |
| title_sort | systematic association mapping identifies nell1 as a novel ibd disease gene |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000691&type=printable |
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