DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Pancreatitis. The EFO term pancreatitis was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: pancreatitis

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

DC Whitcomb, J LaRusch, AM Krasinskas, L Klei, JP Smith, RE Brand, JP Neoptolemos, MM Lerch, M Tector, BS Sandhu, NM Guda, L Orlichenko, S Alkaade, ST Amann, MA Anderson, J Baillie, PA Banks, D Conwell, GA Coté, PB Cotton, J DiSario, LA Farrer, CE Forsmark, M Johnstone, TB Gardner, A Gelrud, W Greenhalf, JL Haines, DJ Hartman, RA Hawes, C Lawrence, M Lewis, J Mayerle, R Mayeux, NM Melhem, ME Money, T Muniraj, GI Papachristou, MA Pericak-Vance, J Romagnuolo, GD Schellenberg, S Sherman, P Simon, VP Singh, A Slivka, D Stolz, R Sutton, FU Weiss, CM Wilcox, NO Zarnescu, SR Wisniewski, MR O'Connell, ML Kienholz, K Roeder, MM Barmada, D Yadav, B Devlin

TITLE:

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

JOURNAL:

Nature genetics Dec 2012, Vol 44, pp. 1349-54

ABSTRACT:

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07). PUBMED: 23143602
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