SNP-SNP interactions discovered by logic regression explain Crohn's disease genetics.
In genome-wide association studies (GWAS), the association between each single nucleotide polymorphism (SNP) and a phenotype is assessed statistically. To further explore genetic associations in GWAS, we considered two specific forms of biologically plausible SNP-SNP interactions, 'SNP intersection' and 'SNP union,' and analyzed the Crohn's Disease (CD) GWAS data of the Wellcome Trust Case Control Consortium for these interactions using a limited form of logic regression. We found strong evidence of CD-association for 195 genes, identifying novel susceptibility genes (e.g., ISX, SLCO6A1, TMEM183A) as well as confirming many previously identified susceptibility genes in CD GWAS (e.g., IL23R, NOD2, CYLD, NKX2-3, IL12RB2, ATG16L1). Notably, 37 of the 59 chromosomal locations indicated for CD-association by a meta-analysis of CD GWAS, involving over 22,000 cases and 29,000 controls, were represented in the 195 genes, as well as some chromosomal locations previously indicated only in linkage studies, but not in GWAS. We repeated the analysis with two smaller GWASs from the Database of Genotype and Phenotype (dbGaP): in spite of differences of populations and study power across the three datasets, we observed some consistencies across the three datasets. Notable examples included TMEM183A and SLCO6A1 which exhibited strong evidence consistently in our WTCCC and both of the dbGaP SNP-SNP interaction analyses. Examining these specific forms of SNP interactions could identify additional genetic associations from GWAS. R codes, data examples, and a ReadMe file are available for download from our website: http://www.ualberta.ca/~yyasui/homepage.html.
School of Public Health, University of Alberta, Edmonton, Alberta, Canada.
Irina
I
Dinu
Surakameth
S
Mahasirimongkol
Qi
Q
Liu
Hideki
H
Yanai
Noha
N
Sharaf Eldin
Erin
E
Kreiter
Xuan
X
Wu
Shahab
S
Jabbari
Katsushi
K
Tokunaga
Yutaka
Y
Yasui
D001499:Bayes Theorem; D003424:Crohn Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008565:Membrane Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
D008565:Membrane Proteins; D027361:Organic Anion Transporters; C513550:TMEM183A protein, human; C487009:SLCO6A1 protein, human