title: A cross-ethnic survey of CFB and SLC44A4, Indian ulcerative colitis GWAS hits, underscores their potential role in disease susceptibility.
abstract: The first ever genome-wide association study (GWAS) of ulcerative colitis in genetically distinct north Indian population identified two novel genes namely CFB and SLC44A4. Considering their biological relevance, we investigated allelic/genetic heterogeneity in these genes among ulcerative colitis cohorts of north Indian, Japanese and Dutch origin using high-density ImmunoChip case-control genotype data. Comparative linkage disequilibrium profiling and test of association were performed. Of the 28 CFB SNPs, similar strength of association was observed for rs4151657 (novel ulcerative colitis GWAS SNP) in north Indians (P=1.73 × 10-10) and Japanese (P=2.02 × 10-12) but not in the Dutch. Further, a three-marker haplotype was shared between north Indians and Japanese (P<10-8), but a different five-marker haplotype was associated (P=2.07 × 10-6) in the Dutch. Of the 22 SLC44A4 SNPs, rs2736428 (novel ulcerative colitis GWAS SNP) was found significantly associated in north Indians (P=4.94 × 10-10) and Japanese (P=3.37 × 10-9), but not among the Dutch. These results suggest (i) apparent allelic heterogeneity in CFB and genetic heterogeneity in SLC44A4 across different ethnic groups; (ii) shared ulcerative colitis genetic etiological factors among Asians; and finally (iii) re-exploration of GWAS findings together with high-density genotyping/sequencing and trans-ethnic fine mapping approaches may help identify shared and population-specific risk variants and enable to explain missing disease heritability.
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Aditi
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Juyal
authors.affiliation: Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.
authors.forename: Ajit
authors.initials: A
authors.lastname: Sood
authors.affiliation: Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Midha
authors.affiliation: Laboratory for Genotyping Development Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Arnau
authors.initials: A
authors.lastname: Vich Vila
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Esaki
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Genotyping Development Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India. bktlab@gmail.com.
authors.forename: B K
authors.initials: BK
authors.lastname: Thelma
mesh_terms: D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D011415:Complement Factor B / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide
chemical_list: D026901:Membrane Transport Proteins; C583905:SLC44A4 protein, human; D011415:Complement Factor B