title: Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans.
abstract: Genome-wide association studies of colorectal cancer (CRC) in Europeans and Asians have identified 21 risk susceptibility regions [29 index single-nucleotide polymorphisms (SNPs)]. Characterizing these risk regions in diverse racial groups with different linkage disequilibrium (LD) structure can help localize causal variants. We examined associations between CRC and all 29 index SNPs in 6597 African Americans (1894 cases and 4703 controls). Nine SNPs in eight regions (5q31.1, 6q26-q27, 8q23.3, 8q24.21, 11q13.4, 15q13.3, 18q21.1 and 20p12.3) formally replicated in our data with one-sided P-values <0.05 and the same risk directions as reported previously. We performed fine-mapping of the 21 risk regions (including 250 kb on both sides of the index SNPs) using genotyped and imputed markers at the density of the 1000 Genomes Project to search for additional or more predictive risk markers. Among the SNPs correlated with the index variants, two markers, rs12759486 (or rs7547751, a putative functional variant in perfect LD with it) in 1q41 and rs7252505 in 19q13.1, were more strongly and statistically significantly associated with CRC (P < 0.0006). The average per allele risk was improved using the replicated index variants and the two new markers (odds ratio = 1.14, P = 6.5 × 10(-16)) in African Americans, compared with using all index SNPs (odds ratio = 1.07, P = 3.4 × 10(-10)). The contribution of the two new risk SNPs to CRC heritability was estimated to be 1.5% in African Americans. This study highlights the importance of fine-mapping in diverse populations.
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Hansong
authors.initials: H
authors.lastname: Wang
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Terrilea
authors.initials: T
authors.lastname: Burnett
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Fortini
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Signorello
authors.forename: William J
authors.initials: WJ
authors.lastname: Blot
authors.forename: Temitope O
authors.initials: TO
authors.lastname: Keku
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Mala
authors.initials: M
authors.lastname: Pande
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Dee W
authors.initials: DW
authors.lastname: West
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000235:genetics*; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide