Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans

被引：29

作者：

Wang, Hansong ^{[1
]}

Haiman, Christopher A. ^{[2
,3
]}

Burnett, Terrilea ^{[1
]}

Fortini, Barbara K. ^{[2
,3
]}

Kolonel, Laurence N. ^{[1
]}

Henderson, Brian E. ^{[2
,3
]}

Signorello, Lisa B. ^{[4
,5
,6
]}

Blot, William J. ^{[4
,5
,6
]}

Keku, Temitope O. ^{[7
]}

Berndt, Sonja I. ^{[8
]}

Newcomb, Polly A. ^{[9
]}

Pande, Mala ^{[10
]}

Amos, Christopher I. ^{[11
]}

West, Dee W. ^{[12
]}

Casey, Graham ^{[2
,3
]}

Sandler, Robert S. ^{[7
]}

Haile, Robert ^{[13
]}

Stram, Daniel O. ^{[2
,3
]}

Le Marchand, Loic ^{[1
]}

机构：

[1] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA

[2] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[3] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA

[4] Int Epidemiol Inst, Rockville, MD USA

[5] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA

[6] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[7] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA

[8] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[9] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[11] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Lebanon, NH 03756 USA

[12] Canc Prevent Inst Calif, Fremont, CA USA

[13] Stanford Canc Inst, Stanford, CA USA

来源：

HUMAN MOLECULAR GENETICS | 2013年 / 22卷 / 24期

关键词：

SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; WINNERS CURSE; METAANALYSIS; SCAN; ALLELES; 8Q24;

D O I：

10.1093/hmg/ddt337

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 5 1.14, P = 6.5 x 10(-16)) in African Americans, compared with using all index SNPs (odds ratio = 1.07, P = 3.4 x 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.

引用

页码：5048 / 5055

页数：8

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