Multiple Common Susceptibility Variants near BMP Pathway Loci , , and Explain Part of the Missing Heritability of Colorectal Cancer


Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10−10) and BMP2 (rs4813802, P = 4.65×10−11). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10−8) and rs11632715 (P = 2.30×10−10). As low-penetrance predisposition variants become harder to identify—owing to small effect sizes and/or low risk allele frequencies—approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.


Vyšlo v časopise: Multiple Common Susceptibility Variants near BMP Pathway Loci , , and Explain Part of the Missing Heritability of Colorectal Cancer. PLoS Genet 7(6): e32767. doi:10.1371/journal.pgen.1002105
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1002105

Souhrn

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10−10) and BMP2 (rs4813802, P = 4.65×10−11). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10−8) and rs11632715 (P = 2.30×10−10). As low-penetrance predisposition variants become harder to identify—owing to small effect sizes and/or low risk allele frequencies—approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.


Zdroje

1. HoulstonRSCheadleJDobbinsSETenesaAJonesAM 2010 Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet 42 973 977

2. TomlinsonIWebbECarvajal-CarmonaLBroderickPKempZ 2007 A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39 984 988

3. HoulstonRSWebbEBroderickPPittmanAMDi BernardoMC 2008 Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40 1426 1435

4. Al OlamaAAKote-JaraiZGilesGGGuyMMorrisonJ 2009 Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet 41 1058 1060

5. JaegerEWebbEHowarthKCarvajal-CarmonaLRowanA 2008 Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 40 26 28

6. DicksonSWangKKrantzIHakonarsonHGoldsteinD 2010 Rare variants create synthetic genome-wide associations. PLoS Biol 8 e1000294 doi:10.1371/journal.pbio.1000294

7. WrayNPurcellSMVisscherPM 2011 Synthetic associations created by rare variants do not explain most GWAS results. PLoS Biol 9 e1000579 doi:10.1371/journal.pbio.1000579

8. BroderickPCarvajal-CarmonaLPittmanAMWebbEHowarthK 2007 A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39 1315 1317

9. HoweJRBairJLSayedMGAndersonMEMitrosFA 2001 Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28 184 187

10. HoweJRRothSRingoldJCSummersRWJarvinenHJ 1998 Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280 1086 1088

11. JaegerEEWoodford-RichensKLLockettMRowanAJSawyerEJ 2003 An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am J Hum Genet 72 1261 1267

12. MidgleyRSMcConkeyCCJohnstoneECDunnJASmithJL 2010 Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J Clin Oncol 28 4575 4580

13. PowerCJefferisBJManorOHertzmanC 2006 The influence of birth weight and socioeconomic position on cognitive development: Does the early home and learning environment modify their effects? J Pediatr 148 54 61

14. NewcombPABaronJCotterchioMGallingerSGroveJ 2007 Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev 16 2331 2343

15. TieJGibbsPLiptonLChristieMJorissenRN 2010 Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer

16. DuffyDLIlesMMGlassDZhuGBarrettJH 2010 IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am J Hum Genet 87 6 16

17. BairdPNSchacheMDiraniM 2010 The GEnes in Myopia (GEM) study in understanding the aetiology of refractive errors. Prog Retin Eye Res 29 520 542

18. AdamsRMeadeAWasanHGriffithsGMaughanT 2008 Cetuximab therapy in first-line metastatic colorectal cancer and intermittent palliative chemotherapy: review of the COIN trial. Expert Rev Anticancer Ther 8 1237 1245

19. AbuliABessaXGonzalezJRRuiz-PonteCCaceresA 2010 Susceptibility genetic variants associated with colorectal cancer risk correlate with cancer phenotype. Gastroenterology 139 788 796, 796 e781–786

20. PetittiDB 1994 Coronary heart disease and estrogen replacement therapy. Can compliance bias explain the results of observational studies? Ann Epidemiol 4 115 118

21. HigginsJPThompsonSG 2002 Quantifying heterogeneity in a meta-analysis. Stat Med 21 1539 1558

22. HoulstonRSFordD 1996 Genetics of coeliac disease. QJM 89 737 743

23. JohnsLEHoulstonRS 2001 A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 2992 3003

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Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2011 Číslo 6
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