Estimating the heritability of colorectal cancer.

A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.

[1]  P C Prorok,et al.  Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. , 2000, Controlled clinical trials.

[2]  N E Day,et al.  The design of case-control studies: the influence of confounding and interaction effects. , 1984, International journal of epidemiology.

[3]  Steven Gallinger,et al.  Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer , 2011, PLoS genetics.

[4]  John D Potter,et al.  Colon Cancer Family Registry: An International Resource for Studies of the Genetic Epidemiology of Colon Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[5]  D. Kerr,et al.  Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk , 2008, Nature Genetics.

[6]  Steven Gallinger,et al.  Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk , 2012, Nature Genetics.

[7]  C. Bocchini,et al.  The status of online Mendelian inheritance in man (OMIM) medio 1994. , 1994, Nucleic acids research.

[8]  Steven Gallinger,et al.  Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer , 2008, Nature Genetics.

[9]  Ben Zhang,et al.  Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer , 2012, Nature Genetics.

[10]  T. Spector,et al.  Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux. , 2013, Journal of the National Cancer Institute.

[11]  S. Küry,et al.  Combinations of Cytochrome P450 Gene Polymorphisms Enhancing the Risk for Sporadic Colorectal Cancer Related to Red Meat Consumption , 2007, Cancer Epidemiology Biomarkers & Prevention.

[12]  Tanya M. Teslovich,et al.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes , 2012, Nature Genetics.

[13]  Doug Speed,et al.  Improved heritability estimation from genome-wide SNPs. , 2012, American journal of human genetics.

[14]  Steven Gallinger,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 , 2007, Nature Genetics.

[15]  K. Czene,et al.  Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family‐cancer database , 2002, International journal of cancer.

[16]  T. Tuohy,et al.  Hereditary and familial colon cancer. , 2010, Gastroenterology.

[17]  Bok-Ghee Han,et al.  Ubiquitous Polygenicity of Human Complex Traits: Genome-Wide Analysis of 49 Traits in Koreans , 2013, PLoS genetics.

[18]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[19]  A. Tenesa,et al.  New insights into the aetiology of colorectal cancer from genome-wide association studies , 2009, Nature Reviews Genetics.

[20]  Julian Peto,et al.  A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3 , 2008, Nature Genetics.

[21]  H. Brenner,et al.  Protection From Colorectal Cancer After Colonoscopy , 2011, Annals of Internal Medicine.

[22]  H. Brenner,et al.  No Evidence for Variation in Colorectal Cancer Risk Associated With Different Types of Postmenopausal Hormone Therapy , 2009, Clinical pharmacology and therapeutics.

[23]  Oliver Sieber,et al.  A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk , 2007, Nature Genetics.

[24]  I. Deary,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21 , 2008, Nature Genetics.

[25]  R. Hayes,et al.  A Pooled Analysis of Smoking and Colorectal Cancer: Timing of Exposure and Interactions with Environmental Factors , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[26]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[27]  P. Visscher,et al.  Estimating missing heritability for disease from genome-wide association studies. , 2011, American journal of human genetics.

[28]  Peter Donnelly,et al.  Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas , 2013, Nature Genetics.

[29]  Jean-Baptiste Cazier,et al.  Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33 , 2010, Nature Genetics.

[30]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[31]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[32]  Peter Kraft,et al.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression , 2013, Human molecular genetics.

[33]  Scott Davis,et al.  Implementation of the Women's Health Initiative study design. , 2003, Annals of epidemiology.

[34]  W. G. Hill,et al.  Genome partitioning of genetic variation for complex traits using common SNPs , 2011, Nature Genetics.

[35]  Peter M Visscher,et al.  Prediction of individual genetic risk to disease from genome-wide association studies. , 2007, Genome research.

[36]  Simon C. Potter,et al.  Using genome-wide complex trait analysis to quantify ‘ missing heritability ’ in Parkinson ’ s disease , 2012 .

[37]  Graham A. Colditz,et al.  The Nurses' Health Study: lifestyle and health among women , 2005, Nature Reviews Cancer.

[38]  J. Potter,et al.  Energy balance and colon cancer--beyond physical activity. , 1997, Cancer research.

[39]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[40]  C. Carlson,et al.  Meta-analysis of new genome-wide association studies of colorectal cancer risk , 2011, Human Genetics.

[41]  S. Ballereau,et al.  Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals , 2012, Gut.

[42]  Oliver Sieber,et al.  A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21 , 2007, Nature Genetics.

[43]  Heather Hampel,et al.  Feasibility of screening for Lynch syndrome among patients with colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Naomi R. Wray,et al.  Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis , 2012, Human molecular genetics.

[45]  Geoffrey S. Tobias,et al.  Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer , 2009, Nature Genetics.

[46]  C. Hennekens,et al.  Design of Physicians' Health Study II--a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. , 2000, Annals of epidemiology.

[47]  Simon G. Coetzee,et al.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis. , 2013, Gastroenterology.

[48]  Dana C. Crawford,et al.  A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study , 2013, PLoS genetics.

[49]  Wei Zheng,et al.  A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33 , 2010, Nature Genetics.

[50]  Peter Kraft,et al.  Heritability in the genome-wide association era , 2012, Human Genetics.

[51]  I. Sartori.  Aspirin Use and the Risk for Colorectal Cancer and Adenoma in Male Health Professionals. , 1996 .