• Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
• Division of Cancer Epidemiology and Genetics and.
• Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA and.
• Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
• Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
• Division of Clinical Epidemiology and Aging Research and Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
• Division of Research, Kaiser Permanente Medical Care Program, Broadway, Oakland, CA, USA.
• School of Public Health, University of Washington, Seattle, WA, USA.
• Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
• Translational Genomics Research Institute, Phoenix, AZ, USA.

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.