title: Estimating the heritability of colorectal cancer.
abstract: 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.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Division of Cancer Epidemiology and Genetics and.
authors.forename: Sonja
authors.initials: S
authors.lastname: Berndt
authors.affiliation: Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA and.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA and.
authors.forename: Katja
authors.initials: K
authors.lastname: Butterbach
authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.affiliation: 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.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Division of Clinical Epidemiology and Aging Research and Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Division of Research, Kaiser Permanente Medical Care Program, Broadway, Oakland, CA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Cancer Epidemiology and Genetics and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Curtis
authors.affiliation: School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Tabitha A
authors.initials: TA
authors.lastname: Harrison
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA and.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: Division of Epidemiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: 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 Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.affiliation: Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA and.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schoen
authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: White
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA lih@fhcrc.org.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
mesh_terms: D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012907:Smoking