Much of the genetic predisposition to colorectal cancer (CRC) in humans is unexplained. Studying a Caucasian-dominated population in the United States, we showed that germline allele-specific expression (ASE) of the gene encoding transforming growth factor-β (TGF-β) type I receptor, TGFBR1, is a quantitative trait that occurs in 10 to 20% of CRC patients and 1 to 3% of controls. ASE results in reduced expression of the gene, is dominantly inherited, segregates in families, and occurs in sporadic CRC cases. Although subtle, the reduction in constitutive TGFBR1 expression alters SMAD-mediated TGF-β signaling. Two major TGFBR1 haplotypes are predominant among ASE cases, which suggests ancestral mutations, but causative germline changes have not been identified. Conservative estimates suggest that ASE confers a substantially increased risk of CRC (odds ratio, 8.7; 95% confidence interval, 2.6 to 29.1), but these estimates require confirmation and will probably show ethnic differences.The annual worldwide incidence of colorectal cancer (CRC) exceeds 1 million, being the second to fourth most common cancer in industrialized countries (1). Although diet and lifestyle are thought to have a strong impact on CRC risk, genes have a key role in the predisposition to this cancer. A positive family history of CRC occurs in 20 to 30% of all probands. Highly penetrant autosomal dominant and recessive hereditary forms of CRC account for at most 5% of all CRC cases (2). Although additional high-and low-penetrance alleles have been proposed, much of the remaining predisposition to CRC remains unexplained (3).Aberrations in the transforming growth factor-β (TGF-β) pathway are heavily involved in CRC carcinogenesis (4). Although mutations in the TGF-β type II receptor gene have been explicitly associated with CRC (5), the type I receptor gene (TGFBR1) has received less attention, although there is evidence that a common variant may be associated with cancer risk (6,7). We hypothesized that TGFBR1 is a notable candidate for a gene that, when mutated, causes predisposition to CRC or acts as a modifier of other genes, resulting in a predisposition. Our study was undertaken to test this assumption.