02530nas a2200313   4500008004100000022001400041245008500055210006900140260001600209520156200225100002801787700002101815700002301836700002401859700002401883700002001907700002201927700002601949700002601975700002102001700001702022700002202039700002002061700002202081700001902103700002002122710003802142856003602180       2018                        eng d  a1432-120300aRare loss of function variants in candidate genes and risk of colorectal cancer.0 aRare loss of function variants in candidate genes and risk of co  c2018 Sep 283 a<p>Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.</p>1 aRosenthal, Elisabeth, A1 aShirts, Brian, H1 aAmendola, Laura, M1 aHorike-Pyne, Martha1 aRobertson, Peggy, D1 aHisama, Fuki, M1 aBennett, Robin, L1 aDorschner, Michael, O1 aNickerson, Deborah, A1 aStanaway, Ian, B1 aNassir, Rami1 aVickers, Kathy, T1 aLi, Christopher1 aGrady, William, M1 aPeters, Ulrike1 aJarvik, Gail, P1 aNHLBI GO Exome Sequencing Project  uhttps://chs-nhlbi.org/node/7847