TY - JOUR
T1 - Rare loss of function variants in candidate genes and risk of colorectal cancer
AU - NHLBI GO Exome Sequencing Project
AU - Pulmonary Arterial Hypertension (PAH)
AU - Severe Asthma Research Program (SARP)
AU - Women’s Health Initiative (WHI)
AU - Anthropometry Project Team
AU - Blood Count/Hematology Project Team
AU - Blood Pressure Project Team
AU - Data Flow Working Group
AU - Early MI Project Team
AU - ELSI Working Group
AU - Executive Committee
AU - Family Study Project Team
AU - Lipids Project Team
AU - Lung Project Team
AU - Personal Genomics Project Team
AU - Phenotype and Harmonization Working Group
AU - Population Genetics and Statistical Analysis Working Group
AU - Publications and Presentations Working Group
AU - Quantitative Analysis Ad Hoc Task Group
AU - Sequencing and Genotyping Working Group
AU - Steering Committee
AU - Stroke Project Team
AU - Structural Variation Working Group
AU - Subclinical/Quantitative Project Team
AU - Acute Lung Injury (ALI)
AU - Atherosclerosis Risk in Communities (ARIC)
AU - Cardiovascular Health Study (CHS)
AU - Chronic Obstructive Pulmonary Disease (COPDGene)
AU - Coronary Artery Risk Development in Young Adults (CARDIA)
AU - Cystic Fibrosis (CF)
AU - Early Pseudomonas Infection Control (EPIC)
AU - Framingham Heart Study (FHS)
AU - Jackson Heart Study (JHS)
AU - Lung Health Study (LHS)
AU - Multi-Ethnic Study of Atherosclerosis (MESA)
AU - Rosenthal, Elisabeth A.
AU - Shirts, Brian H.
AU - Amendola, Laura M.
AU - Horike-Pyne, Martha
AU - Robertson, Peggy D.
AU - Hisama, Fuki M.
AU - Bennett, Robin L.
AU - Dorschner, Michael O.
AU - Nickerson, Deborah A.
AU - Stanaway, Ian B.
AU - Nassir, Rami
AU - Vickers, Kathy T.
AU - Li, Christopher
AU - Grady, William M.
AU - Peters, Ulrike
AU - Jarvik, Gail P.
AU - Gabriel, Stacey B.
AU - Altshuler, David M.
AU - Abecasis, Gonçalo R.
AU - Allayee, Hooman
AU - Cresci, Sharon
AU - Daly, Mark J.
AU - de Bakker, Paul I.W.
AU - DePristo, Mark A.
AU - Do, Ron
AU - Donnelly, Peter
AU - Farlow, Deborah N.
AU - Fennell, Tim
AU - Garimella, Kiran
AU - Hazen, Stanley L.
AU - Hu, Youna
AU - Jordan, Daniel M.
AU - Jun, Goo
AU - Kathiresan, Sekar
AU - Kang, Hyun Min
AU - Kiezun, Adam
AU - Lettre, Guillaume
AU - Li, Bingshan
AU - Li, Mingyao
AU - Newton-Cheh, Christopher H.
AU - Padmanabhan, Sandosh
AU - Peloso, Gina
AU - Pulit, Sara
AU - Rader, Daniel J.
AU - Reich, David
AU - Reilly, Muredach P.
AU - Rivas, Manuel A.
AU - Schwartz, Steve
AU - Scott, Laura
AU - Akey, Joshua M.
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-018-1938-4
DO - 10.1007/s00439-018-1938-4
M3 - Article
C2 - 30267214
AN - SCOPUS:85054525934
SN - 0340-6717
VL - 137
SP - 795
EP - 806
JO - Human Genetics
JF - Human Genetics
IS - 10
ER -