Rare loss of function variants in candidate genes and risk of colorectal cancer

NHLBI GO Exome Sequencing Project, Pulmonary Arterial Hypertension (PAH), Severe Asthma Research Program (SARP), Women’s Health Initiative (WHI), Anthropometry Project Team, Blood Count/Hematology Project Team, Blood Pressure Project Team, Data Flow Working Group, Early MI Project Team, ELSI Working Group, Executive Committee, Family Study Project Team, Lipids Project Team, Lung Project Team, Personal Genomics Project Team, Phenotype and Harmonization Working Group, Population Genetics and Statistical Analysis Working Group, Publications and Presentations Working Group, Quantitative Analysis Ad Hoc Task Group, Sequencing and Genotyping Working GroupSteering Committee, Stroke Project Team, Structural Variation Working Group, Subclinical/Quantitative Project Team, Acute Lung Injury (ALI), Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Chronic Obstructive Pulmonary Disease (COPDGene), Coronary Artery Risk Development in Young Adults (CARDIA), Cystic Fibrosis (CF), Early Pseudomonas Infection Control (EPIC), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Lung Health Study (LHS), Multi-Ethnic Study of Atherosclerosis (MESA)

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)795-806
Number of pages12
JournalHuman Genetics
Volume137
Issue number10
DOIs
StatePublished - Oct 1 2018

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Polyps
Colorectal Neoplasms
Genes
Penetrance
Genetic Testing
Logistic Models
Genotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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NHLBI GO Exome Sequencing Project, Pulmonary Arterial Hypertension (PAH), Severe Asthma Research Program (SARP), Women’s Health Initiative (WHI), Anthropometry Project Team, Blood Count/Hematology Project Team, ... Multi-Ethnic Study of Atherosclerosis (MESA) (2018). Rare loss of function variants in candidate genes and risk of colorectal cancer. Human Genetics, 137(10), 795-806. https://doi.org/10.1007/s00439-018-1938-4

Rare loss of function variants in candidate genes and risk of colorectal cancer. / NHLBI GO Exome Sequencing Project; Pulmonary Arterial Hypertension (PAH); Severe Asthma Research Program (SARP); Women’s Health Initiative (WHI); Anthropometry Project Team; Blood Count/Hematology Project Team; Blood Pressure Project Team; Data Flow Working Group; Early MI Project Team; ELSI Working Group; Executive Committee; Family Study Project Team; Lipids Project Team; Lung Project Team; Personal Genomics Project Team; Phenotype and Harmonization Working Group; Population Genetics and Statistical Analysis Working Group; Publications and Presentations Working Group; Quantitative Analysis Ad Hoc Task Group; Sequencing and Genotyping Working Group; Steering Committee; Stroke Project Team; Structural Variation Working Group; Subclinical/Quantitative Project Team; Acute Lung Injury (ALI); Atherosclerosis Risk in Communities (ARIC); Cardiovascular Health Study (CHS); Chronic Obstructive Pulmonary Disease (COPDGene); Coronary Artery Risk Development in Young Adults (CARDIA); Cystic Fibrosis (CF); Early Pseudomonas Infection Control (EPIC); Framingham Heart Study (FHS); Jackson Heart Study (JHS); Lung Health Study (LHS); Multi-Ethnic Study of Atherosclerosis (MESA).

In: Human Genetics, Vol. 137, No. 10, 01.10.2018, p. 795-806.

Research output: Contribution to journalArticle

NHLBI GO Exome Sequencing Project, Pulmonary Arterial Hypertension (PAH), Severe Asthma Research Program (SARP), Women’s Health Initiative (WHI), Anthropometry Project Team, Blood Count/Hematology Project Team, Blood Pressure Project Team, Data Flow Working Group, Early MI Project Team, ELSI Working Group, Executive Committee, Family Study Project Team, Lipids Project Team, Lung Project Team, Personal Genomics Project Team, Phenotype and Harmonization Working Group, Population Genetics and Statistical Analysis Working Group, Publications and Presentations Working Group, Quantitative Analysis Ad Hoc Task Group, Sequencing and Genotyping Working Group, Steering Committee, Stroke Project Team, Structural Variation Working Group, Subclinical/Quantitative Project Team, Acute Lung Injury (ALI), Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Chronic Obstructive Pulmonary Disease (COPDGene), Coronary Artery Risk Development in Young Adults (CARDIA), Cystic Fibrosis (CF), Early Pseudomonas Infection Control (EPIC), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Lung Health Study (LHS) & Multi-Ethnic Study of Atherosclerosis (MESA) 2018, 'Rare loss of function variants in candidate genes and risk of colorectal cancer', Human Genetics, vol. 137, no. 10, pp. 795-806. https://doi.org/10.1007/s00439-018-1938-4
NHLBI GO Exome Sequencing Project, Pulmonary Arterial Hypertension (PAH), Severe Asthma Research Program (SARP), Women’s Health Initiative (WHI), Anthropometry Project Team, Blood Count/Hematology Project Team et al. Rare loss of function variants in candidate genes and risk of colorectal cancer. Human Genetics. 2018 Oct 1;137(10):795-806. https://doi.org/10.1007/s00439-018-1938-4
NHLBI GO Exome Sequencing Project ; Pulmonary Arterial Hypertension (PAH) ; Severe Asthma Research Program (SARP) ; Women’s Health Initiative (WHI) ; Anthropometry Project Team ; Blood Count/Hematology Project Team ; Blood Pressure Project Team ; Data Flow Working Group ; Early MI Project Team ; ELSI Working Group ; Executive Committee ; Family Study Project Team ; Lipids Project Team ; Lung Project Team ; Personal Genomics Project Team ; Phenotype and Harmonization Working Group ; Population Genetics and Statistical Analysis Working Group ; Publications and Presentations Working Group ; Quantitative Analysis Ad Hoc Task Group ; Sequencing and Genotyping Working Group ; Steering Committee ; Stroke Project Team ; Structural Variation Working Group ; Subclinical/Quantitative Project Team ; Acute Lung Injury (ALI) ; Atherosclerosis Risk in Communities (ARIC) ; Cardiovascular Health Study (CHS) ; Chronic Obstructive Pulmonary Disease (COPDGene) ; Coronary Artery Risk Development in Young Adults (CARDIA) ; Cystic Fibrosis (CF) ; Early Pseudomonas Infection Control (EPIC) ; Framingham Heart Study (FHS) ; Jackson Heart Study (JHS) ; Lung Health Study (LHS) ; Multi-Ethnic Study of Atherosclerosis (MESA). / Rare loss of function variants in candidate genes and risk of colorectal cancer. In: Human Genetics. 2018 ; Vol. 137, No. 10. pp. 795-806.
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abstract = "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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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 - Post, Wendy S

AU - Beaty, Terri L

AU - Gao, Li

AU - Hansel, Nadia

AU - Hassoun, Paul M

AU - Hummers, Laura

AU - Mathai, Stephen

AU - Mathias, Rasika

AU - Mogayzel, Peter

AU - Rosen, Antony

AU - Ruczinski, Ingo

AU - Vergara, Candelaria

AU - Wise, Robert A

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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