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 journalArticlepeer-review

5 Scopus citations

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

Bibliographical note

Funding Information:
Acknowledgements The authors thank Karynne Patterson for help obtaining the ESP raw data. The authors thank Niha Zubair and Tabitha Harrison for help obtaining the WHI raw data. This work was supported by the NHGRI and NCI Clinical Sequencing Exploratory Research program, UO1 HG006507 and HG007307. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. A full listing of WHI investigators can be found at: http://www.whi. org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Inv estigator%20Short%20List.pdf. Whole exome sequencing of WHI was funded via X01-HG006196. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). The ColoCare study is funded by grants 2P30CA015704-40; RO1CA194663, RO1CA189184, UO1152756, Seattle Tumor Translational Research Program, and the Cottrell Family Fund. HeartGO: Atherosclerosis Risk in Communities (ARIC): NHLBI (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C); Cardiovascular Health Study (CHS): NHLBI (HHSN268201200036C, HHSN268200800007C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295), with additional support from NINDS and from NIA (AG-023629, AG-15928, AG-20098, and AG-027058); Coronary Artery Risk Development in

Funding Information:
Young Adults (CARDIA): NHLBI (N01-HC95095 & N01-HC48047, N01-HC48048, N01-HC48049, and N01-HC48050); Framingham Heart Study (FHS): NHLBI (N01-HC-25195 and grant R01 NS17950) with additional support from NIA (AG08122 and AG033193); Jackson Heart Study (JHS): NHLBI and the National Institute on Minority Health and Health Disparities (N01 HC-95170, N01 HC-95171 and N01 HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): NHLBI (N01-HC-95159 through N01-HC-95169 and RR-024156). Lung GO: Cystic Fibrosis (CF): Cystic Fibrosis Foundation (GIBSON07K0, KNOWLE00A0, OBSERV04K0, RDP R026), the NHLBI (R01 HL-068890, R02 HL-095396), NIH National Center for Research Resources (UL1 RR-025014), and the National Human Genome Research Institute (NHGRI) (5R00 HG-004316). Chronic Obstructive Pulmonary Disease (COPDGene): NHLBI (U01 HL-089897, U01 HL-089856), and the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovian. The COPDGene clinical centers and investigators are available at http://www.copdgene.org. Acute Lung Injury (ALI): NHLBI (RC2 HL-101779). Lung Health Study (LHS): NHLBI (RC2 HL-066583), the NHGRI (HG-004738), and the NHLBI Division of Lung Diseases (HR-46002). Pulmonary Arterial Hypertension (PAH): NIH (P50 HL-084946, K23 AR-52742), and the NHLBI (F32 HL-083714). Asthma: NHLBI (RC2 HL-101651), and the NIH (HL-077916, HL-69197, HL-76285, M01 RR-07122). SWISS and ISGS: Siblings with Ischemic Stroke Study (SWISS): National Institute of Neurological Disorders and Stroke (NINDS) (R01 NS039987); Ischemic Stroke Genetics Study (ISGS): NINDS (R01 NS042733). WHISP: Women’s Health Initiative (WHI): The WHI Sequencing Project is funded by the National Heart, Lung, and Blood Institute (HL-102924) as well as the National Institutes of Health (NIH), U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Docum ents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20 List.pdf. NHLBI GO Exome Sequencing Project: BroadGO: Stacey B. Gabriel (Broad Institute)4, 5, 11, 16, 17, David M. Altshuler (Broad Institute, Harvard Medical School, Massachusetts General Hospital)1, 5, 7, 17, Gonçalo R. Abecasis (University of Michigan)3, 5, 9, 13, 15, 17, Hooman Allayee (University of Southern California)5, Sharon Cresci (Washington University School of Medicine)5, Mark J. Daly (Broad Institute, Massachusetts General Hospital), Paul I. W. de Bakker (Broad Institute, Harvard Medical School, University Medical Center Utrecht)3, 15, Mark A. DePristo (Broad Institute)4, 13, 15, 16, Ron Do (Broad Institute)5, 9, 13, 15, Peter Donnelly (University of Oxford)5, Deborah N. Far-low (Broad Institute)3, 4, 5, 12, 14, 16, 17, Tim Fennell (Broad Institute), Kiran Garimella (University of Oxford)4, 16, Stanley L. Hazen (Cleveland Clinic)5, Youna Hu (University of Michigan)3, 9, 15, Daniel M. Jordan (Harvard Medical School, Harvard University)13, Goo Jun (University of Michigan)13, Sekar Kathiresan (Broad Institute, Harvard Medical School, Massachusetts General Hospital)5, 8, 9, 12, 14, 15, 17, 20, Hyun Min Kang (University of Michigan)9, 13, 16, Adam Kiezun (Broad Institute)5, 13, 15, Guillaume Lettre (Broad Institute, Montreal Heart Institute, Université de Montréal)1, 2, 13, 15, Bingshan Li (University of Michigan)3, Mingyao Li (University of Pennsylvania)5, Christopher H. Newton-Cheh (Broad Institute, Massachusetts General Hospital, Harvard Medical School)3, 8, 15, Sandosh Padmanabhan (University of Glasgow School of Medicine)3, 12, 15, Gina Peloso (Broad Institute, Harvard Medical School, Massachusetts General Hospital)5, Sara Pulit (Broad Institute)3, 15, Daniel J. Rader (University of Pennsylvania)5, David Reich (Broad Institute, Harvard Medical School)15, Muredach P. Reilly (University of Pennsylvania)5, Manuel A. Rivas (Broad Institute, Massachusetts General Hospital)5, Steve Schwartz (Fred Hutchinson Cancer Research Center)5, 12, Laura Scott (University of Michigan)1, David S. Siscovick (University of Washington)5, 1, 25, John A. Spertus (University of Missouri Kansas City)5, Nathan O. Stitziel (Brigham and Women’s Hospital)5, 15, Nina Stoletzki (Brigham and Women’s Hospital, Broad Institute, Harvard Medical School)13, Shamil R. Sunyaev (Brigham and Women’s Hospital, Broad Institute, Harvard Medical School)1, 3, 5, 13, 15, Benjamin F. Voight (Broad Institute, Massachusetts General Hospital), Cristen J. Willer (University of Michigan)1, 9, 13, 15. HeartGO: Stephen S. Rich (University of Virginia)2,4, 7, 8,9,11,14, 15,17,18,31, Ermeg Akylbekova (Jackson State University, University of Mississippi Medical Center)29, Larry D. Atwood* (Boston University)1, 11, 28, Christie M. Ballantyne (Baylor College of Medicine, Methodist DeBakey Heart Center)9, 22, Maja Bar-balic (University of Texas Health Science Center Houston)9, 14, 15, 17, 22, R. Graham Barr (Columbia University Medical Center)10, 31, Emelia J. Benjamin (Boston University)14, 20, 28, Joshua Bis (University of Washington)15, 23, Eric Boerwinkle (University of Texas Health Science Center Houston)3, 5, 9, 13, 15, 17, 22, Donald W. Bowden (Wake Forest University)1, 31, Jennifer Brody (University of Washington)3, 5, 15, 23, Matthew Budoff (Harbor-UCLA Medical Center)31, Greg Burke (Wake Forest University)5, 31, Sarah Buxbaum (Jackson State University)3, 13, 15, 29, Jeff Carr (Wake Forest University)25, 29, 31, Donna T. Chen (University of Virginia)6, 11, Ida Y. Chen (Cedars-Sinai Medical Center)1, 31, Wei-Min Chen (University of Virginia)13, 15, 18, Pat Concannon (University of Virginia)11, Jacy Crosby (University of Texas Health Science Center Houston)22, L. Adrienne Cupples (Boston University)1, 3, 5, 9, 13, 15, 18, 28, Ralph D’Agostino (Boston University)28, Anita L. DeStefano (Boston University)13, 18, 28, Albert Dreisbach (University of Mississippi Medical Center)3, 29, Josée Dupuis (Boston University)1, 28, J. Peter Durda (University of Vermont)15, 23, Jaclyn Ellis (University of North Carolina Chapel Hill)1, Aaron R. Folsom (University of Minnesota)5, 22, Myriam Fornage (University of Texas Health Science Center Houston)3, 18, 25, Caroline S. Fox (National Heart, Lung, and Blood Institute)1,28, Ervin Fox (University of Mississippi Medical Center)3, 9, 29, Vincent Funari (Cedars-Sinai Medical Center)1, 11, 31, Santhi K. Ganesh (University of Michigan)2, 22, Julius Gardin (Hack-ensack University Medical Center)25, David Goff (Wake Forest University)25, Ora Gordon (Cedars-Sinai Medical Center)11, 31, Wayne Grody (University of California Los Angeles)11, 31, Myron Gross (University of Minnesota)1, 5, 14, 25, Xiuqing Guo (Cedars-Sinai Medical Center)3, 15, 31, Ira M. Hall (University of Virginia), Nancy L. Heard-Costa (Boston University)1, 11, 28, Susan R. Heckbert (University of Washington)10,14,20,23, Nicholas Heintz (University of Vermont), David M. Herrington (Wake Forest University)5, 31, DeMarc Hickson (Jackson State University, University of Mississippi Medical Center)29, Jie Huang (National Heart, Lung, and Blood Institute)5, 28, Shih-Jen Hwang (Boston University, National Heart, Lung, and Blood Institute)3, 28, David R. Jacobs (University of Minnesota)25, Nancy S. Jenny (University of Vermont)1, 2, 23, Andrew D. Johnson (National Heart, Lung, and Blood Institute)2, 5, 11, 28, Craig W. Johnson (University of Washington)15, 31, Steven Kawut (University of Pennsylvania)10,31, Richard Kronmal (University of Washington)31, Raluca Kurz (Cedars-Sinai Medical Center)11, 31, Ethan M. Lange (University of North Carolina Chapel Hill)3, 5, 9, 13, 34, Leslie A. Lange (University of North Carolina Chapel Hill)1, 2, 3, 5, 9, 12, 13, 15, 17, 18, 20, 25, 34, Martin G. Larson (Boston University)3, 15, 28, Mark Lawson (University of Virginia), Cora E. Lewis (University of Alabama at Birmingham)25,34, Daniel Levy (National Heart, Lung, and Blood Institute)3, 15, 17, 28, Dalin Li (Cedars-Sinai Medical Center)11, 15, 31, Honghuang Lin (Boston University)20, 28, Chunyu Liu (National Heart, Lung, and Blood Institute)3, 28, Jiankang Liu (University of Mississippi Medical Center)1, 29, Kiang Liu (North-western University)25, Xiaoming Liu (University of Texas Health Science Center Houston)15, 22, Yongmei Liu (Wake Forest University)2, 5, 31, William T. Longstreth (University of Washington)18, 23, Cay Loria (National Heart, Lung, and Blood Institute)25, Thomas Lumley (University of Auckland)9,23, Kathryn Lunetta (Boston University)28, Aaron

Funding Information:
The authors thank Karynne Patterson for help obtaining the ESP raw data. The authors thank Niha Zubair and Tabitha Harrison for help obtaining the WHI raw data. This work was supported by the NHGRI and NCI Clinical Sequencing Exploratory Research program, UO1 HG006507 and HG007307. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. Whole exome sequencing of WHI was funded via X01-HG006196. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). The ColoCare study is funded by grants 2P30CA015704-40; RO1CA194663, RO1CA189184, UO1152756, Seattle Tumor Translational Research Program, and the Cottrell Family Fund. HeartGO: Atherosclerosis Risk in Communities (ARIC): NHLBI (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C); Cardiovascular Health Study (CHS): NHLBI (HHSN268201200036C, HHSN268200800007C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295), with additional support from NINDS and from NIA (AG-023629, AG-15928, AG-20098, and AG-027058); Coronary Artery Risk Development in Young Adults (CARDIA): NHLBI (N01-HC95095 & N01-HC48047, N01-HC48048, N01-HC48049, and N01-HC48050); Framingham Heart Study (FHS): NHLBI (N01-HC-25195 and grant R01 NS17950) with additional support from NIA (AG08122 and AG033193); Jackson Heart Study (JHS): NHLBI and the National Institute on Minority Health and Health Disparities (N01 HC-95170, N01 HC-95171 and N01 HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): NHLBI (N01-HC-95159 through N01-HC-95169 and RR-024156). Lung GO: Cystic Fibrosis (CF): Cystic Fibrosis Foundation (GIBSON07K0, KNOWLE00A0, OBSERV04K0, RDP R026), the NHLBI (R01 HL-068890, R02 HL-095396), NIH National Center for Research Resources (UL1 RR-025014), and the National Human Genome Research Institute (NHGRI) (5R00 HG-004316). Chronic Obstructive Pulmonary Disease (COPDGene): NHLBI (U01 HL-089897, U01 HL-089856), and the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovian. The COPDGene clinical centers and investigators are available at http://www.copdgene.org. Acute Lung Injury (ALI): NHLBI (RC2 HL-101779). Lung Health Study (LHS): NHLBI (RC2 HL-066583), the NHGRI (HG-004738), and the NHLBI Division of Lung Diseases (HR-46002). Pulmonary Arterial Hypertension (PAH): NIH (P50 HL-084946, K23 AR-52742), and the NHLBI (F32 HL-083714). Asthma: NHLBI (RC2 HL-101651), and the NIH (HL-077916, HL-69197, HL-76285, M01 RR-07122). SWISS and ISGS: Siblings with Ischemic Stroke Study (SWISS): National Institute of Neurological Disorders and Stroke (NINDS) (R01 NS039987); Ischemic Stroke Genetics Study (ISGS): NINDS (R01 NS042733). WHISP: Women?s Health Initiative (WHI): The WHI Sequencing Project is funded by the National Heart, Lung, and Blood Institute (HL-102924) as well as the National Institutes of Health (NIH), U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C..

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