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

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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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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%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. 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/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.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. Farlow (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 Barbalic (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 (Hackensack 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 (Northwestern 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 J. Mackey (University of Virginia)16, 18, Rachel Mackey (University of Pittsburgh)1, 23, 31, Ani Manichaikul (University of Virginia)8, 15, 18, 31, Taylor Maxwell (University of Texas Health Science Center Houston)22, Barbara McKnight (University of Washington)15, 23, James B. Meigs (Brigham and Women’s Hospital, Harvard Medical School, Massachusetts General Hospital)1, 28, Alanna C. Morrison (University of Texas Health Science Center Houston)3, 15, 17, Solomon K. Musani (University of Mississippi Medical Center)3, 29, Josyf C. Mychaleckyj (University of Virginia)13, 15, 31, Jennifer A. Nettleton (University of Texas Health Science Center Houston)9, 22, Kari North (University of North Carolina Chapel Hill)1, 3, 9, 10, 13, 15, 17, 34, Christopher J. O’Donnell (Massachusetts General Hospital, National Heart, Lung, and Blood Institute)2, 5, 9, 11, 12, 14, 15, 17, 20, 28, Daniel O’Leary (Tufts University School of Medicine)25, 31, Frank S. Ong (Cedars-Sinai Medical Center)3, 11, 31, Walter Palmas (Columbia University)3, 15, 31, James S. Pankow (University of Minnesota)1, 22, Nathan D. Pankratz (Indiana University School of Medicine)15, 25, Shom Paul (University of Virginia), Marco Perez (Stanford University School of Medicine), Sharina D. Person (University of Alabama at Birmingham, University of Alabama at Tuscaloosa)25, Joseph Polak (Tufts University School of Medicine)31, Wendy S. Post (Johns Hopkins University)3, 9, 11, 14, 20, 31, Bruce M. Psaty (Group Health Research Institute, University of Washington)3, 5, 9, 11, 14, 15, 23, Aaron R. Quinlan (University of Virginia)18, 19, Leslie J. Raffel (Cedars-Sinai Medical Center)6, 11, 31, Vasan S. Ramachandran (Boston University)3, 28, Alexander P. Reiner (Fred Hutchinson Cancer Research Center, University of Washington)1, 2, 3, 5, 9, 11, 12, 13, 14, 15, 20, 25, 34, Kenneth Rice (University of Washington)15, 23, Jerome I. Rotter (Cedars-Sinai Medical Center)1, 3, 6, 8, 11, 15, 31, Jill P. Sanders (University of Vermont)23, Pamela Schreiner (University of Minnesota)25, Sudha Seshadri (Boston University)18, 28, Steve Shea (Brigham and Women’s Hospital, Harvard University)28, Stephen Sidney (Kaiser Permanente Division of Research, Oakland, CA)25, Kevin Silverstein (University of Minnesota)25, David S. Siscovick (University of Washington)5, 1, 25, Nicholas L. Smith (University of Washington)2, 15, 20, 23, Nona Sotoodehnia (University of Washington)3, 15, 23, Asoke Srinivasan (Tougaloo College)29, Herman A. Taylor (Jackson State University, Tougaloo College, University of Mississippi Medical Center)5, 29, Kent Taylor (Cedars-Sinai Medical Center)31, Fridtjof Thomas (University of Texas Health Science Center Houston)3, 22, Russell P. Tracy (University of Vermont)5, 9, 11, 12, 14, 15, 17, 20, 23, Michael Y. Tsai (University of Minnesota)9, 31, Kelly A. Volcik (University of Texas Health Science Center Houston)22, Chrstina L Wassel (University of California San Diego)9, 15, 31, Karol Watson (University of California Los Angeles)31, Gina Wei (National Heart, Lung, and Blood Institute)25, Wendy White (Tougaloo College)29, Kerri L. Wiggins (University of Vermont)23, Jemma B. Wilk (Boston University)10, 28, O. Dale Williams (Florida International University)25, Gregory Wilson (Jackson State University)29, James G. Wilson (University of Mississippi Medical Center)1, 2, 5, 8, 9, 11, 12, 14, 17, 20, 29, Phillip Wolf (Boston University)28, Neil A. Zakai (University of Vermont)2, 23. ISGS and SWISS: John Hardy (Reta Lila Weston Research Laboratories, Institute of Neurology, University College London)18, James F. Meschia (Mayo Clinic)18, Michael Nalls (National Institute on Aging)2, 18, Stephen S. Rich (University of Virginia)2, 4, 7, 8, 9, 11, 14, 15, 17, 18, 31, Andrew Singleton (National Institute on Aging)18, Brad Worrall (University of Virginia)18. LungGO: Michael J. Bamshad (Seattle Children’s Hospital, University of Washington)4, 6, 7, 8, 10, 11, 13, 15, 17, 27, Kathleen C. Barnes (Johns Hopkins University)2, 10, 12, 14, 15, 17, 20, 24, 30, 32, Ibrahim Abdulhamid (Children’s Hospital of Michigan)27, Frank Accurso (University of Colorado)27, Ran Anbar (Upstate Medical University)27, Terri Beaty (Johns Hopkins University)24, 30, Abigail Bigham (University of Washington)13, 15, 27, Phillip Black (Children’s Mercy Hospital)27, Eugene Bleecker (Wake Forest University)33, Kati Buckingham (University of Washington)27, Anne Marie Cairns (Maine Medical Center)27, Wei-Min Chen (University of Virginia)13, 15, 18, Daniel Caplan (Emory University)27, Barbara Chatfield (University of Utah)27, Aaron Chidekel (A.I. Dupont Institute Medical Center)27, Michael Cho (Brigham and Women’s Hospital, Harvard Medical School)13, 15, 24, David C. Christiani (Massachusetts General Hospital)21, James D. Crapo (National Jewish Health)24, 30, Julia Crouch (Seattle Children’s Hospital)6, Denise Daley (University of British Columbia)30, Anthony Dang (University of North Carolina Chapel Hill)26, Hong Dang (University of North Carolina Chapel Hill)26, Alicia De Paula (Ochsner Health System)27, Joan DeCelie-Germana (Schneider Children’s Hospital)27, Allen Dozor (New York Medical College, Westchester Medical Center)27, Mitch Drumm (University of North Carolina Chapel Hill)26, Maynard Dyson (Cook Children’s Med. Center)27, Julia Emerson (Seattle Children’s Hospital, University of Washington)27, Mary J. Emond (University of Washington)10, 13, 15, 17, 27, Thomas Ferkol (St. Louis Children’s Hospital, Washington University School of Medicine)27, Robert Fink (Children’s Medical Center of Dayton)27, Cassandra Foster (Johns Hopkins University)30, Deborah Froh (University of Virginia)27, Li Gao (Johns Hopkins University)24, 30, 32, William Gershan (Children’s Hospital of Wisconsin)27, Ronald L. Gibson (Seattle Children’s Hospital, University of Washington)10, 27, Elizabeth Godwin (University of North Carolina Chapel Hill)26, Magdalen Gondor (All Children’s Hospital Cystic Fibrosis Center)27, Hector Gutierrez (University of Alabama at Birmingham)27, Nadia N. Hansel (Johns Hopkins University, Johns Hopkins University School of Public Health)10, 15, 30, Paul M. Hassoun (Johns Hopkins University)10, 14, 32, Peter Hiatt (Texas Children’s Hospital)27, John E. Hokanson (University of Colorado)24, Michelle Howenstine (Indiana University, Riley Hospital for Children)27, Laura K. Hummer (Johns Hopkins University)32, Seema M. Jamal (University of Washington)11, Jamshed Kanga (University of Kentucky)27, Yoonhee Kim (National Human Genome Research Institute)24, 32, Michael R. Knowles (University of North Carolina Chapel Hill)10, 26, Michael Konstan (Rainbow Babies & Children’s Hospital)27, Thomas Lahiri (Vermont Children’s Hospital at Fletcher Allen Health Care)27, Nan Laird (Harvard School of Public Health)24, Christoph Lange (Harvard School of Public Health)24, Lin Lin (Harvard Medical School)21, Xihong Lin (Harvard School of Public Health)21, Tin L. Louie (University of Washington)13, 15, 27, David Lynch (National Jewish Health)24, Barry Make (National Jewish Health)24, Thomas R. Martin (University of Washington, VA Puget Sound Medical Center)10, 21, Steve C. Mathai (Johns Hopkins University)32, Rasika A. Mathias (Johns Hopkins University)10, 13, 15, 30, 32, John McNamara (Children’s Hospitals and Clinics of Minnesota)27, Sharon McNamara (Seattle Children’s Hospital)27, Deborah Meyers (Wake Forest University)33, Susan Millard (DeVos Children’s Butterworth Hospital, Spectrum Health Systems)27, Peter Mogayzel (Johns Hopkins University)27, Richard Moss (Stanford University)27, Tanda Murray (Johns Hopkins University)30, Dennis Nielson (University of California at San Francisco)27, Blakeslee Noyes (Cardinal Glennon Children’s Hospital)27, Wanda O’Neal (University of North Carolina Chapel Hill)26, David Orenstein (Children’s Hospital of Pittsburgh)27, Brian O’Sullivan (University of Massachusetts Memorial Health Care)27, Rhonda Pace (University of North Carolina Chapel Hill)26, Peter Pare (St. Paul’s Hospital)30, H. Worth Parker (Dartmouth-Hitchcock Medical Center, New Hampshire Cystic Fibrosis Center)27, Mary Ann Passero (Rhode Island Hospital)27, Elizabeth Perkett (Vanderbilt University)27, Adrienne Prestridge (Children’s Memorial Hospital)27, Nicholas M. Rafaels (Johns Hopkins University)30, Bonnie Ramsey (Seattle Children’s Hospital, University of Washington)27, Elizabeth Regan (National Jewish Health)24, Clement Ren (University of Rochester)27, George Retsch-Bogart (University of North Carolina Chapel Hill)27, Michael Rock (University of Wisconsin Hospital and Clinics)27, Antony Rosen (Johns Hopkins University)32, Margaret Rosenfeld (Seattle Children’s Hospital, University of Washington)27, Ingo Ruczinski (Johns Hopkins University School of Public Health)13, 15, 30, Andrew Sanford (University of British Columbia)30, David Schaeffer (Nemours Children’s Clinic)27, Cindy Sell (University of North Carolina Chapel Hill)26, Daniel Sheehan (Children’s Hospital of Buffalo)27, Edwin K. Silverman (Brigham and Women’s Hospital, Harvard Medical School)24, 30, Don Sin (Children’s Medical Center of Dayton)30, Terry Spencer (Elliot Health System)27, Jackie Stonebraker (University of North Carolina Chapel Hill)26, Holly K. Tabor (Seattle Children’s Hospital, University of Washington)6, 10, 11, 17, 27, Laurie Varlotta (St. Christopher’s Hospital for Children)27, Candelaria I. Vergara (Johns Hopkins University)30, Robert Weiss 30, Fred Wigley (Johns Hopkins University)32, Robert A. Wise (Johns Hopkins University)30, Fred A. Wright (University of North Carolina Chapel Hill)26, Mark M. Wurfel (University of Washington)10, 14, 21, Robert Zanni (Monmouth Medical Center)27, Fei Zou (University of North Carolina Chapel Hill)26. SeattleGO: Deborah A. Nickerson (University of Washington)3, 4, 5, 7, 8, 9, 11, 15, 17, 18, 19, Mark J. Rieder (University of Washington)4, 11, 13, 15, 16, 17, 19, Phil Green (University of Washington), Jay Shendure (University of Washington)1, 8, 14, 16, 17, Joshua M. Akey (University of Washington)13, 14, 15, Michael J. Bamshad (Seattle Children’s Hospital, University of Washington)4, 6, 7, 8, 10, 11, 13, 15, 17, 27, Kristine L. Bucasas (Baylor College of Medicine)15, Carlos D. Bustamante (Stanford University School of Medicine)3, 13, 15, David R. Crosslin (University of Washington)2, 9, Evan E. Eichler (University of Washington)19, P. Keolu Fox2, Wenqing Fu (University of Washington)13, Adam Gordon (University of Washington)11, Simon Gravel (Stanford University School of Medicine)13, 15, Gail P. Jarvik (University of Washington)9, 15, Jill M. Johnsen (Puget Sound Blood Center, University of Washington)2, Mengyuan Kan (Baylor College of Medicine)13, Eimear E. Kenny (Stanford University School of Medicine)3, 13, 15, Jeffrey M. Kidd (Stanford University School of Medicine)13, 15, Fremiet Lara-Garduno (Baylor College of Medicine)15, Suzanne M. Leal (Baylor College of Medicine)1, 13, 15, 16, 17, 19, 20, Dajiang J. Liu (Baylor College of Medicine)13, 15, Sean McGee (University of Washington)13, 15, 19, Timothy D. O’Connor (University of Washington)13, Bryan Paeper (University of Washington)16, Peggy D. Robertson (University of Washington)4, Joshua D. Smith (University of Washington)4, 16, 19, Jeffrey C. Staples (University of Washington), Jacob A. Tennessen (University of Washington)13, Emily H. Turner (University of Washington)4, 16, Gao Wang (Baylor College of Medicine)1,13,20, Qian Yi (University of Washington)4. WHISP: Rebecca Jackson (Ohio State University)1, 2, 4, 5, 8, 12, 14, 15, 17, 18, 20, 34, Kari North (University of North Carolina Chapel Hill)1, 3, 9, 10, 13, 15, 17, 34, Ulrike Peters (Fred Hutchinson Cancer Research Center)1, 3, 11, 12, 13, 15, 17, 18, 34, Christopher S. Carlson (Fred Hutchinson Cancer Research Center, University of Washington)1, 2, 3, 5, 12, 13, 14, 15, 16, 17, 18, 19, 34, Garnet Anderson (Fred Hutchinson Cancer Research Center)34, Hoda Anton-Culver (University of California at Irvine)34, Themistocles L. Assimes (Stanford University School of Medicine)5, 9, 11, 34, Paul L. Auer (Fred Hutchinson Cancer Research Center)1, 2, 3, 5, 11, 12, 13, 15, 16, 18, 34, Shirley Beresford (Fred Hutchinson Cancer Research Center)34, Chris Bizon (University of North Carolina Chapel Hill)3, 9, 13, 15, 34, Henry Black (Rush Medical Center)34, Robert Brunner (University of Nevada)34, Robert Brzyski (University of Texas Health Science Center San Antonio)34, Dale Burwen (National Heart, Lung, and Blood Institute WHI Project Office)34, Bette Caan (Kaiser Permanente Division of Research, Oakland, CA)34, Cara L. Carty (Fred Hutchinson Cancer Research Center)18, 34, Rowan Chlebowski (Los Angeles Biomedical Research Institute)34, Steven Cummings (University of California at San Francisco)34, J. David Curb* (University of Hawaii)9, 18, 34, Charles B. Eaton (Brown University, Memorial Hospital of Rhode Island)12, 34, Leslie Ford (National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute WHI Project Office)34, Nora Franceschini (University of North Carolina Chapel Hill)2, 3, 9, 10, 15, 34, Stephanie M. Fullerton (University of Washington)6, 11, 34, Margery Gass (University of Cincinnati)34, Nancy Geller (National Heart, Lung, and Blood Institute WHI Project Office)34, Gerardo Heiss (University of North Carolina Chapel Hill)5, 34, Barbara V. Howard (Howard University, MedStar Research Institute)34, Li Hsu (Fred Hutchinson Cancer Research Center)1, 13, 15, 18, 34, Carolyn M. Hutter (Fred Hutchinson Cancer Research Center)13, 15, 18, 34, John Ioannidis (Stanford University School of Medicine)11, 34, Shuo Jiao (Fred Hutchinson Cancer Research Center)34, Karen C. Johnson (University of Tennessee Health Science Center)3, 34, Charles Kooperberg (Fred Hutchinson Cancer Research Center)1, 5, 9, 13, 14, 15, 17, 18, 34, Lewis Kuller (University of Pittsburgh)34, Andrea LaCroix (Fred Hutchinson Cancer Research Center)34, Kamakshi Lakshminarayan (University of Minnesota)18, 34, Dorothy Lane (State University of New York at Stony Brook)34, 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, Norman Lasser (University of Medicine and Dentistry of New Jersey)34, Erin LeBlanc (Kaiser Permanente Center for Health Research, Portland, OR)34, Cora E. Lewis (University of Alabama at Birmingham)25,34, Kuo-Ping Li (University of North Carolina Chapel Hill)9, 34, Marian Limacher (University of Florida)34, Dan-Yu Lin (University of North Carolina Chapel Hill)1, 3, 9, 13, 15, 34, Benjamin A. Logsdon (Fred Hutchinson Cancer Research Center)2, 34, Shari Ludlam (National Heart, Lung, and Blood Institute WHI Project Office)34, JoAnn E. Manson (Brigham and Women’s Hospital, Harvard School of Public Health)34, Karen Margolis (University of Minnesota)34, Lisa Martin (George Washington University Medical Center)9, 34, Joan McGowan (National Heart, Lung, and Blood Institute WHI Project Office)34, Keri L. Monda (Amgen, Inc.)1, 15, 34, Jane Morley Kotchen (Medical College of Wisconsin)34, Lauren Nathan (University of California Los Angeles)34, Judith Ockene (Fallon Clinic, University of Massachusetts)34, Mary Jo O’Sullivan (University of Miami)34, Lawrence S. Phillips (Emory University)34, Ross L. Prentice (Fred Hutchinson Cancer Research Center)34, Alexander P. Reiner (Fred Hutchinson Cancer Research Center, University of Washington)1, 2, 3, 5, 9, 11, 12, 13, 14, 15, 20, 25, 34, John Robbins (University of California at Davis)34, Jennifer G. Robinson (University of Iowa)9, 11, 18, 34, Jacques E. Rossouw (National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute WHI Project Office)5, 14, 17, 20, 34, Haleh Sangi-Haghpeykar (Baylor College of Medicine)34, Gloria E. Sarto (University of Wisconsin)34, Sally Shumaker (Wake Forest University)34, Michael S. Simon (Wayne State University)34, Marcia L. Stefanick (Stanford University School of Medicine)34, Evan Stein (Medical Research Labs)34, Hua Tang (Stanford University)2, 34, Kira C. Taylor (University of Louisville)1, 3, 13, 15, 20, 34, Cynthia A. Thomson (University of Arizona)34, Timothy A. Thornton (University of Washington)13, 15, 18, 34, Linda Van Horn (Northwestern University)34, Mara Vitolins (Wake Forest University)34, Jean Wactawski-Wende (University of Buffalo)34, Robert Wallace (University of Iowa)2, 34, Sylvia Wassertheil-Smoller (Boston University)18, 34, Donglin Zeng (University of North Carolina Chapel Hill)9, 34. *deceased. NHLBI GO ESP Project Team: Deborah Applebaum-Bowden (National Heart, Lung, and Blood Institute)4, 7, 12, 17, Michael Feolo (National Center for Biotechnology Information)12, Weiniu Gan (National Heart, Lung, and Blood Institute)7, 8, 16, 17, Dina N. Paltoo (National Heart, Lung, and Blood Institute)4, 6, 11, 17, Jacques E. Rossouw (National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute WHI Project Office)5, 14, 17, 20, 34, Phyliss Sholinsky (National Heart, Lung, and Blood Institute)4, 12, 17, Anne Sturcke (National Center for Biotechnology Information)12. ESP Groups: 1Anthropometry Project Team, 2Blood Count/Hematology Project Team, 3Blood Pressure Project Team, 4Data Flow Working Group, 5Early MI Project Team, 6ELSI Working Group, 7Executive Committee, 8Family Study Project Team, 9Lipids Project Team, 10Lung Project Team, 11Personal Genomics Project Team, 12Phenotype and Harmonization Working Group, 13Population Genetics and Statistical Analysis Working Group, 14Publications and Presentations Working Group, 15Quantitative Analysis Ad Hoc Task Group, 16Sequencing and Genotyping Working Group, 17Steering Committee, 18Stroke Project Team, 19Structural Variation Working Group, 20Subclinical/Quantitative Project Team. ESP Cohorts: 21Acute Lung Injury (ALI), 22Atherosclerosis Risk in Communities (ARIC), 23Cardiovascular Health Study (CHS), 24Chronic Obstructive Pulmonary Disease (COPDGene), 25Coronary Artery Risk Development in Young Adults (CARDIA), 26Cystic Fibrosis (CF), 27Early Pseudomonas Infection Control (EPIC), 28Framingham Heart Study (FHS), 29Jackson Heart Study (JHS), 30Lung Health Study (LHS), 31Multi-Ethnic Study of Atherosclerosis (MESA), 32Pulmonary Arterial Hypertension (PAH), 33Severe Asthma Research Program (SARP), 34Women’s Health Initiative (WHI).

Author information

Authors and Affiliations

  1. Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA

    Elisabeth A. Rosenthal, Laura M. Amendola, Martha Horike-Pyne, Fuki M. Hisama, Robin L. Bennett & Gail P. Jarvik

  2. Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, WA, USA

    Brian H. Shirts

  3. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    Peggy D. Robertson, Michael O. Dorschner, Deborah A. Nickerson & Gail P. Jarvik

  4. Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA

    Fuki M. Hisama

  5. Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA

    Michael O. Dorschner

  6. Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Washington, Seattle, WA, USA

    Michael O. Dorschner

  7. Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA, USA

    Ian B. Stanaway

  8. Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA

    Rami Nassir

  9. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Kathy T. Vickers, Christopher Li & Ulrike Peters

  10. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    William M. Grady

  11. Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    William M. Grady

  12. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA

    Ulrike Peters & Gail P. Jarvik

Authors
  1. Elisabeth A. Rosenthal
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  2. Brian H. Shirts
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  3. Laura M. Amendola
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  4. Martha Horike-Pyne
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  5. Peggy D. Robertson
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  6. Fuki M. Hisama
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  7. Robin L. Bennett
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  8. Michael O. Dorschner
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  9. Deborah A. Nickerson
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  10. Ian B. Stanaway
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  11. Rami Nassir
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  12. Kathy T. Vickers
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  13. Christopher Li
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  14. William M. Grady
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  15. Ulrike Peters
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  16. Gail P. Jarvik
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Consortia

NHLBI GO Exome Sequencing Project

  • Stacey B. Gabriel
  • , David M. Altshuler
  • , Gonçalo R. Abecasis
  • , Hooman Allayee
  • , Sharon Cresci
  • , Mark J. Daly
  • , Paul I. W. de Bakker
  • , Mark A. DePristo
  • , Ron Do
  • , Peter Donnelly
  • , Deborah N. Farlow
  • , Tim Fennell
  • , Kiran Garimella
  • , Stanley L. Hazen
  • , Youna Hu
  • , Daniel M. Jordan
  • , Goo Jun
  • , Sekar Kathiresan
  • , Hyun Min Kang
  • , Adam Kiezun
  • , Guillaume Lettre
  • , Bingshan Li
  • , Mingyao Li
  • , Christopher H. Newton-Cheh
  • , Sandosh Padmanabhan
  • , Gina Peloso
  • , Sara Pulit
  • , Daniel J. Rader
  • , David Reich
  • , Muredach P. Reilly
  • , Manuel A. Rivas
  • , Steve Schwartz
  • , Laura Scott
  • , David S. Siscovick
  • , John A. Spertus
  • , Nathan O. Stitziel
  • , Nina Stoletzki
  • , Shamil R. Sunyaev
  • , Benjamin F. Voight
  • , Cristen J. Willer
  • , Stephen S. Rich
  • , Ermeg Akylbekova
  • , Larry D. Atwood
  • , Christie M. Ballantyne
  • , Maja Barbalic
  • , R. Graham Barr
  • , Emelia J. Benjamin
  • , Joshua Bis
  • , Eric Boerwinkle
  • , Donald W. Bowden
  • , Jennifer Brody
  • , Matthew Budoff
  • , Greg Burke
  • , Sarah Buxbaum
  • , Jeff Carr
  • , Donna T. Chen
  • , Ida Y. Chen
  • , Wei-Min Chen
  • , Pat Concannon
  • , Jacy Crosby
  • , L. Adrienne Cupples
  • , Ralph D’Agostino
  • , Anita L. DeStefano
  • , Albert Dreisbach
  • , Josée Dupuis
  • , J. Peter Durda
  • , Jaclyn Ellis
  • , Aaron R. Folsom
  • , Myriam Fornage
  • , Caroline S. Fox
  • , Ervin Fox
  • , Vincent Funari
  • , Santhi K. Ganesh
  • , Julius Gardin
  • , David Goff
  • , Ora Gordon
  • , Wayne Grody
  • , Myron Gross
  • , Xiuqing Guo
  • , Ira M. Hall
  • , Nancy L. Heard-Costa
  • , Susan R. Heckbert
  • , Nicholas Heintz
  • , David M. Herrington
  • , DeMarc Hickson
  • , Jie Huang
  • , Shih-Jen Hwang
  • , David R. Jacobs
  • , Nancy S. Jenny
  • , Andrew D. Johnson
  • , Craig W. Johnson
  • , Steven Kawut
  • , Richard Kronmal
  • , Raluca Kurz
  • , Ethan M. Lange
  • , Leslie A. Lange
  • , Martin G. Larson
  • , Mark Lawson
  • , Cora E. Lewis
  • , Daniel Levy
  • , Dalin Li
  • , Honghuang Lin
  • , Chunyu Liu
  • , Jiankang Liu
  • , Kiang Liu
  • , Xiaoming Liu
  • , Yongmei Liu
  • , William T. Longstreth
  • , Cay Loria
  • , Thomas Lumley
  • , Kathryn Lunetta
  • , Aaron J. Mackey
  • , Rachel Mackey
  • , Ani Manichaikul
  • , Taylor Maxwell
  • , Barbara McKnight
  • , James B. Meigs
  • , Alanna C. Morrison
  • , Solomon K. Musani
  • , Josyf C. Mychaleckyj
  • , Jennifer A. Nettleton
  • , Kari North
  • , Christopher J. O’Donnell
  • , Daniel O’Leary
  • , Frank S. Ong
  • , Walter Palmas
  • , James S. Pankow
  • , Nathan D. Pankratz
  • , Shom Paul
  • , Marco Perez
  • , Sharina D. Person
  • , Joseph Polak
  • , Wendy S. Post
  • , Bruce M. Psaty
  • , Aaron R. Quinlan
  • , Leslie J. Raffel
  • , Vasan S. Ramachandran
  • , Alexander P. Reiner
  • , Kenneth Rice
  • , Jerome I. Rotter
  • , Jill P. Sanders
  • , Pamela Schreiner
  • , Sudha Seshadri
  • , Steve Shea
  • , Stephen Sidney
  • , Kevin Silverstein
  • , David S. Siscovick
  • , Nicholas L. Smith
  • , Nona Sotoodehnia
  • , Asoke Srinivasan
  • , Herman A. Taylor
  • , Kent Taylor
  • , Fridtjof Thomas
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Corresponding author

Correspondence to Elisabeth A. Rosenthal.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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The members of NHLBI GO Exome Sequencing Project are listed in acknowledgements.

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Rosenthal, E.A., Shirts, B.H., Amendola, L.M. et al. Rare loss of function variants in candidate genes and risk of colorectal cancer. Hum Genet 137, 795–806 (2018). https://doi.org/10.1007/s00439-018-1938-4

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