Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits

Yuetiva Deming; Jian Xia; Yefei Cai; Jenny Lord; Jorge L Del-Aguila; Maria Victoria Fernandez; David Carrell; Kathleen Black; John Budde; ShengMei Ma; Benjamin Saef; Bill Howells; Sarah Bertelsen; Matthew Bailey; Perry G Ridge; Alzheimer’s Disease Neuroimaging Initiative (ADNI); David Holtzman; John C Morris; Kelly Bales; Eve H Pickering; Jin-Moo Lee; Laura Heitsch; John Kauwe; Alison Goate; Laura Piccio; Carlos Cruchaga

doi:10.1038/srep18092

Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits

Sci Rep. 2016 Jan 4;6(1):18092. doi: 10.1038/srep18092.

Authors

Yuetiva Deming^#¹, Jian Xia^#^{1

2}, Yefei Cai¹, Jenny Lord^{1

3}, Jorge L Del-Aguila¹, Maria Victoria Fernandez¹, David Carrell¹, Kathleen Black¹, John Budde¹, ShengMei Ma¹, Benjamin Saef¹, Bill Howells¹, Sarah Bertelsen¹, Matthew Bailey⁴, Perry G Ridge⁴; Alzheimer’s Disease Neuroimaging Initiative (ADNI); David Holtzman^{5

6

7

8}, John C Morris^{5

6

7

8}, Kelly Bales⁹, Eve H Pickering⁹, Jin-Moo Lee⁵, Laura Heitsch⁵, John Kauwe⁴, Alison Goate^{1

7

8}, Laura Piccio⁵, Carlos Cruchaga^{1

8}

Collaborators

Alzheimer’s Disease Neuroimaging Initiative (ADNI):
Franz Hefti, Howard Fillit, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Maria Carrillo, Adam Fleisher, Stephanie Reeder, Nadira Trncic, Anna Burke, Pierre Tariot, Eric M Reiman, Kewei Chen, Marwan N Sabbagh, Christine M Beiden, Sandra A Jacobson, Sherye A Sirrel, Rachelle S Doody, Javier Villanueva-Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Neil Kowall, Ronald Killiany, Andrew E Budson, Alexander Norbash, Patricia Lynn Johnson, Robert C Green, Gad Marshall, Keith A Johnson, Reisa A Sperling, Peter Snyder, Stephen Salloway, Paul Malloy, Stephen Correia, Charles Bernick, Donna Munic, Yaakov Stern, Lawrence S Honig, Karen L Bell, Norman Relkin, Gloria Chaing, Lisa Ravdin, Steven Paul, Laura A Flashman, Marc Seltzer, Mary L Hynes, Robert B Santulli, Vernice Bates, Horacio Capote, Michelle Rainka, Karl Friedl, P Murali Doraiswamy, Jeffrey R Petrella, Salvador Borges-Neto, Olga James, Terence Wong, Edward Coleman, Adam Schwartz, Janet S Cellar, Allan L Levey, James J Lah, Kelly Behan, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Godfrey D Pearlson, Karen Blank, Karen Anderson, Thomas O Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Martin R Farlow, Andrew J Saykin, Tatiana M Foroud, Li Shen, Kelly Faber, Sungeun Kim, Kwangsik Nho, Ann Marie Hake, Brandy R Matthews, Jared R Brosch, Scott Herring, Cynthia Hunt, Marilyn Albert, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Neill R Graff-Radford, Francine Parfitt, Tracy Kendall, Heather Johnson, Ronald Petersen, Clifford R Jack Jr, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Sara S Mason, Colleen S Albers, David Knopman, Kris Johnson, Howard Chertkow, Chris Hosein, Jacob Mintzer, Kenneth Spicer, David Bachman, Hillel Grossman, Effie Mitsis, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, William Potter, Neil Buckholtz, John Hsiao, Smita Kittur, James E Galvin, Brittany Cerbone, Christina A Michel, Dana M Pogorelec, Henry Rusinek, Mony J de Leon, Lidia Glodzik, Susan De Santi, Nancy Johnson, Chuang-Kuo, Diana Kerwin, Borna Bonakdarpour, Sandra Weintraub, Jordan Grafman, Kristine Lipowski, Marek-Marsel Mesulam, Douglas W Scharre, Maria Kataki, Anahita Adeli, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Michael Borrie, T-Y Lee, Rob Bartha, Walter Martinez, Teresa Villena, Carl Sadowsky, Zaven Khachaturian, Brian R Ott, Henry Querfurth, Geoffrey Tremont, Richard Frank, Debra Fleischman, Konstantinos Arfanakis, Raj C Shah, Leyla deToledo-Morrell, Greg Sorensen, Elizabeth Finger, Stephen Pasternack, Irina Rachinsky, Dick Drost, John Rogers, Andrew Kertesz, Ansgar J Furst, Stevan Chad, Jerome Yesavage, Joy L Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Michele Assaly, Nick Fox, Susan K Schultz, Laura L Boles Ponto, Hyungsub Shim, Karen Ekstam Smith, Jeffrey M Burns, Russell H Swerdlow, William M Brooks, Daniel Marson, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson, Marissa Natelson Love, Charles DeCarli, Owen Carmichael, John Olichney, Pauline Maillard, Evan Fletcher, Dana Nguyen, Andrian Preda, Steven Potkin, Ruth A Mulnard, Gaby Thai, Catherine McAdams-Ortiz, Susan Landau, William Jagust, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H S Silverman, Po H Lu, George Bartzokis, Paul Thompson, Michael Donohue, Ronald G Thomas, Sarah Walter, Devon Gessert, James Brewer, Helen Vanderswag, Tamie Sather, Gus Jiminez, Archana B Balasubramanian, Jennifer Mason, Iris Sim, Paul Aisen, Melissa Davis, Rosemary Morrison, Danielle Harvey, Lean Thal, Laurel Beckett, Thomas Neylan, Shannon Finley, Michael W Weiner, Jacqueline Hayes, Howard J Rosen, Bruce L Miller, David Perry, Dino Massoglia, Olga Brawman-Mentzer, Norbert Schuff, Charles D Smith, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Robert A Koeppe, Joanne L Lord, Judith L Heidebrink, Steven E Arnold, Jason H Karlawish, David Wolk, Christopher M Clark, John Q Trojanowki, Leslie M Shaw, Virginia Lee, Magdalena Korecka, Michal Figurski, Arthur W Toga, Karen Crawford, Scott Neu, Lon S Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M Spann, Kyle Womack, Dana Mathews, Mary Quiceno, Norm Foster, Tom Montine, J Jay Fruehling, Sandra Harding, Sterling Johnson, Sanjay Asthana, Cynthia M Carlsson, Eric C Petrie, Elaine Peskind, Gail Li, Anton P Porsteinsson, Bonnie S Goldstein, Kim Martin, Kelly M Makino, M Saleem Ismail, Connie Brand, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Lew Kuller, Chet Mathis, Mary Ann Oakley, Oscar L Lopez, Donna M Simpson, Kaycee M Sink, Leslie Gordineer, Jeff D Williamson, Pradeep Garg, Franklin Watkins, Nigel J Cairns, Marc Raichle, John C Morris, Erin Householder, Lisa Taylor-Reinwald, David Holtzman, Beau Ances, Maria Carroll, Mary L Creech, Erin Franklin, Mark A Mintun, Stacy Schneider, Angela Oliver, Ranjan Duara, Daniel Varon, Maria T Greig, Peggy Roberts, Pradeep Varma, Martha G MacAvoy, Richard E Carson, Christopher H van Dyck, Peter Davies

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, 63110, MO, USA.
² Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, P.R. China.
³ Human Genetics Programme, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.
⁴ Department of Biology, Brigham Young University, Provo, UT, USA.
⁵ Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, 63110, MO, USA.
⁶ Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, 63110, MO, USA.
⁷ Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Ave., St Louis, 63108, MO, USA.
⁸ Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, 63110, MO, USA.
⁹ Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, USA.

^# Contributed equally.

Abstract

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects and complex disease associations in the same locus.

Abstract

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