Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Journal: MedRxiv : The Preprint Server For Health Sciences
Published:
Abstract

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Authors
Farid Rajabli, Penelope Benchek, Giuseppe Tosto, Nicholas Kushch, Jin Sha, Katrina Bazemore, Congcong Zhu, Wan-ping Lee, Jacob Haut, Kara Hamilton Nelson, Nicholas Wheeler, Yi Zhao, John Farrell, Michelle Grunin, Yuk Leung, Pavel Kuksa, Donghe Li, Eder Lucio Da Fonseca, Jesse Mez, Ellen Palmer, Jagan Pillai, Richard Sherva, Yeunjoo Song, Xiaoling Zhang, Taha Iqbal, Omkar Pathak, Otto Valladares, Amanda Kuzma, Erin Abner, Perrie Adams, Alyssa Aguirre, Marilyn Albert, Roger Albin, Mariet Allen, Lisa Alvarez, Liana Apostolova, Steven Arnold, Sanjay Asthana, Craig Atwood, Gayle Ayres, Clinton Baldwin, Robert Barber, Lisa Barnes, Sandra Barral, Thomas Beach, James Becker, Gary Beecham, Duane Beekly, Bruno Benitez, David Bennett, John Bertelson, Thomas Bird, Deborah Blacker, Bradley Boeve, James Bowen, Adam Boxer, James Brewer, James Burke, Jeffrey Burns, Joseph Buxbaum, Nigel Cairns, Laura Cantwell, Chuanhai Cao, Christopher Carlson, Cynthia Carlsson, Regina Carney, Minerva Carrasquillo, Scott Chasse, Marie-francoise Chesselet, Nathaniel Chin, Helena Chui, Jaeyoon Chung, Suzanne Craft, Paul Crane, David Cribbs, Elizabeth Crocco, Carlos Cruchaga, Michael Cuccaro, Munro Cullum, Eveleen Darby, Barbara Davis, Philip De Jager, Charles Decarli, John Detoledo, Malcolm Dick, Dennis Dickson, Beth Dombroski, Rachelle Doody, Ranjan Duara, Nilüfer Ertekin Taner, Denis Evans, Kelley Faber, Thomas Fairchild, Kenneth Fallon, David Fardo, Martin Farlow, Victoria Fernandez Hernandez, Steven Ferris, Tatiana Foroud, Matthew Frosch, Brian Fulton Howard, Douglas Galasko, Adriana Gamboa, Marla Gearing, Daniel Geschwind, Bernardino Ghetti, John Gilbert, Alison Goate, Thomas Grabowski, Neill Graff Radford, Robert Green, John Growdon, Hakon Hakonarson, James Hall, Ronald Hamilton, Oscar Harari, John Hardy, Lindy Harrell, Elizabeth Head, Victor Henderson, Michelle Hernandez, Timothy Hohman, Lawrence Honig, Ryan Huebinger, Matthew Huentelman, Christine Hulette, Bradley Hyman, Linda Hynan, Laura Ibanez, Gail Jarvik, Suman Jayadev, Lee-way Jin, Kim Johnson, Leigh Johnson, M Kamboh, Anna Karydas, Mindy Katz, John Kauwe, Jeffrey Kaye, C Keene, Aisha Khaleeq, Ronald Kim, Janice Knebl, Neil Kowall, Joel Kramer, Walter Kukull, Frank Laferla, James Lah, Eric Larson, Alan Lerner, James Leverenz, Allan Levey, Andrew Lieberman, Richard Lipton, Mark Logue, Oscar Lopez, Kathryn Lunetta, Constantine Lyketsos, Douglas Mains, Flanagan Margaret, Daniel Marson, Eden Martin, Frank Martiniuk, Deborah Mash, Eliezer Masliah, Paul Massman, Arjun Masurkar, Wayne Mccormick, Susan Mccurry, Andrew Mcdavid, Stefan Mcdonough, Ann Mckee, Marsel Mesulam, Bruce Miller, Carol Miller, Joshua Miller, Thomas Montine, Edwin Monuki, John Morris, Shubhabrata Mukherjee, Amanda Myers, Trung Nguyen, Sid O'bryant, John Olichney, Marcia Ory, Raymond Palmer, Joseph Parisi, Henry Paulson, Valory Pavlik, David Paydarfar, Victoria Perez, Elaine Peskind, Ronald Petersen, Aimee Pierce, Marsha Polk, Wayne Poon, Huntington Potter, Liming Qu, Mary Quiceno, Joseph Quinn, Ashok Raj, Murray Raskind, Eric Reiman, Barry Reisberg, Joan Reisch, John Ringman, Erik Roberson, Monica Rodriguear, Ekaterina Rogaeva, Howard Rosen, Roger Rosenberg, Donald Royall, Mark Sager, Mary Sano, Andrew Saykin, Julie Schneider, Lon Schneider, William Seeley, Susan Slifer, Scott Small, Amanda Smith, Janet Smith, Joshua Sonnen, Salvatore Spina, Peter St George Hyslop, Robert Stern, Alan Stevens, Stephen Strittmatter, David Sultzer, Russell Swerdlow, Rudolph Tanzi, Jeffrey Tilson, John Trojanowski, Juan Troncoso, Debby Tsuang, Vivianna Van Deerlin, Linda Van Eldik, Jeffery Vance, Badri Vardarajan, Robert Vassar, Harry Vinters, Jean-paul Vonsattel, Sandra Weintraub, Kathleen Welsh Bohmer, Patrice Whitehead, Ellen Wijsman, Kirk Wilhelmsen, Benjamin Williams, Jennifer Williamson, Henrik Wilms, Thomas Wingo, Thomas Wisniewski, Randall Woltjer, Martin Woon, Clinton Wright, Chuang-kuo Wu, Steven Younkin, Chang-en Yu, Lei Yu, Xiongwei Zhu, Brian Kunkle, William Bush, Li-san Wang, Lindsay Farrer, Jonathan Haines, Richard Mayeux, Margaret Pericak Vance, Gerard Schellenberg, Gyungah Jun, Christiane Reitz, Adam Naj
Relevant Conditions

Alzheimer's Disease, Dementia