Whole genome sequence analyses of brain imaging measures in the Framingham Study

Chloé Sarnowski; Claudia L Satizabal; Charles DeCarli; Achilleas N Pitsillides; L Adrienne Cupples; Ramachandran S Vasan; James G Wilson; Joshua C Bis; Myriam Fornage; Alexa S Beiser; Anita L DeStefano; Josée Dupuis; Sudha Seshadri; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Neurocognitive Working Group

doi:10.1212/WNL.0000000000004820

Whole genome sequence analyses of brain imaging measures in the Framingham Study

Neurology. 2018 Jan 16;90(3):e188-e196. doi: 10.1212/WNL.0000000000004820. Epub 2017 Dec 27.

Authors

Collaborators

Donna K Arnett, Diane Becker, Joshua Bis, Eric Boerwinkle, Michael Bowers, Jan Bressler, Adolfo Correa, Anita DeStefano, Jingzhong Ding Ding, David Fardo, Myriam Fornage, Alex Garcia Lugo, David Glahn, Hector Gonzalez, Kathleen Hayden, Susan Heckbert, Karin Hoth, Timothy Hughes, Cashell Jaquish, Xueqiu Jian, Emma Knowles, Lenore Launer, Honghuang Lin, Will Longstreth, Richard Mayeux, Biswapriya Misra, Thomas Mosley, Paul Nyquist, Michael Olivier, Emmanuel Peprah, Bruce Psaty, Shaun Purcell, Jerome Rotter, Chloé Sarnowski, Claudia Satizabal, Gerard Schellenberg, Sudha Seshadri, Jeannette Simino, Jennifer Smith, Sylvia Smoller, Beverly Snively, Sophie Sokolow, Kate Wehr, Lisa Yanek, Qiong Yang, Abe Namiko, Abecasis Goncalo, Albert Christine, Allred Nicholette Nichole Palmer, Almasy Laura, Alonso Alvaro, Ament Seth, Anderson Peter, Anugu Pramod, Applebaum-Bowden Deborah, Arking Dan, Arnett Donna K, Ashley-Koch Allison, Aslibekyan Stella, Assimes Tim, Auer Paul, Avramopoulos Dimitrios, Barnard John, Barnes Kathleen, Barr R Graham, Barron-Casella Emily, Beaty Terri, Becker Diane, Becker Lewis, Beer Rebecca, Begum Ferdouse, Beitelshees Amber, Benjamin Emelia, Bezerra Marcos, Bielak Larry, Bis Joshua, Blackwell Thomas, Blangero John, Boerwinkle Eric, Borecki Ingrid, Bowler Russell, Brody Jennifer, Broeckel Ulrich, Broome Jai, Bunting Karen, Burchard Esteban, Cardwell Jonathan, Carlson Sara, Carty Cara, Casaburi Richard, Casella James, Chaffin Mark, Chang Christy, Chasman Daniel, Chavan Sameer, Chen Bo-Juen, Chen Wei-Min, Chen Yii-Der Ida, Cho Michael, Choi Seung Hoan, Chuang Lee-Ming, Chung Mina, Cornell Elaine, Correa Adolfo, Crandall Carolyn, Crapo James, Cupples L Adrienne, Curran Joanne, Curtis Jeffrey, Custer Brian, Damcott Coleen, Darbar Dawood, Das Sayantan, David Sean, Davis Colleen, Daya Michelle de Andrade Mariza, DeBaun Michael, Deka Ranjan, DeMeo Dawn, Devine Scott, Do Ron, Duan Qing, Duggirala Ravi, Durda Peter, Dutcher Susan, Eaton Charles, Ekunwe Lynette, Ellinor Patrick, Emery Leslie, Farber Charles, Farnam Leanna, Fingerlin Tasha, Flickinger Matthew, Fornage Myriam, Franceschini Nora, Fu Mao, Fullerton Malia, Fulton Lucinda, Gabriel Stacey, Gan Weiniu, Gao Yan, Gass Margery, Geng Xiaoqi Priscilla, Germer Soren, Gignoux Chris, Gladwin Mark, Glahn David, Gogarten Stephanie, Gong Da-Wei, Goring Harald, Gu C Charles, Guan Yue, Guo Xiuqing, Haessler Jeff, Hall Michael, Harris Daniel, Hawley Nicola, He Jiang, Heavner Ben, Heckbert Susan, Hernandez Ryan, Herrington David, Hersh Craig, Hidalgo Bertha, Hixson James, Hokanson John, Hong Elliott, Hoth Karin, Hsiung Chao Agnes, Huston Haley, Hwu Chii Min, Irvin Marguerite Ryan, Jackson Rebecca, Jain Deepti, Jaquish Cashell, Jhun Min A, Johnsen Jill, Johnson Andrew, Johnson Craig, Johnston Rich, Jones Kimberly, Kang Hyun Min, Kaplan Robert, Kardia Sharon, Kathiresan Sekar, Kaufman Laura, Kelly Shannon, Kenny Eimear, Kessler Michael, Khan Alyna, Kinney Greg, Konkle Barbara, Kooperberg Charles, Kramer Holly, Krauter Stephanie, Lange Christoph, Lange Ethan, Lange Leslie, Laurie Cathy, Laurie Cecelia, LeBoff Meryl, Lee Seunggeun Shawn, Lee Wen-Jane, LeFaive Jonathon, Levine David, Levy Dan, Lewis Joshua, Li Yun, Lin Honghuang, Lin Keng Han, Liu Simin, Liu Yongmei, Loos Ruth, Lubitz Steven, Lunetta Kathryn, Luo James, Mahaney Michael, Make Barry, Manichaikul Ani, Manson JoAnn, Margolin Lauren, Martin Lisa, Mathai Susan, Mathias Rasika, McArdle Patrick, McDonald Merry-Lynn, McFarland Sean, McGarvey Stephen, Mei Hao, Meyers Deborah A, Mikulla Julie, Min Nancy, Minear Mollie, Minster Ryan L, Mitchell Braxton, Montasser May E, Musani Solomon, Mwasongwe Stanford, Mychaleckyj Josyf C, Nadkarni Girish, Naik Rakhi, Natarajan Pradeep, Nekhai Sergei, Nickerson Deborah, North Kari, O'Connell Jeff, O'Connor Tim, Ochs-Balcom Heather, Pankow James, Papanicolaou George, Parker Margaret, Parsa Afshin, Pattison Jessica Tangarone, Penchev Sara, Peralta Juan Manuel, Perez Marco, Perry James, Peters Ulrike, Peyser Patricia, Phillips Larry, Phillips Sam, Pollin Toni, Post Wendy, Powers Becker Julia, Preethi Boorgula Meher, Preuss Michael, Prokopenko Dmitry, Psaty Bruce, Qasba Pankaj, Qiao Dandi, Qin Zhaohui, Rafaels Nicholas, Raffield Laura, Ramachandran Vasan, D C Rao, Rasmussen-Torvik Laura, Ratan Aakrosh, Redline Susan, Reed Robert, Regan Elizabeth, Reiner Alex, Rice Ken, Rich Stephen, Roden Dan, Roselli Carolina, Rotter Jerome, Ruczinski Ingo, Russell Pamela, Ruuska Sarah, Ryan Kathleen, Sakornsakolpat Phuwanat, Salimi Shabnam, Salzberg Steven, Sandow Kevin, Sankaran Vijay, Scheller Christopher, Schmidt Ellen, Schwander Karen, Schwartz David, Sciurba Frank, Sheehan Vivien, Shetty Amol, Shetty Aniket, Sheu Wayne Hui-Heng, Shoemaker M Benjamin, Silver Brian, Silverman Edwin, Smith Jennifer, Smith Josh, Smith Nicholas, Smith Tanja, Smoller Sylvia, Snively Beverly, Sofer Tamar, Sotoodehnia Nona, Stilp Adrienne, Streeten Elizabeth, Sung Yun Ju, Sylvia Jody, Szpiro Adam, Sztalryd Carole, Taliun Daniel, Tang Hua, Taub Margaret, Taylor Kent, Taylor Simeon, Telen Marilyn, Thornton Timothy A, Tinker Lesley, Tirschwell David, Tiwari Hemant, Tracy Russell, Tsai Michael, Vaidya Dhananjay, VandeHaar Peter, Vrieze Scott, Walker Tarik, Wallace Robert, Walts Avram, Wan Emily, Wang Fei Fei, Watson Karol, Weeks Daniel E, Weir Bruce, Weiss Scott, Weng Lu-Chen, Willer Cristen, Williams Kayleen, Williams L Keoki, Wilson Carla, Wilson James, Wong Quenna, Xu Huichun, Yanek Lisa, Yang Ivana, Yang Rongze, Zaghloul Norann, Zhang Yingze, Zhao Snow Xueyan, Zhao Wei, Zheng Xiuwen, Zhi Degui, Zhou Xiang, Zody Michael, Zoellner Sebastian

Affiliations

¹ From the Department of Epidemiology (C.S., L.A.C., A.S.B., A.L.D., J.D.), Boston University School of Public Health; Boston University and the NHLBI's Framingham Heart Study (C.L.S., A.N.P., L.A.C., R.S.V., A.S.B., A.L.D., J.D., S.S.); Departments of Neurology (C.L.S., A.S.B., A.L.D., S.S.) and Cardiology, Preventive Medicine & Epidemiology (R.S.V.), Boston University School of Medicine, Boston, MA; Department of Neurology and Center for Neuroscience (C.D.), University of California at Davis; Department of Physiology and Biophysics (J.G.W.), University of Mississippi Medical Center, Jackson; Cardiovascular Health Research Unit (J.C.B.), Department of Medicine, University of Washington, Seattle; and Institute of Molecular Medicine (M.F.), University of Texas Health Science Center, Houston. chloesar@bu.edu.
² From the Department of Epidemiology (C.S., L.A.C., A.S.B., A.L.D., J.D.), Boston University School of Public Health; Boston University and the NHLBI's Framingham Heart Study (C.L.S., A.N.P., L.A.C., R.S.V., A.S.B., A.L.D., J.D., S.S.); Departments of Neurology (C.L.S., A.S.B., A.L.D., S.S.) and Cardiology, Preventive Medicine & Epidemiology (R.S.V.), Boston University School of Medicine, Boston, MA; Department of Neurology and Center for Neuroscience (C.D.), University of California at Davis; Department of Physiology and Biophysics (J.G.W.), University of Mississippi Medical Center, Jackson; Cardiovascular Health Research Unit (J.C.B.), Department of Medicine, University of Washington, Seattle; and Institute of Molecular Medicine (M.F.), University of Texas Health Science Center, Houston.

Abstract

Objective: We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.

Methods: We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.

Results: We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10^-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10^-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10^-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10^-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10^-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.

Conclusions: Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aged
Brain / anatomy & histology
Brain / diagnostic imaging*
Female
Genetic Variation*
Genome-Wide Association Study
Humans
Magnetic Resonance Imaging
Male
Massachusetts
Middle Aged
Organ Size
Phenotype
Prospective Studies

Abstract

Publication types

MeSH terms

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