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1. Neurostructural subgroup in 4291 individuals with schizophrenia identified using the subtype and stage inference algorithm

Author

Yuchao Jiang, Cheng Luo, Jijun Wang, Lena Palaniyappan, Xiao Chang, Shitong Xiang, Jie Zhang, Mingjun Duan, Huan Huang, Christian Gaser, Kiyotaka Nemoto, Kenichiro Miura, Ryota Hashimoto, Lars T. Westlye, Genevieve Richard, Sara Fernandez-Cabello, Nadine Parker, Ole A. Andreassen, Tilo Kircher, Igor Nenadić, Frederike Stein, Florian Thomas-Odenthal, Lea Teutenberg, Paula Usemann, Udo Dannlowski, Tim Hahn, Dominik Grotegerd, Susanne Meinert, Rebekka Lencer, Yingying Tang, Tianhong Zhang, Chunbo Li, Weihua Yue, Yuyanan Zhang, Xin Yu, Enpeng Zhou, Ching-Po Lin, Shih-Jen Tsai, Amanda L. Rodrigue, David Glahn, Godfrey Pearlson, John Blangero, Andriana Karuk, Edith Pomarol-Clotet, Raymond Salvador, Paola Fuentes-Claramonte, María Ángeles Garcia-León, Gianfranco Spalletta, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Jingliang Cheng, Zhening Liu, Jie Yang, Ali Saffet Gonul, Ozgul Uslu, Birce Begum Burhanoglu, Aslihan Uyar Demir, Kelly Rootes-Murdy, Vince D. Calhoun, Kang Sim, Melissa Green, Yann Quidé, Young Chul Chung, Woo-Sung Kim, Scott R. Sponheim, Caroline Demro, Ian S. Ramsay, Felice Iasevoli, Andrea de Bartolomeis, Annarita Barone, Mariateresa Ciccarelli, Arturo Brunetti, Sirio Cocozza, Giuseppe Pontillo, Mario Tranfa, Min Tae M. Park, Matthias Kirschner, Foivos Georgiadis, Stefan Kaiser, Tamsyn E. Van Rheenen, Susan L. Rossell, Matthew Hughes, William Woods, Sean P. Carruthers, Philip Sumner, Elysha Ringin, Filip Spaniel, Antonin Skoch, David Tomecek, Philipp Homan, Stephanie Homan, Wolfgang Omlor, Giacomo Cecere, Dana D. Nguyen, Adrian Preda, Sophia I. Thomopoulos, Neda Jahanshad, Long-Biao Cui, Dezhong Yao, Paul M. Thompson, Jessica A. Turner, Theo G. M. van Erp, Wei Cheng, ENIGMA Schizophrenia Consortium, Jianfeng Feng, and ZIB Consortium

Subjects
Science
Abstract

Abstract Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Published
2024
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2. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

Author

Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner

Subjects
EWAS, DNA methylation, IgE, Asthma, RNA-Sequencing, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Published
2023
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3. Social isolation is linked to classical risk factors of Alzheimer’s disease-related dementias

Author

Kimia Shafighi, Sylvia Villeneuve, Pedro Rosa Neto, AmanPreet Badhwar, Judes Poirier, Vaibhav Sharma, Yasser Iturria Medina, Patricia P. Silveira, Laurette Dube, David Glahn, and Danilo Bzdok

Subjects
Medicine, Science
Abstract

Alzheimer’s disease and related dementias is a major public health burden–compounding over upcoming years due to longevity. Recently, clinical evidence hinted at the experience of social isolation in expediting dementia onset. In 502,506 UK Biobank participants and 30,097 participants from the Canadian Longitudinal Study of Aging, we revisited traditional risk factors for developing dementia in the context of loneliness and lacking social support. Across these measures of subjective and objective social deprivation, we have identified strong links between individuals’ social capital and various indicators of Alzheimer’s disease and related dementias risk, which replicated across both population cohorts. The quality and quantity of daily social encounters had deep connections with key aetiopathological factors, which represent 1) personal habits and lifestyle factors, 2) physical health, 3) mental health, and 4) societal and external factors. Our population-scale assessment suggest that social lifestyle determinants are linked to most neurodegeneration risk factors, highlighting them as promising targets for preventive clinical action.

Published
2023

4. Effects of weather and season on human brain volume.

Author

Gregory A Book, Shashwath A Meda, Ronald Janssen, Alecia D Dager, Andrew Poppe, Michael C Stevens, Michal Assaf, David Glahn, and Godfrey D Pearlson

Subjects
Medicine, Science
Abstract

We present an exploratory cross-sectional analysis of the effect of season and weather on Freesurfer-derived brain volumes from a sample of 3,279 healthy individuals collected on two MRI scanners in Hartford, CT, USA over a 15 year period. Weather and seasonal effects were analyzed using a single linear regression model with age, sex, motion, scan sequence, time-of-day, month of the year, and the deviation from average barometric pressure, air temperature, and humidity, as covariates. FDR correction for multiple comparisons was applied to groups of non-overlapping ROIs. Significant negative relationships were found between the left- and right- cerebellum cortex and pressure (t = -2.25, p = 0.049; t = -2.771, p = 0.017). Significant positive relationships were found between left- and right- cerebellum cortex and white matter between the comparisons of January/June and January/September. Significant negative relationships were found between several subcortical ROIs for the summer months compared to January. An opposing effect was observed between the supra- and infra-tentorium, with opposite effect directions in winter and summer. Cohen's d effect sizes from monthly comparisons were similar to those reported in recent psychiatric big-data publications, raising the possibility that seasonal changes and weather may be confounds in large cohort studies. Additionally, changes in brain volume due to natural environmental variation have not been reported before and may have implications for weather-related and seasonal ailments.

Published
2021
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5. Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Author

Joaquim Radua, Eduard Vieta, Russell Shinohara, Peter Kochunov, Yann Quidé, Melissa J. Green, Cynthia S. Weickert, Thomas Weickert, Jason Bruggemann, Tilo Kircher, Igor Nenadić, Murray J. Cairns, Marc Seal, Ulrich Schall, Frans Henskens, Janice M. Fullerton, Bryan Mowry, Christos Pantelis, Rhoshel Lenroot, Vanessa Cropley, Carmel Loughland, Rodney Scott, Daniel Wolf, Theodore D. Satterthwaite, Yunlong Tan, Kang Sim, Fabrizio Piras, Gianfranco Spalletta, Nerisa Banaj, Edith Pomarol-Clotet, Aleix Solanes, Anton Albajes-Eizagirre, Erick J. Canales-Rodríguez, Salvador Sarro, Annabella Di Giorgio, Alessandro Bertolino, Michael Stäblein, Viola Oertel, Christian Knöchel, Stefan Borgwardt, Stefan du Plessis, Je-Yeon Yun, Jun Soo Kwon, Udo Dannlowski, Tim Hahn, Dominik Grotegerd, Clara Alloza, Celso Arango, Joost Janssen, Covadonga Díaz-Caneja, Wenhao Jiang, Vince Calhoun, Stefan Ehrlich, Kun Yang, Nicola G. Cascella, Yoichiro Takayanagi, Akira Sawa, Alexander Tomyshev, Irina Lebedeva, Vasily Kaleda, Matthias Kirschner, Cyril Hoschl, David Tomecek, Antonin Skoch, Therese van Amelsvoort, Geor Bakker, Anthony James, Adrian Preda, Andrea Weideman, Dan J. Stein, Fleur Howells, Anne Uhlmann, Henk Temmingh, Carlos López-Jaramillo, Ana Díaz-Zuluaga, Lydia Fortea, Eloy Martinez-Heras, Elisabeth Solana, Sara Llufriu, Neda Jahanshad, Paul Thompson, Jessica Turner, Theo van Erp, David Glahn, Godfrey Pearlson, Elliot Hong, Axel Krug, Vaughan Carr, Paul Tooney, Gavin Cooper, Paul Rasser, Patricia Michie, Stanley Catts, Raquel Gur, Ruben Gur, Fude Yang, Fengmei Fan, Jingxu Chen, Hua Guo, Shuping Tan, Zhiren Wang, Hong Xiang, Federica Piras, Francesca Assogna, Raymond Salvador, Peter McKenna, Aurora Bonvino, Margaret King, Stefan Kaiser, Dana Nguyen, and Julian Pineda-Zapata

Subjects
Brain, Cortical thickness, Gray matter, Mega-analysis, Neuroimaging, Schizophrenia, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Published
2020
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6. 3069 Characterizing the Neural Signature of Metabolic Syndrome

Author

Eithan Kotkowski, Larry R. Price, Crystal G. Franklin, Maximino Salazar, Ralph A. DeFronzo, David Glahn, John Blangero, and Peter T. Fox

Subjects
Medicine
Abstract

OBJECTIVES/SPECIFIC AIMS: Our objective is to understand the influence of the features comprising metabolic syndrome (central obesity, raised fasting plasma glucose, triglycerides, blood pressure, and decreased HDL cholesterol) on brain structure in men and women. With the understanding that MetS is a strong predictor of gray matter volume loss in specific brain regions, in this study we sought to quantify the influence of each of the metabolic syndrome biometric variables on the structures involved in the neural signature of metabolic syndrome. METHODS/STUDY POPULATION: We conducted multiple linear regression analyses on a cross-sectional sample of 800 individuals from the Genetics of Brian Structure (GOBS) image archive (352 men and 448 women). GOBS is an offshoot of the San Antonio Heart Study involving an extended pedigree of Mexican Americans from the greater San Antonio area. Its goal is to localize, identify, and characterize genes/quantitative trait loci associated with variations in brain structure and function (Winkler, 2010). The archive has continuously added participants from approximately 40 families since 2006. Neuroanatomic (T1-weighted MRI scans obtained on a Siemens 3T scanner and processed using FSL), neurocognitive, and biometric phenotypes have been obtained for each subject (including blood lipids). Linear regressions were run using SPSS and incorporated biometric and gray matter volume values obtained from 800 GOBS participants. RESULTS/ANTICIPATED RESULTS: Linear regressions incorporating metabolic syndrome variables as dependent variables and gray matter volume from regions involved in the neural signature of metabolic syndrome as predictors show significant predictive patterns that are largely similar between men and women, with some differences. Another linear regression conducted with gray matter volume from the neural signature of metabolic syndrome as the dependent variable and metabolic syndrome variables as predictors show that waist circumference and triglycerides are the greatest predictors of gray matter volume loss in men, and fasting plasma glucose and waist circumference are the greatest predictors of gray matter volume loss in women. DISCUSSION/SIGNIFICANCE OF IMPACT: Significant sex differences in the relationships between metabolic syndrome variables and gray matter volume changes between brain regions comprising the neural signature of metabolic syndrome were identified. waist circumference, fasting plasma glucose, and triglycerides are the most reliable predictors of gray matter volume loss. The variance in gray matter volume of the neural signature of metabolic syndrome in men is more significantly explained by waist circumference and triglycerides (when accounting for age) and in women is more significantly explained by waist circumference and fasting plasma glucose (when accounting for age). A model of metabolic syndrome that emphasizes a risk of neurodegeneration should focus on waist circumference for both men and women and weigh the remaining variables accordingly by sex (triglycerides in men and fasting plasma glucose in women).

Published
2019
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7. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author

Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Published
2022
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8. Connectome architecture shapes large-scale cortical reorganization in schizophrenia: a worldwide ENIGMA study

Author

Foivos Georgiadis, Sara Larivière, David Glahn, L. Elliot Hong, Peter Kochunov, Bryan Mowry, Carmel Loughland, Christos Pantelis, Frans A. Henskens, Melissa J. Green, Murray J. Cairns, Patricia T Michie, Paul E. Rasser, Paul Tooney, Rodney J. Scott, Stanley Catts, Ulrich Schall, Vaughan Carr, Yann Quidé, Axel Krug, Frederike Stein, Igor Nenadić, Katharina Brosch, Tilo Kircher, Raquel Gur, Ruben Gur, Theodore D. Satterthwaite, Andriana Karuk, Edith Pomarol-Clotet, Joaquim Radua, Paola Fuentes-Claramonte, Raymond Salvador, Gianfranco Spalletta, Aristotle Voineskos, Kang Sim, Benedicto Crespo-Facorro, Diana Tordesillas Gutiérrez, Stefan Ehrlich, Nicolas Crossley, Dominik Grotegerd, Jonathan Repple, Rebekka Lencer, Udo Dannlowski, Vince Calhoun, Caroline Demro, Ian S. Ramsay, Scott. Sponheim, Andre Schmidt, Stefan Borgwardt, Alexander S. Tomyshev, Irina Lebedeva, Cyril Hoschl, Filip Spaniel, Adrian Preda, Dana Nguyen, Anne Uhlmann, Dan J Stein, Fleur M Howells, Henk S. Temmingh, Ana M. Diaz Zuluaga, Carlos López Jaramillo, Felice Iasevoli, Ellen Ji, Stephanie Homan, Wolfgang Omlor, Philipp Homan, Stefan Kaiser, Erich Seifritz, Bratislav Misic, Paul Thompson, Theo G.M. van Erp, Jessica Turner, Boris Bernhardt, and Matthias Kirschner

Abstract

ObjectiveSchizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder.MethodsWe studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps.ResultsIn schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, pspinspin=0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders.ConclusionsCortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.

Published
2023
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9. 292. Large-Scale Investigation of Bipolar Disorder Topological Variance: A Graph Theory Analysis of 959 Individuals From the Enigma Bipolar Disorder Working Group

Author

Leila Nabulsi, Neda Jahanshad, Benno Haarman, Colm McDonald, Dan Stein, David Glahn, Edith Pomarol-Clotet, Eduard Vieta, Josselin Houenou, Mircea Polosan, Paolo Brambilla, Philip Mitchell, Udo Dannlowski, Michèle Wessa, Mary Phillips, Tilo Kircher, Paul M. Thompson, Christopher R.K. Ching, Ole A. Andreassen, and Dara M. Cannon

Subjects
Biological Psychiatry
Published
2023
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10. Dissociable Cellular and Genetic Mechanisms of Cortical Thinning at Different Life Stages

Author

Amirhossein Modabbernia, Didac Vidal-Pineiro, Ingrid Agartz, Ole Andreassen, Rosa Ayesa-Arriola, Alessandro Bertolino, D Boomsma, Josiane Bourque, Alan Breier, Henry Brodaty, Rachel Brouwer, Jan Buitelaar, Erick Canales-Rodriguez, Xavier Caseras, Patricia Conrod, Benedicto Crespo-Facorro, Fabrice Crivello, Eveline Crone, Greig De Zubicaray, Erin Dickie, Danai Dima, Thomas Espeseth, Stefan Frenzel, Simon Fisher, Barbara Franke, David Glahn, Hans Grabe, Dominik Grotegerd, Oliver Gruber, Amalia Guerrero-Pedraza, Raquel Gur, Ruben Gur, Catharina Hartman, Pieter Hoekstra, Hilleke Hulshoff Pol, Neda Jahanshad, Terry Jernigan, Jiyang Jiang, Andrew Kalnin, Nicole Kochan, Bernard Mazoyer, Brenna McDonald, Katie McMahon, Lars Nyberg, Jaap Oosterlaan, E Pomarol-Clotet, Joaquim Radua, Joshua Roffman, Perminder Sachdev, Theodore Satterthwaite, Raymond Salvador, Salvador Sarró, Andrew Saykin, Gunter Schumann, Jordan Smoller, Iris Sommer, Christian Tamnes, Sophia Thomopoulos, Julian Trollor, Dennis van 't Ent, Aristotle Voineskos, Yang Wang, Bernd Weber, Wei Wen, Lars T. Westlye, Heather Whalley, Lara wierenga, Steven Williams, Katharina Wittfeld, Margaret Wright, Paul Thompson, Tomas Paus, and Sophia Frangou

Abstract

Mechanisms underpinning neurotypical age-related variations in cortical thickness in the human brain remain insufficiently specified. Here we used cell-specific marker genes, followed by gene ontology and enrichment analyses, to quantify the association between gene-expression levels and inter-regional age-related variations in neurotypical cortical thinning using multicohort neuroimaging data from 14,248 individuals ages 4-89 years. We found that early-life (60 years) were associated with distinct patterns of association between inter-regional profiles of cortical thickness and expression profiles of markers genes for CA1 and S1 pyramidal cells, astrocytes, and microglia. Gene ontology and enrichment analyses indicated each of the three life-stages was associated with different biological processes and cellular components; these related to synaptic modeling in early life, neurotransmission in mid-life, and neurodegeneration in late-life. These findings provide mechanistic insights on age-related cortical thinning during typical development and ageing.

Published
2022
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13. IMPACT OF COPY NUMBER VARIANTS AND POLYGENIC RISK SCORES ON PSYCHOPATHOLOGY IN THE UK BIOBANK

Author

Josephine Mollon, Laura Schultz, Guillaume Huguet, Emma Knowles, Samuel Mathias, Amanda Rodrigue, Aaron Alexander-Bloch, Martineau Jean Louis, Kuldeep Kumar, Elise Douard, Laura Almasy, Sébastien Jacquemont, and David Glahn

Subjects
Pharmacology, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical), Biological Psychiatry
Published
2022
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14. Shared sets of correlated polygenic risk scores and voxel-wise grey matter across multiple traits identified via bi-clustering

Author

Md Abdur Rahaman, Amanda Rodrigue, David Glahn, Jessica Turner, and Vince Calhoun

Subjects
Multifactorial Inheritance, Risk Factors, Brain, Cluster Analysis, Humans, Gray Matter
Abstract

Neuropsychiatric disorders involve complex polygenic determinants as well as brain alterations. The combination of genetic inheritance and neuroimaging approaches could advance our understanding of psychiatric disorders. However, cross-disorder overlap is a current issue since psychiatric conditions share some neurogenetic correlates, symptoms, and brain effects. Exploring the impact of genetic risk on the brain across disorders could help understand commonalities across multiple psychopathologies. To do this, we first compute the linear relationship between PRS and voxel-wise grey matter volume to generate brain maps for five psychiatric and three control traits. Next, we use the biclustering approach to identify regions of the brain associated with polygenic risk scores in one or more traits. Our results demonstrate a significant overlap in brain regions connected to polygenic risk across psychiatric traits. Moreover, such brain domains are highly allied with the polygenic risk for non-psychiatric control traits. This multi-trait overlap characterizes the nonspecific relationship between neural anatomy and inherited risk factors in psychiatric conditions, and in some cases, the overlap in neural features linked to genetic risk for non-psychiatric attributes.Clinical Relevance-This study presents biclusters of multiple psychiatric and control traits. The analysis reported various brain regions, including cerebellum, cuneus, precuneus, fusiform, supplementary motor area, that show significant correlation with polygenic risk scores across diverse groups of psychiatric conditions and non-psychiatric control traits.

Published
2021

15. Prevalence of Rate of Deleterious Copy Number Variants Similar in Early Onset Psychosis and Autism Spectrum Disorders: Implications for Clinical Practice

Author

Catherine Brownstein, Elise Douard, Josephine Mollon, Richard Smith, Margaret Hojlo, Emily Garvey, Kristin Cabral, Joshua Bowen, Emma Deaso, Abhijit Rao, Casie Genetti, Devon Carroll, Emma Knowles, Pankaj Agrawal, Alan Beggs, Eugene D’Angelo, Laura Almasy, Zohra Saci, Clara Moreau, Guillaume Huguet, Sébastien Jacquemont, David Glahn, and Joseph Gonzalez-Heydrich

Subjects
Biological Psychiatry
Published
2022
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18. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author

Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Costa Rica, Male, Pulmonary and Respiratory Medicine, Adolescent, Vital Capacity, Single-nucleotide polymorphism, Pedigree chart, Critical Care and Intensive Care Medicine, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Polymorphism (computer science), Forced Expiratory Volume, Humans, Medicine, SNP, 030212 general & internal medicine, Child, Asthma, Whole Genome Sequencing, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Minor allele frequency, 030228 respiratory system, Genetic epidemiology, Child, Preschool, Interferon Regulatory Factors, Immunology, Respiratory Physiological Phenomena, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules
Abstract

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Published
2019
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21. P181. Cortical Similarities Between Bipolar I Disorder and Schizophrenia: A Multivariate Approach

Author

Jesse Edmond, Kelly Rootes-Murdy, Wenhao Jiang, Jiayu Chen, Nora Perrone-Bizzozero, Vince Calhoun, Theo G.M. van Erp, Stefan Ehrlich, Ingrid Agartz, Erik G. Jönsson, Ole Andreassen, Lei Wang, Godfrey D. Pearlson, David Glahn, Elliot Hong, Aristotle Voineskos, Anil Malhotra, Robert Buchanan, Jingyu Liu, and Jessica Turner

Subjects
Biological Psychiatry
Published
2022
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22. Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Author

Guillaume Huguet, Catherine Schramm, Elise Douard, Tamer Petra, Antoine Main, Pauline Monin, Jade England, Khadije Jizi, Thomas Renne, Myriam Poirier, Sabrina Nowak, Charles-Olivier Martin, Nadine Younis, Inga Sophia Knoth, Martineau Jean-Louis, Zohra Saci, Maude Auger, Frédérique Tihy, Géraldine Mathonnet, Catalina Maftei, France Léveillé, David Porteous, Gail Davies, Paul Redmond, Sarah E. Harris, W. David Hill, Emmanuelle Lemyre, Gunter Schumann, Thomas Bourgeron, Zdenka Pausova, Tomas Paus, Sherif Karama, Sarah Lippe, Ian J. Deary, Laura Almasy, Aurélie Labbe, David Glahn, Celia M.T. Greenwood, and Sébastien Jacquemont

Subjects
Genetics, Regulation of gene expression, 0303 health sciences, Inheritance (genetic algorithm), Biology, medicine.disease, Gene dosage, Genome, 03 medical and health sciences, 0302 clinical medicine, medicine, Autism, Copy-number variation, Haploinsufficiency, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well.Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency.We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

Published
2020
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23. Deep Learning for Quality Control of Subcortical Brain 3D Shape Models

Author

Dmitry, Petrov, Gutman, Boris A., Egor, Kuznetsov, van Erp, Theo G. M., Turner, Jessica A., Lianne, Schmaal, Dick, Veltman, Lei, Wang, Kathryn, Alpert, Dmitry, Isaev, Artemis, Zavaliangos-Petropulu, Ching, Christopher R. K., Vince, Calhoun, David, Glahn, Satterthwaite, Theodore D., Ole Andreas Andreassen, Stefan, Borgwardt, Fleur, Howells, Nynke, Groenewold, Aristotle, Voineskos, Joaquim, Radua, Potkin, Steven G., Benedicto, Crespo-Facorro, Diana, Tordesillas-Gutirrez, Shen, Li, Irina, Lebedeva, Gianfranco, Spalletta, Gary, Donohoe, Peter, Kochunov, Rosa, Pedro G. P., Anthony, James, Udo, Dannlowski, Baune, Bernhard T., Andr, Aleman, Gotlib, Ian H., Henrik, Walter, Martin, Walter, Soares, Jair C., Stefan, Ehrlich, Gur, Ruben C., Trung Doan, N., Ingrid, Agartz, Westlye, Lars T., Fabienne, Harrisberger, Anita Riecher-R ossler, Anne, Uhlmann, Stein, Dan J., Dickie, Erin W., Edith, Pomarol-Clotet, Paola, Fuentes-Claramonte, Erick Jorge Canales-Rodrguez, Raymond, Salvador, Huang, Alexander J., Roberto, Roiz-Santiaez, Shan, Cong, Alexander, Tomyshev, Piras, Fabrizio, Vecchio, Daniela, Nerisa, Banaj, Ciullo, Valentina, Elliot, Hong, Geraldo, Busatto, Zanetti, Marcus V., Serpa, Mauricio H., Simon, Cervenka, Sinead, Kelly, Dominik, Grotegerd, Sacchet, Matthew D., Veer, Ilya M., Meng, Li, Mon-Ju, Wu, Benson, Irungu, Thompson, Esther Walton and Paul M., and for the ENIGMA consortium

Subjects
deep learning, subcortical shape analysis, quality checking, deep learning, quality checking, subcortical shape analysis
Published
2018

24. Clinical Heterogeneity Arising from Categorical and Dimensional Features of the Neurobiology of Psychiatric Diagnoses

Author

John H. Krystal, Alan Anticevic, John D. Murray, David Glahn, Naomi Driesen, Genevieve Yang, and Xiao-Jing Wang

Abstract

Clinical heterogeneity presents important challenges to optimizing psychiatric diagnoses and treatments. Patients clustered within current diagnostic schema vary widely on many features of their illness, including their responses to treatments. As outlined by the American Psychiatric Association Diagnostic and Statistical Manual (DSM), psychiatric diagnoses have been refined since DSM was introduced in 1952. These diagnoses serve as the targets for current treatments and supported the emergence of psychiatric genomics. However, the Research Domain Criteria highlight DSM’s shortcomings, including its limited ability to encompass dimensional features linking patients across diagnoses. This chapter considers elements of the dimensional and categorical features of psychiatric diagnoses, with a particular focus on schizophrenia. It highlights ways that computational neuroscience approaches have shed light on both dimensional and categorical features of the biology of schizophrenia. It also considers opportunities and challenges associated with attempts to reduce clinical heterogeneity through categorical and dimensional approaches to clustering patients. Finally, discussion will consider ways that one might work with both approaches in parallel or sequentially, as well as diagnostic schema that might integrate both perspectives.

Published
2016
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25. 278. ENIGMA-Relatives – Brain Volumes in First-Degree Relatives of Schizophrenia and Bipolar Patients

Author

Sonja de Zwarte, Rachel Brouwer, Manon Hillegers, Wiepke Cahn, Hilleke Hulshoff Pol, René Kahn, Kathryn Alpert, Lei Wang, Elvira Bramon, Fergus Kane, Robin Murray, Tomas Hajek, Martin Alda, Gloria Roberts, Philip Mitchell, Peter Schofield, Janice Fullerton, Anja Richter, Oliver Gruber, Aurora Bonvino, Alessandro Bertolino, Annabella Di Giorgio, Xavier Caseras, Ali Saffet Gonul, Mehmet Cagdas Eker, Fatma Simsek, Scott Fears, Carrie Bearden, David Glahn, Theo van Erp, Paul Thompson, Ole Andreassen, Jessica Turner, Neeltje van Haren, and null group ENIGMA-Relatives Group

Subjects
medicine.medical_specialty, Schizophrenia, business.industry, Meta-analysis, medicine, Bipolar disorder, First-degree relatives, medicine.disease, business, Psychiatry, Biological Psychiatry
Published
2017
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26. 98. Cortical and Subcortical Differences between Alcohol Dependent Individuals and Controls: Meta Analysis Results from the Enigma-Addiction Working Group

Author

Patricia Conrod, Hugh Garavan, Scott Mackey, Jacob Lavoie, David Glahn, and null Enigma Addiction Working Group

Subjects
Group (mathematics), Addiction, media_common.quotation_subject, Alcohol, 030227 psychiatry, Developmental psychology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Meta-analysis, Psychology, 030217 neurology & neurosurgery, Biological Psychiatry, media_common, Clinical psychology
Published
2017
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27. Neural substrates of visual masking by object substitution in schizophrenia

Author

Junghee, Lee, Mark S, Cohen, Stephen A, Engel, David, Glahn, Keith H, Nuechterlein, Jonathan K, Wynn, and Michael F, Green

Subjects
Adult, Male, Brain Mapping, Brain, Neuropsychological Tests, behavioral disciplines and activities, Magnetic Resonance Imaging, Article, Interview, Psychological, Schizophrenia, Visual Perception, Humans, Female, Schizophrenic Psychology, Perceptual Masking, Photic Stimulation
Abstract

Despite a well-known behavioral finding of visual backward masking impairment in schizophrenia, its underlying neural mechanism remains obscure. This study examined neural correlates of a distinct type of visual backward masking, object substitution masking (OSM), in schizophrenia. Twenty schizophrenia patients and 26 healthy controls completed a 4-Dot OSM task and three functional localizer tasks for the lateral occipital (LO), human motion-sensitive (hMT+), and retinotopic areas in the scanner. In 4-dot masking, subjects detected a target that was followed by a mask consisting of 4 dots that surrounded a target. Stimulus-onset asynchrony (SOA) between target and mask was varied to examine the modulation of masking: (1) within three visual processing areas regions of interest (ROI) (i.e., ROI analysis) and (2) in brain regions outside the three visual processing areas (i.e., whole brain analysis). In the ROI analyses, LO and retinotopic areas showed increased peak amplitude when SOA become longer in both patients and controls. There was also an effect of ROI in that both groups showed higher activation in LO and hMT+ compared with the retinotopic areas. The whole brain analyses revealed a significantly activated area for longer SOAs vs. a short SOA in the occipital cortex in controls only, but the group contrast was not significant. Overall, this study did not find strong evidence for neural abnormalities of OSM in schizophrenia, suggesting that neural substrates of OSM in schizophrenia are not as compromised as those involved in the more common masking methods that rely on disruption of object formation.

Published
2013

28. Kinetics and activation parameters of electrochemical polymerization of 3-alkylthiophenes in the presence of various aromatic additives

Author

David Glahn, Yen Wei, Deryn Chu, Jing Tian, and Bin Wang

Subjects
Reaction rate, Indole test, chemistry.chemical_compound, Monomer, Terthiophene, Electrochemical polymerization, Polymerization, Chemistry, Kinetics, General Engineering, Physical and Theoretical Chemistry, First order, Photochemistry
Abstract

Electrochemical polymerization of 3-alkylthiophenes was performed in the presence of a small amount of 2,2'-bipyrrole, indole, 5-methoxyindole, 2,2'-bithiophene, or 2,2':5';2''-terthiophene. The presence of these additives effects a significant increase in the rate of polymerization. The applied potentials required for the polymerization to proceed can be reduced to values lower than the oxidation potentials of the monomers. The reaction rate was found to be first order in the monomer concentration and 0.5 order in the additive concentration

Published
1993
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29. ChemInform Abstract: Kinetics and Activation Parameters of Electrochemical Polymerization of 3-Alkylthiophenes in the Presence of Various Aromatic Additives

Author

Yen Wei, Deryn Chu, Jing Tian, Bin Wang, and David Glahn

Subjects
Indole test, Reaction rate, chemistry.chemical_compound, Monomer, Terthiophene, chemistry, Polymerization, Electrochemical polymerization, Kinetics, Polymer chemistry, General Medicine, First order
Abstract

Electrochemical polymerization of 3-alkylthiophenes was performed in the presence of a small amount of 2,2'-bipyrrole, indole, 5-methoxyindole, 2,2'-bithiophene, or 2,2':5';2''-terthiophene. The presence of these additives effects a significant increase in the rate of polymerization. The applied potentials required for the polymerization to proceed can be reduced to values lower than the oxidation potentials of the monomers. The reaction rate was found to be first order in the monomer concentration and 0.5 order in the additive concentration

Published
2010
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30. Voltage-clamp study of the activation currents and fast block to polyspermy in the egg of Xenopus laevis

Author

David, Glahn and Richard, Nuccitelli

Subjects
Male, Sperm-Ovum Interactions, Xenopus laevis, Patch-Clamp Techniques, Fertilization, Animals, Female, Spermatozoa, Membrane Potentials, Ovum
Abstract

Voltage-clamped mature, jelly-intact Xenopus eggs were used to carefully examine the ionic currents crossing the plasma membrane before, during, and after fertilization. The bulk of the fertilization current was transient, of large amplitude, and reversed at the predicted Cl- reversal potential. However, the large amplitude fertilization current was preceded by a small, step-like increase in holding current. This small increase in holding current is referred to in this paper as Ion to acknowledge its qualitative similarity to the Ion current previously described in the sea urchin. It was observed in both fertilized and artificially activated eggs, and was found to be unaffected by 10 mm tetra-ethyl ammonium (TEA), a concentration found to block K+ currents in Rana pipiens. Current-voltage relationships are presented for the large fertilization potential, and show that the fertilization currents have a marked outward rectification and are voltage sensitive. These properties are in contrast to the total lack of rectification and slight voltage sensitivity seen before or after the fertilization currents. The time required for sperm to fertilize the egg was found to be voltage dependent with a relatively more depolarized voltage requiring a longer time for fertilization to occur. The percentage of eggs blocked with varying potential levels was determined and this information was fitted to a modified Boltzmann equation having a midpoint of -9 mV.

Published
2003

32. Memory and verbal learning functions in twins with bipolar-I disorder, and the role of information-processing speed.

Author

TUULA KIESEPPÄ, ANNAMARI TUULIO-HENRIKSSON, JARI HAUKKA, THEO VAN ERP, DAVID GLAHN, TYRONE D. CANNON, TIMO PARTONEN, JAAKKO KAPRIO, and JOUKO LÖNNQVIST

Subjects
BIPOLAR disorder, VERBAL learning, HUMAN information processing, NEUROPSYCHOLOGICAL tests, SHORT-term memory, FACE perception
Abstract

Background. Euthymic bipolar-I disorder (BP I) patients and their siblings have shown impairments in verbal learning and memory functions compared with controls, suggesting that these impairments may be genetic in origin. Reduced information-processing speed has been associated with impaired memory in the elderly, and recently in schizophrenia. The authors compared verbal learning and memory functioning in twins with BP I and co-twins to control twins, and examined whether the observed deficits are related to information-processing speed.Method. Finnish Medical and Population Registers and Twin Cohorts were used to identify the BP I and control twins. Neuropsychological tests assessing verbal learning and memory, working memory, facial recognition, visual memory, and information-processing speed were administered to 26 BP I twins, 19 non-bipolar co-twins, and 114 controls. Group differences were analyzed by generalized estimation equation modeling.Results. BP I patients, but not co-twins, showed impairments in all memory tests compared with controls. Female co-twins showed impairment in verbal learning and memory. Information-processing speed had a significant effect on encoding and learning efficiency.Conclusions. This study showed for the first time that information-processing speed is related to memory functioning and verbal learning in BP I in a population-based, representative and euthymic sample. Furthermore, the data support the view that defects in verbal memory may be related to the genetic factors predisposing to BP I in females. [ABSTRACT FROM AUTHOR]

Published
2005
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