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2. Valuing Policies Using the Valuation Conventions of the Regulations.

Author

Brody, Lawrence

Subjects
GIFT taxes, FISCAL policy, TAX returns, VALUATION
Abstract

This article discusses Treasury Regulation Section 25.2512-6, which provides valuation conventions for federal gift tax purposes for policies transferred during the insured's life. The article analyzes the Regulation Section by the broad policy types it attempts to value, analyzes the conventions for those broad policy types, and discusses the issues the Regulation Section continues to raise for practitioners who are filing federal gift tax returns for clients who gift policies to a third party during life. [ABSTRACT FROM AUTHOR]

Published
2024

3. Exome sequencing identifies genetic variants in anophthalmia and microphthalmia

Author

Li, Jingjing, Yang, Wei, Wang, Yuejun Jessie, Ma, Chen, Curry, Cynthia J, McGoldrick, Daniel, Nickerson, Deborah A, Chong, Jessica X, Blue, Elizabeth E, Mullikin, James C, Reefhuis, Jennita, Nembhard, Wendy N, Romitti, Paul A, Werler, Martha M, Browne, Marilyn L, Olshan, Andrew F, Finnell, Richard H, Feldkamp, Marcia L, Pangilinan, Faith, Almli, Lynn M, Bamshad, Mike J, Brody, Lawrence C, Jenkins, Mary M, Shaw, Gary M, Program, NISC Comparative Sequencing, Genomics, University of Washington Center for Mendelian, and Study, Birth Defects Prevention

Subjects
Eye Disease and Disorders of Vision, Genetics, Prevention, Pediatric, Human Genome, Clinical Research, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Anophthalmos, Exome, Humans, Infant, Microphthalmos, Mutation, Missense, Exome Sequencing, congenital abnormalities, genetic epidemiology, newborn eye abnormalities, NISC Comparative Sequencing Program, University of Washington Center for Mendelian Genomics, National Birth Defects Prevention Study, Clinical Sciences
Abstract

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

Published
2022

4. Consumers’ Use of Web-Based Information and Their Decisions About Multiplex Genetic Susceptibility Testing

Author

Kaphingst, Kimberly A, McBride, Colleen M, Wade, Christopher, Alford, Sharon Hensley, Brody, Lawrence C, and Baxevanis, Andreas D

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundFew data exist to inform concerns raised by online direct-to-consumer marketing of genetic susceptibility tests, such as those offered by commercial entities like 23andme, Navigenics, and DNA Direct. The Multiplex Initiative, a population-based study of healthy adults, provides the first opportunity to evaluate how use of a Web-based decision tool that conveyed information about a genetic susceptibility test influenced individuals’ test decisions. ObjectiveTo inform the ongoing debate over whether individuals offered genetic susceptibility testing without the involvement of a health care provider (eg, through direct-to-consumer testing) can make informed decisions about testing when guided by online decision aids. MethodsParticipants were 526 members of a large health maintenance organization aged 25 to 40 years old who visited a study website. Multivariate logistic regression models were tested to examine the association of website usage with downstream test decisions. ResultsParticipants viewed an average of 2.9 of the 4 pages introducing the multiplex test, 2.2 of the 8 pages describing the health conditions, and 3.2 of the 15 pages describing the genes. For each page viewed, participants were more likely to describe their decision-making as easy (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07) and to decide to be tested (OR 1.08, 95% CI 1.05-1.11). ConclusionsHealthy adults in this study perceived Web-based genomic information presented using evidence-based communications approaches to be helpful in supporting both decisions to test and not to test. Continued research is needed to ensure that these results generalize to target groups with lower literacy and less Internet savvy.

Published
2010
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5. A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C.

Published
2024
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6. Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits

Author

Nicoletti, Paola, Zafer, Samreen, Matok, Lital, Irron, Inbar, Patrick, Meidva, Haklai, Rotem, Evangelista, John Erol, Marino, Giacomo B., Ma’ayan, Avi, Sewda, Anshuman, Holmes, Greg, Britton, Sierra R., Lee, Won Jun, Wu, Meng, Ru, Ying, Arnaud, Eric, Botto, Lorenzo, Brody, Lawrence C., Byren, Jo C., Caggana, Michele, Carmichael, Suzan L., Cilliers, Deirdre, Conway, Kristin, Crawford, Karen, Cuellar, Araceli, Di Rocco, Federico, Engel, Michael, Fearon, Jeffrey, Feldkamp, Marcia L., Finnell, Richard, Fisher, Sarah, Freudlsperger, Christian, Garcia-Fructuoso, Gemma, Hagge, Rhinda, Heuzé, Yann, Harshbarger, Raymond J., Hobbs, Charlotte, Howley, Meredith, Jenkins, Mary M., Johnson, David, Justice, Cristina M., Kane, Alex, Kay, Denise, Gosain, Arun Kumar, Langlois, Peter, Legal-Mallet, Laurence, Lin, Angela E., Mills, James L., Morton, Jenny E.V., Noons, Peter, Olshan, Andrew, Persing, John, Phipps, Julie M., Redett, Richard, Reefhuis, Jennita, Rizk, Elias, Samson, Thomas D., Shaw, Gary M., Sicko, Robert, Smith, Nataliya, Staffenberg, David, Stoler, Joan, Sweeney, Elizabeth, Taub, Peter J., Timberlake, Andrew T., Topczewska, Jolanta, Wall, Steven A., Wilson, Alexander F., Wilson, Louise C., Boyadjiev, Simeon A., Wilkie, Andrew O.M., Richtsmeier, Joan T., Jabs, Ethylin Wang, Romitti, Paul A., Karasik, David, Birnbaum, Ramon Y., and Peter, Inga

Published
2024
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7. The Newfoundland and Labrador mosaic founder population descends from an Irish and British diaspora from 300 years ago

Author

Gilbert, Edmund, Zurel, Heather, MacMillan, Margaret E., Demiriz, Sedat, Mirhendi, Sadra, Merrigan, Michael, O’Reilly, Seamus, Molloy, Anne M., Brody, Lawrence C., Bodmer, Walter, Leach, Richard A., Scott, Roderick E. M., Mugford, Gerald, Randhawa, Ranjit, Stephens, J. Claiborne, Symington, Alison L., Cavalleri, Gianpiero L., and Phillips, Michael S.

Published
2023
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8. Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations

Author

Stevelink, Remi, Luykx, Jurjen J, Lin, Bochao D, Leu, Costin, Lal, Dennis, Smith, Alexander W, Schijven, Dick, Carpay, Johannes A, Rademaker, Koen, Baldez, Roiza A Rodrigues, Devinsky, Orrin, Braun, Kees PJ, Jansen, Floor E, Smit, Dirk JA, Koeleman, Bobby PC, Abou‐Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J, Bast, Thomas, Baum, Larry, Becker, Albert J, Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F, Boysen, Katja E, Bradfield, Jonathan P, Brody, Lawrence C, Buono, Russell J, Campbell, Ellen, Cascino, Gregory D, Catarino, Claudia B, Cavalleri, Gianpiero L, Cherny, Stacey S, Chinthapalli, Krishna, Coffey, Alison J, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J, de Haan, Gerrit‐Jan, De Jonghe, Peter, de Kovel, Carolien GF, Delanty, Norman, Depondt, Chantal, Dlugos, Dennis J, Doherty, Colin P, Elger, Christian E, Eriksson, Johan G, Ferraro, Thomas N, Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A, Freytag, Saskia, Gaus, Verena, Geller, Eric B, Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B, Gui, Hongsheng, Guo, Youling, Haas, Kevin F, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas‐Khoda, Jennifer, Johnson, Michael R, Kälviäinen, Reetta, Kantanen, Anne‐Mari, Kasperavičiūte, Dalia, Trenite, Dorothee Kasteleijn‐Nolst, Kirsch, Heidi E, Knowlton, Robert C, Krause, Roland, Krenn, Martin, Kunz, Wolfram S, Kuzniecky, Ruben, Kwan, Patrick, Lau, Yu‐Lung, Lehesjoki, Anna‐Elina, Lerche, Holger, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D, Lopes‐Cendes, Iscia, Lowenstein, Daniel H, Malovini, Alberto, Marson, Anthony G, Mayer, Thomas, McCormack, Mark, and Mills, James L

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Brain Disorders, Clinical Research, Human Genome, Neurodegenerative, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Algorithms, Beta Rhythm, Cohort Studies, Databases, Factual, Electroencephalography, Epilepsy, Generalized, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mendelian Randomization Analysis, Risk Assessment, Theta Rhythm, beta power, EEG, generalized epilepsy, GGE, oscillations, PRS, International League Against Epilepsy Consortium on Complex Epilepsies, Epi25 Collaborative, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

Published
2021

9. Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome

Author

Blue, Elizabeth E., White, Janson J., Dush, Michael K., Gordon, William W., Wyatt, Brent H., White, Peter, Marvin, Colby T., Helle, Emmi, Ojala, Tiina, Priest, James R., Jenkins, Mary M., Almli, Lynn M., Reefhuis, Jennita, Pangilinan, Faith, Brody, Lawrence C., McBride, Kim L., Garg, Vidu, Shaw, Gary M., Romitti, Paul A., Nembhard, Wendy N., Browne, Marilyn L., Werler, Martha M., Kay, Denise M., Mital, Seema, Chong, Jessica X., Nascone-Yoder, Nanette M., and Bamshad, Michael J.

Published
2023
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10. A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis

Author

Justice, Cristina M, Cuellar, Araceli, Bala, Krithi, Sabourin, Jeremy A, Cunningham, Michael L, Crawford, Karen, Phipps, Julie M, Zhou, Yan, Cilliers, Deirdre, Byren, Jo C, Johnson, David, Wall, Steven A, Morton, Jenny EV, Noons, Peter, Sweeney, Elizabeth, Weber, Astrid, Rees, Katie EM, Wilson, Louise C, Simeonov, Emil, Kaneva, Radka, Yaneva, Nadezhda, Georgiev, Kiril, Bussarsky, Assen, Senders, Craig, Zwienenberg, Marike, Boggan, James, Roscioli, Tony, Tamburrini, Gianpiero, Barba, Marta, Conway, Kristin, Sheffield, Val C, Brody, Lawrence, Mills, James L, Kay, Denise, Sicko, Robert J, Langlois, Peter H, Tittle, Rachel K, Botto, Lorenzo D, Jenkins, Mary M, LaSalle, Janine M, Lattanzi, Wanda, Wilkie, Andrew OM, Wilson, Alexander F, Romitti, Paul A, and Boyadjiev, Simeon A

Subjects
Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

Published
2020

11. Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy

Author

Stevelink, Remi, Pangilinan, Faith, Jansen, Floor E, Braun, Kees PJ, Epilepsies, International League Against Epilepsy Consortium on Complex, Molloy, Anne M, Brody, Lawrence C, and Koeleman, Bobby PC

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurodegenerative, Epilepsy, Brain Disorders, Neurosciences, Prevention, Human Genome, Nutrition, Aetiology, 2.1 Biological and endogenous factors, Pyridoxine, GGE, GWAS, SNP, Pharmacogenetics, International League Against Epilepsy Consortium on Complex Epilepsies, Biochemistry and Cell Biology, Clinical sciences
Abstract

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.

Published
2019

12. Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults

Author

Brosnan, John T, Mills, James L, Ueland, Per M, Shane, Barry, Fan, Ruzong, Chiu, Chi-Yang, Pangilinan, Faith, Brody, Lawrence C, Brosnan, Margaret E, Pongnopparat, Theerawat, and Molloy, Anne M

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Clinical Research, Genetics, Nutrition, Prevention, Complementary and Integrative Health, Good Health and Well Being, Adolescent, Adult, Choline, Cross-Sectional Studies, Female, Formates, Genotyping Techniques, Humans, Incidence, Life Style, Male, Methionine, Methylenetetrahydrofolate Reductase (NADPH2), Polymorphism, Single Nucleotide, Serine, Tryptophan, Young Adult, folate, vitamin B-12, methylenetetrahydrofolate reductase, one-carbon metabolism, Trinity Student Study, Engineering, Medical and Health Sciences, Nutrition & Dietetics, Clinical sciences, Nutrition and dietetics
Abstract

BackgroundFormate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants.ObjectiveThis study aimed to define formate concentrations and their determinants in a healthy young population.DesignSerum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors.ResultsSerum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12.ConclusionsFormate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

Published
2018

14. The genetic landscape of polycystic kidney disease in Ireland

Author

Benson, Katherine A., Murray, Susan L., Senum, Sarah R., Elhassan, Elhussein, Conlon, Eoin T., Kennedy, Claire, Conlon, Shane, Gilbert, Edmund, Connaughton, Dervla, O’Hara, Paul, Khamis, Sarah, Cormican, Sarah, Brody, Lawrence C., Molloy, Anne M., Lynch, Sally Ann, Casserly, Liam, Griffin, Matthew D., Carton, Robert, Yachnin, Kevin, Harris, Peter C., Cavalleri, Gianpiero L., and Conlon, Peter

Published
2021
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15. Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

Author

Blue, Elizabeth E., Moore, Kristin J., North, Kari E., Desrosiers, Tania A., Carmichael, Suzan L., White, Janson J., Chong, Jessica X., Bamshad, Michael J., Jenkins, Mary M., Almli, Lynn M., Brody, Lawrence C., Freedman, Sharon F., Reefhuis, Jennita, Romitti, Paul A., Shaw, Gary M., Werler, Martha, Kay, Denise M., Browne, Marilyn L., Feldkamp, Marcia L., and Finnell, Richard H.

Abstract

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997–2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. Results: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). Conclusion: Variation in the genes identified in this population‐based study may help to further explain the genetics of PCG. [ABSTRACT FROM AUTHOR]

Published
2024
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18. A genetic association study of circulating coagulation Factor VIII and von Willebrand Factor levels

Author

de Vries, Paul S., primary, Reventun, Paula, additional, Brown, Michael R, additional, Heath, Adam S, additional, Huffman, Jennifer E., additional, Le, Ngoc-Quynh, additional, Bebo, Allison, additional, Brody, Jennifer A, additional, Temprano-Sagrera, Gerard, additional, Raffield, Laura M, additional, Ozel, Ayse Bilge, additional, Thibord, Florian, additional, Jain, Deepti, additional, Lewis, Joshua P, additional, Rodriguez, Benjamin A.T., additional, Pankratz, Nathan, additional, Taylor, Kent D, additional, Polasek, Ozren, additional, Chen, Ming-Huei, additional, Yanek, Lisa R, additional, Carrasquilla, German, additional, Marioni, Riccardo, additional, Kleber, Marcus E, additional, Trégouët, David-Alexandre, additional, Yao, Jie, additional, Li-Gao, Ruifang, additional, Joshi, Peter K, additional, Trompet, Stella, additional, Martinez-Perez, Angel, additional, Ghanbari, Mohsen, additional, Howard, Tom E., additional, Reiner, Alex P, additional, Arvanitis, Marios, additional, Ryan, Kathleen A, additional, Bartz, Traci M, additional, Rudan, Igor, additional, Faraday, Nauder, additional, Linneberg, Allan, additional, Ekunwe, Lynette, additional, Davies, Gail, additional, Delgado, Graciela E, additional, Suchon, Pierre, additional, Guo, Xiuqing, additional, Rosendaal, Frits R., additional, Klaric, Lucija, additional, Noordam, Raymond, additional, van Rooij, Frank J.A., additional, Curran, Joanne, additional, Wheeler, Marsha Maria, additional, Osburn, William O, additional, O'Connell, Jeffrey R, additional, Boerwinkle, Eric, additional, Beswick, Andrew, additional, Psaty, Bruce M., additional, Kolcic, Ivana, additional, Souto, Juan Carlos Carlos, additional, Becker, Lewis, additional, Hansen, Torben, additional, Doyle, Margaret F., additional, Harris, Sarah, additional, Moissl, Angela Patricia, additional, Deleuze, Jean-François, additional, Rich, Stephen S, additional, van Hylckama Vlieg, Astrid, additional, Campbell, Harry, additional, Stott, David, additional, Soria, Jose Manuel, additional, de Maat, Moniek P.M., additional, Almasy, Laura, additional, Brody, Lawrence C., additional, Auer, Paul, additional, Mitchell, Braxton D, additional, Ben-Shlomo, Yoav, additional, Fornage, Myriam, additional, Hayward, Caroline, additional, Mathias, Rasika, additional, Kilpeläinen, Tuomas O, additional, Lange, Leslie, additional, Cox, Simon R, additional, Maerz, Winfried, additional, Morange, Pierre-Emmanuel, additional, Rotter, Jerome I, additional, Mook-Kanamori, Dennis O, additional, Wilson, James, additional, van der Harst, Pim, additional, Jukema, Johan Wouter W., additional, Ikram, Mohammad Arfan, additional, Blangero, John, additional, Kooperberg, Charles, additional, Desch, Karl, additional, Johnson, Andrew D., additional, Sabater-Lleal, Maria, additional, Lowenstein, Charles, additional, Smith, Nicholas L., additional, and Morrison, Alanna, additional

Published
2024
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20. Strategic vision for improving human health at The Forefront of Genomics

Author

Green, Eric D., Gunter, Chris, Biesecker, Leslie G., Di Francesco, Valentina, Easter, Carla L., Feingold, Elise A., Felsenfeld, Adam L., Kaufman, David J., Ostrander, Elaine A., Pavan, William J., Phillippy, Adam M., Wise, Anastasia L., Dayal, Jyoti Gupta, Kish, Britny J., Mandich, Allison, Wellington, Christopher R., Wetterstrand, Kris A., Bates, Sarah A., Leja, Darryl, Vasquez, Susan, Gahl, William A., Graham, Bettie J., Kastner, Daniel L., Liu, Paul, Rodriguez, Laura Lyman, Solomon, Benjamin D., Bonham, Vence L., Brody, Lawrence C., Hutter, Carolyn M., and Manolio, Teri A.

Published
2020
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21. Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects

Author

Pangilinan, Faith, Molloy, Anne M, Mills, James L, Troendle, James F, Parle-McDermott, Anne, Kay, Denise M, Browne, Marilyn L, McGrath, Emily C, Abaan, Hatice Ozel, Sutton, Marie, Kirke, Peadar N, Caggana, Michele, Shane, Barry, Scott, John M, and Brody, Lawrence C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Pediatric, Congenital Structural Anomalies, Clinical Research, Neurosciences, Spina Bifida, Rare Diseases, Prevention, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase, Adenosine Deaminase, Black or African American, Aldehyde Dehydrogenase 1 Family, Asian People, DNA-Binding Proteins, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Neural Tube Defects, New York, Nuclear Proteins, Polymorphism, Single Nucleotide, Retinal Dehydrogenase, Transcription Factors, United Kingdom, White People, Neural tube defects, Spina bifida, Folate, Folic acid, One-carbon metabolism, Replication, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundNeural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population.MethodsReplication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS.ResultsOf the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans.ConclusionsWe report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis.

Published
2014

25. Evaluation of common genetic variants in 82candidate genes as risk factors for neural tubedefects

Author

Pangilinan, Faith, Molloy, Anne M, Mills, James L, Troendle, James F, Parle-McDermott, Anne, Signore, Caroline, O’Leary, Valerie B, Chines, Peter, Seay, Jessica M, Geiler-Samerotte, Kerry, Mitchell, Adam, VanderMeer, Julia E, Krebs, Kristine M, Sanchez, Angelica, Cornman-Homonoff, Joshua, Stone, Nicole, Conley, Mary, Kirke, Peadar N, Shane, Barry, Scott, John M, and Brody, Lawrence C

Abstract

AbstractBackgroundNeural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.MethodsA tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.ResultsNearly 70 SNPs in 30 genes were found to be associated with NTDs at the p

Published
2012

29. Whole-genome sequencing of 175 Mongolians uncovers population-specific genetic architecture and gene flow throughout North and East Asia

Author

Bai, Haihua, Guo, Xiaosen, Narisu, Narisu, Lan, Tianming, Wu, Qizhu, Xing, Yanping, Zhang, Yong, Bond, Stephen R., Pei, Zhili, Zhang, Yanru, Zhang, Dandan, Jirimutu, Jirimutu, Zhang, Dong, Yang, Xukui, Morigenbatu, Morigenbatu, Zhang, Li, Ding, Bingyi, Guan, Baozhu, Cao, Junwei, Lu, Haorong, Liu, Yiyi, Li, Wangsheng, Dang, Ningxin, Jiang, Mingyang, Wang, Shenyuan, Xu, Huixin, Wang, Dingzhu, Liu, Chunxia, Luo, Xin, Gao, Ying, Li, Xueqiong, Wu, Zongze, Yang, Liqing, Meng, Fanhua, Ning, Xiaolian, Hashenqimuge, Hashenqimuge, Wu, Kaifeng, Wang, Bo, Suyalatu, Suyalatu, Liu, Yingchun, Ye, Chen, Wu, Huiguang, Leppälä, Kalle, Li, Lu, Fang, Lin, Chen, Yujie, Xu, Wenhao, Li, Tao, Liu, Xin, Xu, Xun, Gignoux, Christopher R., Yang, Huanming, Brody, Lawrence C., Wang, Jun, Kristiansen, Karsten, Burenbatu, Burenbatu, Zhou, Huanmin, and Yin, Ye

Published
2018
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36. Getting It Right: How Public Engagement Might (and Might Not) Help Us Determine What Is Equitable in Genomics and Precision Medicine.

Author

Hull, Sara Chandros, Brody, Lawrence C., and Sterling, Rene

Subjects
*PATIENT participation, *SERIAL publications, *PUBLIC health, *INDIVIDUALIZED medicine, *GENOMICS, *BIOETHICS
Abstract

The article focuses on the role of public engagement (PE) in achieving equity in genomics and precision medicine. Topics covered include advances in genetic and genomic technologies, historical legacies of inequities in genomics, and the need for inclusive and informed PE approaches. The article emphasizes the importance of considering equity and justice in genomics research and policy-making, and highlights the challenges and potential benefits of PE in addressing these issues.

Published
2023
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39. The role of common genetic variation in presumed monogenic epilepsies

Author

Campbell, Ciarán, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan, Moreau, Claudia, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis, Cavalleri, Gianpiero L., collaborative, Epi K., Consortium, Genomics England Research, Collaborative, The Epi, May, Patrick, Krause, Roland, Fonds National de la Recherche - FnR [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Epilepsy, Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], Genetic diagnostics, DEEs, Genetics & genetic processes [F10] [Life sciences], PRS, Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

Summary: Background The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings 0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. Interpretation: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders.

Published
2022

40. The role of common genetic variation in presumed monogenic epilepsies

Author

Campbell, Ciarán, primary, Leu, Costin, additional, Feng, Yen-Chen Anne, additional, Wolking, Stefan, additional, Moreau, Claudia, additional, Ellis, Colin, additional, Ganesan, Shiva, additional, Martins, Helena, additional, Oliver, Karen, additional, Boothman, Isabelle, additional, Benson, Katherine, additional, Molloy, Anne, additional, Brody, Lawrence, additional, Michaud, Jacques L., additional, Hamdan, Fadi F., additional, Minassian, Berge A., additional, Lerche, Holger, additional, Scheffer, Ingrid E., additional, Sisodiya, Sanjay, additional, Girard, Simon, additional, Cosette, Patrick, additional, Delanty, Norman, additional, Lal, Dennis, additional, and Cavalleri, Gianpiero L., additional

Published
2022
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41. Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Author

Desch, Karl C., Ozel, Ayse B., Siemieniak, David, Kalish, Yossi, Shavit, Jordan A., Thornburg, Courtney D., Sharathkumar, Anjali A., McHugh, Caitlin P., Laurie, Cathy C., Crenshaw, Andrew, Mirel, Daniel B., Kim, Yoonhee, Cropp, Cheryl D., Molloy, Anne M., Kirke, Peadar N., Bailey-Wilson, Joan E., Wilson, Alexander F., Mills, James L., Scott, John M., Brody, Lawrence C., Li, Jun Z., and Ginsburg, David

Published
2013

42. The role of common genetic variation in presumed monogenic epilepsies

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Campbell, Ciarán, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan, Moreau, Claudia, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis, Cavalleri, Gianpiero L., collaborative, Epi K., Consortium, Genomics England Research, Collaborative, The Epi, May, Patrick, Krause, Roland, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Campbell, Ciarán, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan, Moreau, Claudia, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis, Cavalleri, Gianpiero L., collaborative, Epi K., Consortium, Genomics England Research, Collaborative, The Epi, May, Patrick, and Krause, Roland

Abstract

Summary: Background The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings 0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. Interpretation: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders.

Published
2022

44. Exome‐wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants.

Author

Sok, Pagna, Sabo, Aniko, Almli, Lynn M., Jenkins, Mary M., Nembhard, Wendy N., Agopian, A. J., Bamshad, Michael J., Blue, Elizabeth E., Brody, Lawrence C., Brown, Austin L., Browne, Marilyn L., Canfield, Mark A., Carmichael, Suzan L., Chong, Jessica X., Dugan‐Perez, Shannon, Feldkamp, Marcia L., Finnell, Richard H., Gibbs, Richard A., Kay, Denise M., and Lei, Yunping

Abstract

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein‐altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child–parent trios, one child–mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio‐based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case–control analysis using a sequence kernel‐based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Newfoundland and Labrador: A mosaic founder population of an Irish and British diaspora from 300 years ago

Author

Gilbert, Edmund, primary, Zurel, Heather, additional, MacMillan, Margaret E., additional, Demiriz, Sedat, additional, Mirhendi, Sadra, additional, Merrigan, Michael, additional, O’Reilly, Seamus, additional, Molloy, Anne M., additional, Brody, Lawrence C., additional, Bodmer, Walter, additional, Leach, Richard A., additional, Scott, Roderick E. M., additional, Mugford, Gerald, additional, Randhawa, Ranjit, additional, Stephens, J. Claiborne, additional, Symington, Alison L., additional, Cavalleri, Gianpiero L., additional, and Phillips, Michael S., additional

Published
2022
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48. Biomarkers of vitamin B-12 status in NHANES: a roundtable summary

Author

Yetley, Elizabeth A, Pfeiffer, Christine M, Phinney, Karen W, Bailey, Regan L, Blackmore, Sheena, Bock, Jay L, Brody, Lawrence C, Carmel, Ralph, Curtin, L Randy, Durazo-Arvizu, Ramón A, Eckfeldt, John H, Green, Ralph, Gregory, Jesse F, III, Hoofnagle, Andrew N, Jacobsen, Donald W, Jacques, Paul F, Lacher, David A, Molloy, Anne M, Massaro, Joseph, Mills, James L, Nexo, Ebba, Rader, Jeanne I, Selhub, Jacob, Sempos, Christopher, Shane, Barry, Stabler, Sally, Stover, Patrick, Tamura, Tsunenobu, Tedstone, Alison, Thorpe, Susan J, Coates, Paul M, Johnson, Clifford L, and Picciano, Mary Frances

Published
2011
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49. Biomarkers of folate status in NHANES: a roundtable summary

Author

Yetley, Elizabeth A, Pfeiffer, Christine M, Phinney, Karen W, Fazili, Zia, Lacher, David A, Bailey, Regan L, Blackmore, Sheena, Bock, Jay L, Brody, Lawrence C, Carmel, Ralph, Curtin, L Randy, Durazo-Arvizu, Ramón A, Eckfeldt, John H, Green, Ralph, Gregory, Jesse F, III, Hoofnagle, Andrew N, Jacobsen, Donald W, Jacques, Paul F, Molloy, Anne M, Massaro, Joseph, Mills, James L, Nexo, Ebba, Rader, Jeanne I, Selhub, Jacob, Sempos, Christopher, Shane, Barry, Stabler, Sally, Stover, Patrick, Tamura, Tsunenobu, Tedstone, Alison, Thorpe, Susan J, Coates, Paul M, Johnson, Clifford L, and Picciano, Mary Frances

Published
2011
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50. Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene

Author

Pangilinan, Faith, primary, Watkins, David, additional, Bernard, David, additional, Chen, Yue, additional, Dong, Ningzheng, additional, Wu, Qingyu, additional, Ozel‐Abaan, Hatice, additional, Kaur, Manjit, additional, Caggana, Michele, additional, Morrissey, Mark, additional, Browne, Marilyn L., additional, Mills, James L., additional, Van Ryzin, Carol, additional, Shchelochkov, Oleg, additional, Sloan, Jennifer, additional, Venditti, Charles P., additional, Sarafoglou, Kyriakie, additional, Rosenblatt, David S., additional, Kay, Denise M., additional, and Brody, Lawrence C., additional

Published
2022
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