Search

Your search keyword '"Heiman, Gary A"' showing total 185 results
Start Over Author "Heiman, Gary A" Language english
185 results on '"Heiman, Gary A"'

1. Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD

Author

Wang, Sheng, Wang, Belinda, Drury, Vanessa, Drake, Sam, Sun, Nawei, Alkhairo, Hasan, Arbelaez, Juan, Duhn, Clif, Bal, Vanessa H., Langley, Kate, Martin, Joanna, Hoekstra, Pieter J., Dietrich, Andrea, Xing, Jinchuan, Heiman, Gary A., Tischfield, Jay A., Fernandez, Thomas V., Owen, Michael J., O’Donovan, Michael C., Thapar, Anita, State, Matthew W., and Willsey, A. Jeremy

Published
2023
Full Text
View/download PDF

2. Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Author

Barr, Cathy L., Batterson, James R., Berlin, Cheston, Budman, Cathy L., Coppola, Giovanni, Cox, Nancy J., Darrow, Sabrina, Dion, Yves, Freimer, Nelson B., Grados, Marco A., Greenberg, Erica, Hirschtritt, Matthew E., Huang, Alden Y., Illmann, Cornelia, King, Robert A., Kurlan, Roger, Leckman, James F., Lyon, Gholson J., Malaty, Irene A., McMahon, William M., Neale, Benjamin M., Okun, Michael S., Osiecki, Lisa, Robertson, Mary M., Rouleau, Guy A., Sandor, Paul, Singer, Harvey S., Smit, Jan H., Sul, Jae Hoon, Androutsos, Christos, Basha, Entela, Farkas, Luca, Fichna, Jakub, Janik, Piotr, Kapisyzi, Mira, Karagiannidis, Iordanis, Koumoula, Anastasia, Nagy, Peter, Puchala, Joanna, Szejko, Natalia, Szymanska, Urszula, Tsironi, Vaia, Apter, Alan, Ball, Juliane, Bodmer, Benjamin, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Garcia-Delgar, Blanca, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Drineas, Petros, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nawaz, Muhammad S., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J.W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Fernandez, Thomas V., Gilbert, Donald L., Hong, Hyun Ju, Ibanez-Gomez, Laura, Kim, Eun-Joo, Kim, Young Key, Kim, Young-Shin, Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett L., Maras, Athanasios, Murphy, Tara L., Shin, Eun-Young, Song, Dong-Ho, Song, Jungeun, State, Matthew W., Visscher, Frank, Wang, Sheng, Zinner, Samuel H., Tsetsos, Fotis, Topaloudi, Apostolia, Jain, Pritesh, Yang, Zhiyu, Yu, Dongmei, Kolovos, Petros, Tumer, Zeynep, Rizzo, Renata, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Müller-Vahl, Kirsten R., Cath, Danielle C., Boomsma, Dorret I., Wolanczyk, Tomasz, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Padmanabhuni, Shanmukha S., Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Yannaki, Evangelia, Stamatoyannopoulos, John A., Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Mir, Pablo, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Roessner, Veit, Walitza, Susanne, Schrag, Anette, Martino, Davide, Tischfield, Jay A., Heiman, Gary A., Willsey, A. Jeremy, Dietrich, Andrea, Davis, Lea K., Crowley, James J., Mathews, Carol A., Scharf, Jeremiah M., Georgitsi, Marianthi, Hoekstra, Pieter J., and Paschou, Peristera

Published
2024
Full Text
View/download PDF

3. Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

Author

Cao, Xiaolong, Zhang, Yeting, Abdulkadir, Mohamed, Deng, Li, Fernandez, Thomas V., Garcia-Delgar, Blanca, Hagstrøm, Julie, Hoekstra, Pieter J., King, Robert A., Koesterich, Justin, Kuperman, Samuel, Morer, Astrid, Nasello, Cara, Plessen, Kerstin J., Thackray, Joshua K., Zhou, Lisheng, Dietrich, Andrea, Tischfield, Jay A., Heiman, Gary A., and Xing, Jinchuan

Published
2021
Full Text
View/download PDF

4. Investigation of gene–environment interactions in relation to tic severity

Author

Abdulkadir, Mohamed, Yu, Dongmei, Osiecki, Lisa, King, Robert A., Fernandez, Thomas V., Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Garcia-Delgar, Blanca, Gilbert, Donald L., Grice, Dorothy E., Hagstrøm, Julie, Hedderly, Tammy, Heyman, Isobel, Hong, Hyun Ju, Huyser, Chaim, Ibanez-Gomez, Laura, Kim, Young Key, Kim, Young-Shin, Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett, Madruga-Garrido, Marcos, Maras, Athanasios, Mir, Pablo, Morer, Astrid, Münchau, Alexander, Plessen, Kerstin J., Roessner, Veit, Shin, Eun-Young, Song, Dong-Ho, Song, Jungeun, Visscher, Frank, Zinner, Samuel H., Mathews, Carol A., Scharf, Jeremiah M., Tischfield, Jay A., Heiman, Gary A., Dietrich, Andrea, and Hoekstra, Pieter J.

Published
2021
Full Text
View/download PDF

5. Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, striatal dopamine in mice.

Author

Nasello, Cara, Poppi, Lauren A., Junbing Wu, Kowalski, Tess F., Thackray, Joshua K., Wang, Riley, Persaud, Angelina, Mahboob, Mariam, Lin, Sherry, Spaseska, Rodna, Johnson, C. K., Gordon, Derek, Tissir, Fadel, Heiman, Gary A., Tischfield, Jay A., Bocarsly, Miriam, and Tischfield, Max A.

Subjects
REWARD (Psychology), TOURETTE syndrome, REINFORCEMENT (Psychology), NEURAL inhibition, DOPAMINE, GENETIC counseling
Abstract

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

9. Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder

Author

Abdulkadir, Mohamed, Tischfield, Jay A., King, Robert A., Fernandez, Thomas V., Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., de Bruijn, Sebastian F.T.M., Elzerman, Lonneke, Garcia-Delgar, Blanca, Gilbert, Donald L., Grice, Dorothy E., Hagstrøm, Julie, Hedderly, Tammy, Heyman, Isobel, Hong, Hyun Ju, Huyser, Chaim, Ibanez-Gomez, Laura, Kim, Young Key, Kim, Young-Shin, Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Lamerz, Andreas, Leventhal, Bennett, Ludolph, Andrea G., Madruga-Garrido, Marcos, Maras, Athanasios, Messchendorp, Marieke D., Mir, Pablo, Morer, Astrid, Münchau, Alexander, Murphy, Tara L., Openneer, Thaïra J.C., Plessen, Kerstin J., Rath, Judith J.G., Roessner, Veit, Fründt, Odette, Shin, Eun-Young, Sival, Deborah A., Song, Dong-Ho, Song, Jungeun, Stolte, Anne-Marie, Tübing, Jennifer, van den Ban, Els, Visscher, Frank, Wanderer, Sina, Woods, Martin, Zinner, Samuel H., State, Matthew W., Heiman, Gary A., Hoekstra, Pieter J., and Dietrich, Andrea

Published
2016
Full Text
View/download PDF

10. Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Author

Abdulkadir, Mohamed, Londono, Douglas, Gordon, Derek, Fernandez, Thomas V., Brown, Lawrence W., Cheon, Keun-Ah, Coffey, Barbara J., Elzerman, Lonneke, Fremer, Carolin, Fründt, Odette, Garcia-Delgar, Blanca, Gilbert, Donald L., Grice, Dorothy E., Hedderly, Tammy, Heyman, Isobel, Hong, Hyun Ju, Huyser, Chaim, Ibanez-Gomez, Laura, Jakubovski, Ewgeni, Kim, Young Key, Kim, Young Shin, Koh, Yun-Joo, Kook, Sodahm, Kuperman, Samuel, Leventhal, Bennett, Ludolph, Andrea G., Madruga-Garrido, Marcos, Maras, Athanasios, Mir, Pablo, Morer, Astrid, Müller-Vahl, Kirsten, Münchau, Alexander, Murphy, Tara L., Plessen, Kerstin J., Roessner, Veit, Shin, Eun-Young, Song, Dong-Ho, Song, Jungeun, Tübing, Jennifer, van den Ban, Els, Visscher, Frank, Wanderer, Sina, Woods, Martin, Zinner, Samuel H., King, Robert A., Tischfield, Jay A., Heiman, Gary A., Hoekstra, Pieter J., and Dietrich, Andrea

Published
2018
Full Text
View/download PDF

12. Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Author

Jain, Pritesh, Miller-Fleming, Tyne, Topaloudi, Apostolia, Yu, Dongmei, Drineas, Petros, Georgitsi, Marianthi, Yang, Zhiyu, Rizzo, Renata, Müller-Vahl, Kirsten R., Tumer, Zeynep, Mol Debes, Nanette, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Mir, Pablo, Cath, Danielle C., Boomsma, Dorret I., Roessner, Veit, Wolanczyk, Tomasz, Janik, Piotr, Szejko, Natalia, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Walitza, Susanne, Schrag, Anette, Martino, Davide, Dietrich, Andrea, Mathews, Carol A., Scharf, Jeremiah M., Hoekstra, Pieter J., Davis, Lea K., Paschou, Peristera, Als, Thomas D., Aschauer, Harald, Atzmon, Gil, Bækvad-Hansen, Matie, Barr, Cathy L., Barzilai, Nir, Batterson, James R., Batterson, Robert, Benarroch, Fortu, Berlin, Cheston, Boberg, Julia, Bodmer, Benjamin, Bohnenpoll, Julia, Børglum, Anders D., Brown, Lawrence W., Bruun, Ruth, Budman, Cathy L., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cheon, Keun-Ah, Chouinard, Sylvain, Coffey, Barbara J., Coppola, Giovanni, Crowley, James J., Dahl, Niklas, Darrow, Sabrina M., Daly, Mark J., De Rubeis, Silvia, Dion, Yves, Djurfeldt, Diana R., Domenech-Salgado, Laura, Eapen, Valsamma, Elzerman, Lonneke, Fernandez, Thomas V., Freimer Carolin Fremer, Nelson B., Garcia-Delgar, Blanca, Garrido, Marcos, Gilbert, Donald L., Giusti-Rodriguez, Paola, Grados, Marco, Greenberg, Erica, Grove, Jakob, Hagstrom, Julie, Halvorsen, Matt, Hansen, Bjarne, Haavik, Jan, Hebebrand, Johannes, Heiman, Gary A., Herrera, Luis, Hinney, Anke, Hirschtritt, Matthew E., Sul, Jae Hoon, Hong, Hyun Ju, Hougaard, David M., Huang, Alden Y., Ibanez-Gomez, Laura, Ivankovic, Franjo, Jankovic, Joseph, Karlsson, Elinor K., Kaprio, Jakko A., Kim, Young Key, Kim, Young-Shin, King, Robert A., Knowles, James A., Koh, Yun-Joo, Kook, Sodham, Khalifa, Najah, Konstantinidis, Anastasios, Kuperman, Samuel, Kurlan, Roger, Kvale, Gerd, Leckman, James, Lee, Paul C., Leventhal, Bennett, Lichtenstein, Paul, Lindbald-Toh, Kerstin, Lowe, Thomas, Ludolph, Andrea, da Silva, Claudia Luhrs, Luðvigsson, Pétur, Luykx, Jurjen, Lyon, Gholson J., Mahjani, Behrang, Maras, Athanasios, Mataix-Cols, David, Mattheisen, Manuel, Malaty, Irene A., McMahon, William M., McQuillin, Andrew, Meier, Sandra M., Moessner, Rainald, Mortensen, Preben B., Mors, Ole, Mudgal, Poorva, Nagy, Peter, Naarden, Allan, Neale, Benjamin M., Nawaz, Muhammad S., Nissen, Judith Becker, Nöthen Merete Nordentoft, Markus M., Nordsletten, Ashley E., Okun, Michael S., Ophoff, Roel, Osiecki, Lisa, Palotie, Aarno, Palviainen, Teemu P., Pato Michele T. Pato, Carlos N., Pittenger, Christopher, Pollak, Yehuda, Posthuma, Danielle, Ramos, Eliana, Reichert, Jennifer, Robertson, Mary M., Roffman, Joshua L., Rouleau, Guy, Rück, Christian, Sæmundsen, Evald, Samuels, Jack, Sandin, Sven, Sandor, Paul, Schlögelhofer, Monika, Shin, Eun-Young, Singer, Harvey S., Smit, Jan, Smoller, Jordan W., State, Matthew, Solem, Stian, Song, Dong-Ho, Song, Jungeun, Stamenkovic, Mara, Stefansson, Kári, Strom, Nora, Stuhrmann, Manfred, Szatkiewicz, Jin, Szymanska, Urszula, Tischfield, Jay A., Tsetsos, Fotis, Thorarensen, Ólafur, Tubing, Jennifer, Visscher, Frank, Wagner, Michael, Wanderer, Sina, Wang, Sheng, Werge, Thomas, Willsey, Jeremy A., Wolancyk, Tomasz, Woods, Douglas W., Woods, Martin, Zelaya, Ivette, Zinner, Samuel H., Apter, Alan, Ball, Juliane, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J. W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Dynamic Earth and Resources, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Medizin, Autism Spectrum Disorder/genetics, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Diabetes Mellitus, Type 2, Risk Factors, Diabetes Mellitus, Tourette Syndrome/genetics, Humans, Female, Attention Deficit Disorder with Hyperactivity/genetics, Type 2, Biological Psychiatry
Abstract

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders. Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Published
2023

14. Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study

Author

McGrath, Lauren M., Yu, Dongmei, Marshall, Christian, Davis, Lea K., Thiruvahindrapuram, Bhooma, Li, Bingbin, Cappi, Carolina, Gerber, Gloria, Wolf, Aaron, Schroeder, Frederick A., Osiecki, Lisa, O'Dushlaine, Colm, Kirby, Andrew, Illmann, Cornelia, Haddad, Stephen, Gallagher, Patience, Fagerness, Jesen A., Barr, Cathy L., Bellodi, Laura, Benarroch, Fortu, Bienvenu, O. Joseph, Black, Donald W., Bloch, Michael H., Bruun, Ruth D., Budman, Cathy L., Camarena, Beatriz, Cath, Danielle C., Cavallini, Maria C., Chouinard, Sylvain, Coric, Vladimir, Cullen, Bernadette, Delorme, Richard, Denys, Damiaan, Derks, Eske M., Dion, Yves, Rosário, Maria C., Eapen, Valsama, Evans, Patrick, Falkai, Peter, Fernandez, Thomas V., Garrido, Helena, Geller, Daniel, Grabe, Hans J., Grados, Marco A., Greenberg, Benjamin D., Gross-Tsur, Varda, Grünblatt, Edna, Heiman, Gary A., Hemmings, Sian M.J., Herrera, Luis D., Hounie, Ana G., Jankovic, Joseph, Kennedy, James L., King, Robert A., Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F., Lennertz, Leonhard, Lochner, Christine, Lowe, Thomas L., Lyon, Gholson J., Macciardi, Fabio, Maier, Wolfgang, McCracken, James T., McMahon, William, Murphy, Dennis L., Naarden, Allan L., Neale, Benjamin M., Nurmi, Erika, Pakstis, Andrew J., Pato, Michele T., Pato, Carlos N., Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Reus, Victor I., Richter, Margaret A., Riddle, Mark, Robertson, Mary M., Rosenberg, David, Rouleau, Guy A., Ruhrmann, Stephan, Sampaio, Aline S., Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey S., Smit, Jan H., Stein, Dan J., Tischfield, Jay A., Vallada, Homero, Veenstra-VanderWeele, Jeremy, Walitza, Susanne, Wang, Ying, Wendland, Jens R., Shugart, Yin Yao, Miguel, Euripedes C., Nicolini, Humberto, Oostra, Ben A., Moessner, Rainald, Wagner, Michael, Ruiz-Linares, Andres, Heutink, Peter, Nestadt, Gerald, Freimer, Nelson, Petryshen, Tracey, Posthuma, Danielle, Jenike, Michael A., Cox, Nancy J., Hanna, Gregory L., Brentani, Helena, Scherer, Stephen W., Arnold, Paul D., Stewart, S. Evelyn, Mathews, Carol A., Knowles, James A., Cook, Edwin H., Pauls, David L., Wang, Kai, and Scharf, Jeremiah M.

Published
2014
Full Text
View/download PDF

16. Rate of manifesting carriers and other unexpected findings on carrier screening.

Author

Clevenger, Sydney K., Brandt, Justin S., Khan, Shama P., Shingala, Pranali, Carrick, Jillian, Aluwalia, Ruchi, Heiman, Gary A., and Ashkinadze, Elena

Abstract

Objectives: To ascertain the rate of unexpected findings on carrier screening (CS) and assess whether implications are disclosed to patients. Methods: We performed a retrospective observational study of subjects who had CS after pre‐test counseling from a licensed genetic counselor at a large tertiary care center. We quantified the rate of unexpected finding on CS, defined as manifesting carriers (MCs), genotypes predicting phenotype, and chromosome abnormalities. We determined how often patients were informed of implications. We performed subgroup analyses by type of unexpected finding and calculated odds ratios (OR) and 95% confidence intervals (CI) for carrier testing methodology (genotype) and number of genes tested. Results: A total of 4685 patients had CS over the selected time frame. Of those patients, 412 patients (8.8%) had one unexpected finding and 29 patients (0.6%) had two or more findings. In total, 466 unexpected findings were identified, including 437 MC conditions, 23 genotypes predicting phenotype, and 6 chromosome abnormalities. Patients were informed of the implications for MCs, genotypes predicting phenotype, and chromosome abnormalities in 27.6%, 91.3%, and 100% of cases, respectively. More unexpected findings were detected with sequencing compared to genotyping (OR 2.21 and 95% CI 1.76–2.76) and with ≥200 gene panels compared to <200 gene panels (OR 1.79 and 95% CI 1.47–2.17). Conclusion: This study highlights that nondisclosure of unexpected findings on CS is common and underscores the need for further research to improve post‐test counseling and follow‐up. Key points: What is already known about this topic? Previous studies have examined carrier screening (CS) detection rates, but less is known about unexpected findings and whether implications are disclosed to patients. What does this study add? Unexpected findings are common on CS.Most unexpected findings are manifesting carriers (MCs). Patients infrequently had post‐test counseling about their implications and were counseled more frequently about chromosomal abnormalities and genotypes predicting phenotype.This study shows provider education about the frequency of unexpected findings and post‐test counseling about their implications is important to ensure patients have comprehensive genetic counseling. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

26. GDNF gene is associated with tourette syndrome in a family study

Author

Huertas-Fernández, Ismael, Gómez-Garre, Pilar, Madruga-Garrido, Marcos, Bernal-Bernal, Inmaculada, Bonilla-Toribio, Marta, Martín-Rodríguez, Juan Francisco, Cáceres-Redondo, María Teresa, Vargas-González, Laura, Carrillo, Fátima, Pascual, Alberto, Tischfield, Jay A., King, Robert A., Heiman, Gary A., and Mir, Pablo

Published
2015
Full Text
View/download PDF

28. Genetic counseling certificate program: A program evaluation of undergraduate exposure to genetic counseling.

Author

McGraw, Erin, Rispoli, Jessica, Horner, Michele B., and Heiman, Gary A.

Abstract

Undergraduate genetic counseling exposure can generate interest in a growing field, help students prepare to apply to graduate‐level programs, and introduce underrepresented populations to the career. One form of exposure that currently exists is the Genetic Counseling Certificate Program (GCCP), which is offered to undergraduate students at Rutgers University. To determine the effectiveness, benefits, and limitations of the GCCP, a program evaluation was conducted. Former GCCP students were surveyed to assess how they perceived the program. Overall, most students thought the program successfully met its objectives and thought their participation in the GCCP was beneficial. Because it is viewed favorably by former students, implementing something similar to the GCCP may be an option for institutions looking to offer additional opportunities to their undergraduates. Not only could creating programs like the GCCP enhance undergraduates' knowledge of the genetic counseling profession, but it could also contribute toward diversification of the field. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

30. L-histidine decarboxylase and Tourette's syndrome

Author

Ercan-Sencicek, A. Gulhan, Stillman, Althea A., Ghosh, Ananda K., Bilguvar, Kaya, O'Roak, Brian J., Mason, Christopher E., Abbott, Thomas, Gupta, Abha, King, Robert A., Pauls, David L., Tischfield, Jay A., Heiman, Gary A., Singer, Harvey S., Gilbert, Donald L., Hoekstra, Pieter J., Morgan, Thomas M., Loring, Erin, Yasuno, Katsuhito, Fernandez, Thomas, Sanders, Stephan, Louvi, Angeliki, Cho, Judy H., Mane, Shrikant, Colangelo, Christopher M., Biederer, Thomas, Lifton, Richard P., Gunel, Murat, and State, Matthew W.

Subjects
Decarboxylases -- Genetic aspects, Gene mutations -- Analysis, Histidine -- Research, Tourette's syndrome -- Genetic aspects, Tourette's syndrome -- Diagnosis, Tourette's syndrome -- Care and treatment
Abstract

An analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase and Tourette's syndrome, the rate-limiting enzyme in histamine biosynthesis is described. The study findings along with the published data from model system provide insight into the role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.

Published
2010

32. Clinical and EEG factors associated with antiseizure medication resistance in idiopathic generalized epilepsy.

Author

Kamitaki, Brad K., Janmohamed, Mubeen, Kandula, Padmaja, Elder, Christopher, Mani, Ram, Wong, Stephen, Perucca, Piero, O'Brien, Terence J., Lin, Haiqun, Heiman, Gary A., and Choi, Hyunmi

Subjects
EPILEPSY, MYOCLONUS, ELECTROENCEPHALOGRAPHY, SEIZURES (Medicine), DRUGS, ODDS ratio, IMMUNOGLOBULIN E
Abstract

Objective: We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)–resistant vs ASM‐responsive outcome for patients with idiopathic generalized epilepsy (IGE). Methods: This was a case‐control study of ASM‐resistant cases and ASM‐responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM‐resistant IGE. Results: We identified 118 ASM‐resistant cases and 114 ASM‐responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM‐resistant IGE (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.32–10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure‐type combinations (absence, myoclonic, and generalized tonic‐clonic seizures [OR 7.06, 95% CI 2.55–20.96]; absence and generalized tonic‐clonic seizures [OR 4.45, 95% CI 1.84–11.34]), as well as EEG markers of increased generalized spike‐wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12–11.36 for frequent and OR 7.21, 95% CI 1.50–54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs; OR 5.49, 95% CI 1.27–38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver‐operating characteristic curve, was 0.80. Significance: Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure‐type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

36. Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with ε-sarcoglycan mutations

Author

Raymond, Deborah, Saunders-Pullman, Rachel, de Carvalho Aguiar, Patricia, Schule, Birgitt, Kock, Norman, Friedman, Jennifer, Harris, Juliette, Ford, Blair, Frucht, Steven, Heiman, Gary A., Jennings, Danna, Doheny, Dana, Brin, Mitchell F., de Leon Brin, Deborah, Multhaupt-Buell, Trisha, Lang, Anthony E., Kurlan, Roger, Klein, Christine, Ozelius, Laurie, and Bressman, Susan

Published
2008
Full Text
View/download PDF

37. Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies

Author

Yu, Dongmei, Sul, Jae Hoon, Tsetsos, Fotis, Nawaz, Muhammad S., Huang, Alden Y., Zelaya, Ivette, Illmann, Cornelia, Osiecki, Lisa, Darrow, Sabrina M., Hirschtritt, Matthew E., Greenberg, Erica, Muller-Vahl, Kirsten R., Stuhrmann, Manfred, Dion, Yves, Rouleau, Guy, Aschauer, Harald, Stamenkovic, Mara, Schlögelhofer, Monika, Sandor, Paul, Barr, Cathy L., Grados, Marco, Singer, Harvey S., Nöthen, Markus M., Hebebrand, Johannes, Hinney, Anke, King, Robert A., Fernandez, Thomas V., Barta, Csaba, Tarnok, Zsanett, Nagy, Peter, Depienne, Christel, Worbe, Yulia, Hartmann, Andreas, Budman, Cathy L., Rizzo, Renata, Lyon, Gholson J., McMahon, William M., Batterson, James R., Cath, Danielle C., Malaty, Irene A., Okun, Michael S., Berlin, Cheston, Woods, Douglas W., Lee, Paul C., Jankovic, Joseph, Robertson, Mary M., Gilbert, Donald L., Brown, Lawrence W., Coffey, Barbara J., Dietrich, Andrea, Hoekstra, Pieter J., Kuperman, Samuel, Zinner, Samuel H., Luðvigsson, Pétur, Sæmundsen, Evald, Thorarensen, Ólafur, Atzmon, Gil, Barzilai, Nir, Wagner, Michael, Moessner, Rainald, Ophoff, Roel, Pato, Carlos N., Pato, Michele T., Knowles, James A., Roffman, Joshua L., Smoller, Jordan W., Buckner, Randy L., Jeremy Willsey, A., Tischfield, Jay A., Heiman, Gary A., Stefansson, Hreinn, Stefansson, Kári, Posthuma, Danielle, Cox, Nancy J., Pauls, David L., Freimer, Nelson B., Neale, Benjamin M., Davis, Lea K., Paschou, Peristera, Coppola, Giovanni, Mathews, Carol A., Scharf, Jeremiah M., Bruun, Ruth D., Chouinard, Sylvain, Grados, Marco A., Kurlan, Roger, Leckman, James F., Rouleau, Guy A., Smit, Jan, Wolanczyk, Tomasz, Complex Trait Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, Plastic, Reconstructive and Hand Surgery, ANS - Cellular & Molecular Mechanisms, and Child Psychiatry

Subjects
medicine.medical_specialty, Multifactorial Inheritance, congenital, hereditary, and neonatal diseases and abnormalities, Tourette's syndrome, Medizin, Genome-wide association study, Biology, Tourette syndrome, Polymorphism, Single Nucleotide, Severity of Illness Index, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Risk Factors, mental disorders, Child and adolescent psychiatry, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Genetics, COPY NUMBER VARIANTS, RISK, medicine.disease, Genetic architecture, 030227 psychiatry, Psychiatry and Mental health, fms-Like Tyrosine Kinase 3, Case-Control Studies, Tic Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study, Tourette Syndrome
Abstract

Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity.Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined.Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette'sassociated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects.Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Published
2019

42. Reproductive male partner testing when the female is identified to be a genetic disease carrier.

Author

Simone, Laurie, Khan, Shama, Ciarlariello, Molly, Lin, Julia, Trackman, Sarah, Heiman, Gary A., and Ashkinadze, Elena

Abstract

Objective: To quantify carrier testing uptake rates for male partners of women found to be a carrier(s) for autosomal recessive conditions and to understand reasons for declining testing (uptake rate). Methods: A retrospective chart review of 513 female patients seen at Rutgers‐Robert Wood Johnson Medical School found to be carriers through expanded carrier screening (ECS) panels. The aims of this study were to determine how often their male partner chose testing, reasons for declining and the type of methodology chosen for their screening. Results: Male partner uptake rate was 77%. We identified that the most significant barrier to male partner testing is female patients not following up on their own carrier screening results, thus missing the opportunity for partner testing. When male partners were provided options for testing, the most reported reason for declining is the belief it would have no impact on pregnancy management (20%). A carrier couple rate of 8.3% was identified of partners tested. Conclusion: Despite a relatively high male testing uptake rate, a quarter of carrier females did not proceed with testing their partner. To ascertain fetal risk, results for both parents is necessary. Pretest counseling should stress need for potential male partner follow‐up testing. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

43. New Jersey Center for Tourette Syndrome Sharing Repository: methods and sample description

Author

King Robert A, Heiman Gary A, and Tischfield Jay A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Tourette Syndrome is a neuropsychiatric disorder characterized by chronic motor and phonic tics. Affected individuals and their family members are at an increased risk for other neuropsychiatric conditions including obsessive-compulsive disorder and attention deficit hyperactivity disorder. While there is consistent evidence that genetic factors play a significant etiologic role, no replicable susceptibility alleles have thus far been identified. Description Here we discuss a sharing resource of clinical and genetic data, the New Jersey Center for Tourette Syndrome Sharing Repository, whose goal is to provide clinical data, DNA, and lymphoblastoid cell lines to qualified researchers. Conclusion Opening access to the data and patient material to the widest possible research community will hasten the identification of causal genetic factors and facilitate better understanding and treatment of this often impairing disorder.

Published
2008
Full Text
View/download PDF

44. Empiric Recurrence Risk Estimates for Chronic Tic Disorders: Implications for Genetic Counseling.

Author

Heiman, Gary A., Rispoli, Jessica, Seymour, Christine, Leckman, James F., King, Robert A., and Fernandez, Thomas V.

Subjects
GENETIC counseling, TIC disorders, GENETIC disorders, NEUROBEHAVIORAL disorders, FAMILY history (Medicine)
Abstract

Background: Tourette disorder (TD) and other chronic tic disorders are neurodevelopmental/neuropsychiatric disorders characterized by motor and/or vocal tics. Family studies indicate that TD strongly aggregates within families and that other chronic tic disorders are biologically related such that studies typically combine them into any chronic tic disorder (CTD). Because of stigma, bullying, and comorbidity with other neuropsychiatric disorders, CTDs can severely impact the quality of life of individuals with these disorders. Objectives: The genetic architecture of CTDs is complex and heterogeneous, involving a myriad of genetic variants. Thus, providing familial recurrence risks is based on empirical recurrence risk estimates rather than genetic testing. Because empiric recurrence risks for CTDs have not been published, the purpose of this study is to calculate and report these recurrence risks estimates. Methods: Based on population prevalence and increased risk to different relatives from a large population-based family study, we calculated the empiric recurrent risk estimate for each relative type (full sibling, parents, offspring, all first-degree, and all second-degree). Results: The recurrence risk estimate for CTDs in first-degree relatives is 29.9% [95% confidence interval (CI) = 23.2–38.5%]. The risk is higher in males, 33.7% (95% CI = 26.2–43.3%), than females, 24.3% (95% CI = 18.9–31.3%). Conclusions: Given the complex, heterogeneous genetic architecture of CTDs, individuals concerned about recurrence risk should be referred to genetic counseling. Such counseling should include discussion of the derivation and limitations of these empiric recurrence risk estimates, including the upper and lower limits of the range of risk. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

45. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette Syndrome and Obsessive-Compulsive Disorder

Author

Yu, Dongmei, Mathews, Carol A., Scharf, Jeremiah M., Neale, Benjamin M., Davis, Lea K., Gamazon, Eric R., Derks, Eske M., Evans, Patrick, Edlund, Christopher K., Crane, Jacquelyn, Fagerness, Jesen A., Osiecki, Lisa, Gallagher, Patience, Gerber, Gloria, Haddad, Stephen, Illmann, Cornelia, McGrath, Lauren M., Mayerfeld, Catherine, Arepalli, Sampath, Barlassina, Cristina, Barr, Cathy L., Bellodi, Laura, Benarroch, Fortu, Berrió, Gabriel Bedoya, Bienvenu, O. Joseph, Black, Donald, Bloch, Michael H., Brentani, Helena, Bruun, Ruth D., Budman, Cathy L., Camarena, Beatriz, Campbell, Desmond D., Cappi, Carolina, Cardona Silgado, Julio C., Cavallini, Maria C., Chavira, Denise A., Chouinard, Sylvain, Cook, Edwin H., Cookson, M. R., Coric, Vladimir, Cullen, Bernadette, Cusi, Daniele, Delorme, Richard, Denys, Damiaan, Dion, Yves, Eapen, Valsama, Egberts, Karin, Falkai, Peter, Fernandez, Thomas, Fournier, Eduardo, Garrido, Helena, Geller, Daniel, Gilbert, Donald, Girard, Simon L., Grabe, Hans J., Grados, Marco A., Greenberg, Benjamin D., Gross-Tsur, Varda, Grünblatt, Edna, Hardy, John, Heiman, Gary A., Hemmings, Sian M.J., Herrera, Luis D., Hezel, Dianne M., Hoekstra, Pieter J., Jankovic, Joseph, Kennedy, James L., King, Robert A., Konkashbaev, Anuar I., Kremeyer, Barbara, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F., Lennertz, Leonhard, Liu, Chunyu, Lochner, Christine, Lowe, Thomas L., Lupoli, Sara, Macciardi, Fabio, Maier, Wolfgang, Manunta, Paolo, Marconi, Maurizio, McCracken, James T., Mesa Restrepo, Sandra C., Moessner, Rainald, Moorjani, Priya, Morgan, Jubel, Muller, Heike, Murphy, Dennis L., Naarden, Allan L., Ochoa, William Cornejo, Ophoff, Roel A., Pakstis, Andrew J., Pato, Michele T., Pato, Carlos N., Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Rauch, Scott L., Renner, Tobias, Reus, Victor I., Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Romero, Roxana, Rosário, Maria C., Rosenberg, David, Ruhrmann, Stephan, Sabatti, Chiara, Salvi, Erika, Sampaio, Aline S., Samuels, Jack, Sandor, Paul, Service, Susan K., Sheppard, Brooke, Singer, Harvey S., Smit, Jan H., Stein, Dan J., Strengman, Eric, Tischfield, Jay A., Turiel, Maurizio, Valencia Duarte, Ana V., Vallada, Homero, Veenstra-VanderWeele, Jeremy, Walitza, Susanne, Walkup, John, Wang, Ying, Weale, Mike, Weiss, Robert, Wendland, Jens R., Westenberg, Herman G.M., Yao, Yin, Hounie, Ana G., Miguel, Euripedes C., Nicolini, Humberto, Wagner, Michael, Ruiz-Linares, Andres, Cath, Danielle C., McMahon, William, Posthuma, Danielle, Oostra, Ben A., Nestadt, Gerald, Rouleau, Guy A., Purcell, Shaun, Jenike, Michael A., Heutink, Peter, Hanna, Gregory L., Conti, David V., Arnold, Paul D., Freimer, Nelson, Stewart, S. Evelyn, Knowles, James A., Cox, Nancy J., and Pauls, David L.

Subjects
Adult, Male, Psychiatric Status Rating Scales, Obsessive-Compulsive Disorder, Comorbidity, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Severity of Illness Index, Article, mental disorders, Humans, Female, Genome-Wide Association Study, Tourette Syndrome
Abstract

Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Published
2014

49. Partitioning the heritability of Tourette Syndrome and obsessive compulsive disorder reveals differences in genetic architecture

Author

Keller, Matthew C., Davis, Lea K., Yu, Dongmei, Keenan, Clare L., Gamazon, Eric R., Konkashbaev, Anuar I., Derks, Eske M., Neale, Benjamin M., Yang, Jian, Lee, S. Hong, Evans, Patrick, Barr, Cathy L., Bellodi, Laura, Benarroch, Fortu, Berrio, Gabriel Bedoya, Bienvenu, Oscar J., Bloch, Michael H., Blom, Rianne M., Bruun, Ruth D., Budman, Cathy L., Camarena, Beatriz, Campbell, Desmond, Cappi, Carolina, Cardona Silgado, Julio C., Cath, Danielle C., Cavallini, Maria C., Chavira, Denise A., Chouinard, Sylvain, Conti, David V., Cook, Edwin H., Coric, Vladimir, Cullen, Bernadette A., Deforce, Dieter, Delorme, Richard, Dion, Yves, Edlund, Christopher K., Egberts, Karin, Falkai, Peter, Fernandez, Thomas V., Gallagher, Patience J., Garrido, Helena, Geller, Daniel, Girard, Simon L., Grabe, Hans J., Grados, Marco A., Greenberg, Benjamin D., Gross-Tsur, Varda, Haddad, Stephen, Heiman, Gary A., Hemmings, Sian M. J., Hounie, Ana G., Illmann, Cornelia, Jankovic, Joseph, Jenike, Michael A., Kennedy, James L., King, Robert A., Kremeyer, Barbara, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F., Lennertz, Leonhard, Liu, Chunyu, Lochner, Christine, Lowe, Thomas L., Macciardi, Fabio, McCracken, James T., McGrath, Lauren M., Mesa Restrepo, Sandra C., Moessner, Rainald, Morgan, Jubel, Muller, Heike, Murphy, Dennis L., Naarden, Allan L., Ochoa, William Cornejo, Ophoff, Roel A., Osiecki, Lisa, Pakstis, Andrew J., Pato, Michele T., Pato, Carlos N., Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Rauch, Scott L., Renner, Tobias J., Reus, Victor I., Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Romero, Roxana, Rosàrio, Maria C., Rosenberg, David, Rouleau, Guy A., Ruhrmann, Stephan, Ruiz-Linares, Andres, Sampaio, Aline S., Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey S., Smit, Jan H., Stein, Dan J., Strengman, E., Tischfield, Jay A., Valencia Duarte, Ana V., Vallada, Homero, Van Nieuwerburgh, Filip, Veenstra-VanderWeele, Jeremy, Walitza, Susanne, Wang, Ying, Wendland, Jens R., Westenberg, Herman G. M., Shugart, Yin Yao, Miguel, Euripedes C., McMahon, William, Wagner, Michael, Nicolini, Humberto, Posthuma, Danielle, Hanna, Gregory L., Heutink, Peter, Denys, Damiaan, Arnold, Paul D., Oostra, Ben A., Nestadt, Gerald, Freimer, Nelson B., Pauls, David L., Wray, Naomi R., Stewart, S. Evelyn, Mathews, Carol A., Knowles, James A., Cox, Nancy J., and Scharf, Jeremiah M.

Subjects
Gilles, Missing Heritability, Autism, Life Sciences, Brain, Neuropsychiatric Disorders, Expression, Social and Behavioral Sciences, Tic Disorders, Common Snps, mental disorders, Medicine and Health Sciences, Complex Diseases, Family
Abstract

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results