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1. Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

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 W, Bloch, Michael H, Brentani, Helena, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Campbell, Desmond D, Cappi, Carolina, Silgado, Julio C Cardona, Cavallini, Maria C, Chavira, Denise A, Chouinard, Sylvain, Cook, Edwin H, Cookson, MR, 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 L, Girard, Simon L, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Grünblatt, Edna, Hardy, John, Heiman, Gary A, Hemmings, Sian MJ, 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, Nurmi, Erika, Ochoa, William Cornejo, Ophoff, Roel A, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, and Pollak, Yehuda

Subjects
Humans, Tourette Syndrome, Severity of Illness Index, Obsessive-Compulsive Disorder, Psychiatric Status Rating Scales, Comorbidity, Polymorphism, Single Nucleotide, Adult, Female, Male, Genome-Wide Association Study, Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Neurodegenerative, Prevention, Anxiety Disorders, Mental Health, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Mental health, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveObsessive-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.MethodThe 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.ResultsAlthough 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).ConclusionsPrevious 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
2015

2. 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 MJ, 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, and Oostra, Ben A

Subjects
Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Neurodegenerative, Mental Health, Tourette Syndrome, Neurosciences, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, DNA Copy Number Variations, Diagnostic and Statistical Manual of Mental Disorders, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette syndrome, obsessive-compulsive disorder, copy number variation, genetics, 16p13.11, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental & Child Psychology
Abstract

ObjectiveObsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (

Published
2014

3. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Author

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, and Smit, Jan H

Subjects
Missing Heritability, Tic Disorders, Neuropsychiatric Disorders, Complex Diseases, Common Snps, Gilles, Family, Brain, Expression, Autism
Published
2013

4. 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

5. 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

9. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Author

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.

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
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10. Genome-wide association study of Tourette Syndrome

Author

Scharf, Jeremiah M., Yu, Dongmei, Mathews, Carol A., Neale, Benjamin M., Stewart, S. Evelyn, Fagerness, Jesen A, Evans, Patrick, Gamazon, Eric, Edlund, Christopher K., Service, Susan, Tikhomirov, Anna, Osiecki, Lisa, Illmann, Cornelia, Pluzhnikov, Anna, Konkashbaev, Anuar, Davis, Lea K, Han, Buhm, Crane, Jacquelyn, Moorjani, Priya, Crenshaw, Andrew T., Parkin, Melissa A., Reus, Victor I., Lowe, Thomas L., Rangel-Lugo, Martha, Chouinard, Sylvain, Dion, Yves, Girard, Simon, Cath, Danielle C, Smit, Jan H, King, Robert A., Fernandez, Thomas, Leckman, James F., Kidd, Kenneth K., Kidd, Judith R., Pakstis, Andrew J., State, Matthew, Herrera, Luis Diego, Romero, Roxana, Fournier, Eduardo, Sandor, Paul, Barr, Cathy L, Phan, Nam, Gross-Tsur, Varda, Benarroch, Fortu, Pollak, Yehuda, Budman, Cathy L., Bruun, Ruth D., Erenberg, Gerald, Naarden, Allan L, Lee, Paul C, Weiss, Nicholas, Kremeyer, Barbara, Berrío, Gabriel Bedoya, Campbell, Desmond, Silgado, Julio C. Cardona, Ochoa, William Cornejo, Restrepo, Sandra C. Mesa, Muller, Heike, Duarte, Ana V. Valencia, Lyon, Gholson J, Leppert, Mark, Morgan, Jubel, Weiss, Robert, Grados, Marco A., Anderson, Kelley, Davarya, Sarah, Singer, Harvey, Walkup, John, Jankovic, Joseph, Tischfield, Jay A., Heiman, Gary A., Gilbert, Donald L., Hoekstra, Pieter J., Robertson, Mary M., Kurlan, Roger, Liu, Chunyu, Gibbs, J. Raphael, Singleton, Andrew, Hardy, John, Strengman, Eric, Ophoff, Roel, Wagner, Michael, Moessner, Rainald, Mirel, Daniel B., Posthuma, Danielle, Sabatti, Chiara, Eskin, Eleazar, Conti, David V., Knowles, James A., Ruiz-Linares, Andres, Rouleau, Guy A., Purcell, Shaun, Heutink, Peter, Oostra, Ben A., McMahon, William, Freimer, Nelson, Cox, Nancy J., and Pauls, David L.

Subjects
Tourette Syndrome, tics, genetics, GWAS, neurodevelopmental disorder
Abstract

Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Published
2012
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11. Facial Pain of Neurologic Origin Mimicking Oral Pathologic Conditions: Some Current Concepts and Treatment

Author

Lazar, Martin L., Greenlee, Ralph G., and Naarden, Allan L.

Abstract

Some neurologic entities produce pain and mimic oral pathologic conditions. Recent observations have helped to clarify the causes and treatment of these neurologic conditions. As specific treatment aimed at the source of pain is superior to general treatment designed to treat only pain, it is important for practitioners to recognize these entities early.

Published
1980
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