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2013•PLoS GeneticsOpen access

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

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

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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.

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What this paper is about

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.

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Available 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.

Key concepts: Heritability, Genetic architecture, Biology, Genetics, Genome-wide association study, Missing heritability problem, Genetic correlation, Quantitative trait locus

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