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

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

doi:10.1371/journal.pgen.1003864

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

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

Research output: Contribution to journal › Article › peer-review

202 Scopus citations

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.

Original language	English
Article number	e1003864
Journal	PLoS Genetics
Volume	9
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1003864
State	Published - Oct 2013
Externally published	Yes

Bibliographical note

Funding Information:
The following authors have read the journal's policy and have the following conflicts: CLBu: Currently receiving funding for TS clinical trials from Otsuka Pharmaceutical, JFL: recevies research support from NIH and Grifols, LLC as well royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press, MARic: received honoraria from Lundbeck, and research funding from Great-West Life Assurance Company of Canada and Eli Lilly Canada Ltd, MCR: grant from CNPq (Brazilian National Counsil) and has received research grants and/or consultancy honoraria from Novartis and Shire, DR: received consulting fees for Shire, JMS: received research support, honoraria and travel support from the Tourette Syndrome Association (TSA), DJS: received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Biocodex, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah, and Wyeth, TVF: received research funding from NIMH (K08 MH099424-01), the Simons Foundation, Allison Foundation, and Shire, PS: received research support for this study from the Tourette Syndrome Association (TSA), Tourette Syndrome Foundation of Canada and NIH, DY: received research support from the Tourette Syndrome Association (TSA) and NIH, MMR: received grants from the Tourette's Action-UK, TSA-USA, honoraria from Janssen-Cilag, and book royalties from Wiley - Blackwell, David Fulton/Granada/Taylor Francis, Oxford University Press and Jessica Kingsley Publishers, is a Patron of Tourette's Action (UK), sits on the Medical Advisory Board of the Italian Tourette Syndrome Association and The Tourette Syndrome Foundation of Canada, DAC: NIH/NIMH funding for K01 MH072952 and R34 MH090149, SLR: participated in research funded by Medtronic and Cyberonics, JRW: Past employee of F. Hoffmann-La Roche and current employee of Pfizer, SW: received lecture honoraria from Janssen Cilag, AstraZeneca and Eli Lilly, research funds Swiss National Science Foundation (SNF), Deutsche Forschungsgemeinschaft, EU FP7, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, JV: funding from Seaside Therapeutics, Novartis, Roche Pharmaceuticals, Forest, and SynapDx. Consulting/Advisory Board for Novartis, JTM: Tourette Syndrome Association-Speaker honoraria; Otuska-research grant; Roche-consultant; 1R01MH079487-01A1, JLK: honoraria from Roche, Eli Lilly, and Novartis, PDA: Unrestricted research grant from DNA Genotek SLG, HJG, ML, DLP, SES, NL, JHS, CLBa, LB, FB, GBB, OJB, MHB, RMB, RDB, DC, CC, JCCS, DCC, MCC, SC, DVC, EHC, VC, NJC, BAC, LKD, DDen, DDef, RD, EMD, YD, CKE, KE, PF, NBF, PJG, ERG, HG, MAG, BDG, VGT, SH, GLH, GAH, SMJH, PH, AGH, CI, JJ, MAJ, CLK, RAK, JAK, AIK, BK, RK, SHL, LL, CLi, CLo, TLL, FM, CAM, LMM, WM, SCMR, ECM, RM, JM, HM, DLM, ALN, BMN, GN, HN, WCO, BAO, RAO, LO, AJP, MTP, CNP, CP, YP, DP, TJR, VIR, MARid, GAR, SR, ARL, ASS, JS, BS, HSS, ES, JAT, AVVD, HV, MW, YW, JY, HGMW, PE, BC, RR have declared that no competing interests exist.

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10.1371/journal.pgen.1003864

Cite this

Davis, L. K., Yu, D., Keenan, C. L., Gamazon, E. R., Konkashbaev, A. I., Derks, E. M., Neale, B. M., Yang, J., Lee, S. H., Evans, P., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Bloch, M. H., Blom, R. M., Bruun, R. D., Budman, C. L., ... Scharf, J. M. (2013). Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture. PLoS Genetics, 9(10), Article e1003864. https://doi.org/10.1371/journal.pgen.1003864

@article{329bcea4c3e24f0fa6a3510702b0d639,

title = "Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture",

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.",

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

note = "Funding Information: The following authors have read the journal's policy and have the following conflicts: CLBu: Currently receiving funding for TS clinical trials from Otsuka Pharmaceutical, JFL: recevies research support from NIH and Grifols, LLC as well royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press, MARic: received honoraria from Lundbeck, and research funding from Great-West Life Assurance Company of Canada and Eli Lilly Canada Ltd, MCR: grant from CNPq (Brazilian National Counsil) and has received research grants and/or consultancy honoraria from Novartis and Shire, DR: received consulting fees for Shire, JMS: received research support, honoraria and travel support from the Tourette Syndrome Association (TSA), DJS: received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Biocodex, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah, and Wyeth, TVF: received research funding from NIMH (K08 MH099424-01), the Simons Foundation, Allison Foundation, and Shire, PS: received research support for this study from the Tourette Syndrome Association (TSA), Tourette Syndrome Foundation of Canada and NIH, DY: received research support from the Tourette Syndrome Association (TSA) and NIH, MMR: received grants from the Tourette's Action-UK, TSA-USA, honoraria from Janssen-Cilag, and book royalties from Wiley - Blackwell, David Fulton/Granada/Taylor Francis, Oxford University Press and Jessica Kingsley Publishers, is a Patron of Tourette's Action (UK), sits on the Medical Advisory Board of the Italian Tourette Syndrome Association and The Tourette Syndrome Foundation of Canada, DAC: NIH/NIMH funding for K01 MH072952 and R34 MH090149, SLR: participated in research funded by Medtronic and Cyberonics, JRW: Past employee of F. Hoffmann-La Roche and current employee of Pfizer, SW: received lecture honoraria from Janssen Cilag, AstraZeneca and Eli Lilly, research funds Swiss National Science Foundation (SNF), Deutsche Forschungsgemeinschaft, EU FP7, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, JV: funding from Seaside Therapeutics, Novartis, Roche Pharmaceuticals, Forest, and SynapDx. Consulting/Advisory Board for Novartis, JTM: Tourette Syndrome Association-Speaker honoraria; Otuska-research grant; Roche-consultant; 1R01MH079487-01A1, JLK: honoraria from Roche, Eli Lilly, and Novartis, PDA: Unrestricted research grant from DNA Genotek SLG, HJG, ML, DLP, SES, NL, JHS, CLBa, LB, FB, GBB, OJB, MHB, RMB, RDB, DC, CC, JCCS, DCC, MCC, SC, DVC, EHC, VC, NJC, BAC, LKD, DDen, DDef, RD, EMD, YD, CKE, KE, PF, NBF, PJG, ERG, HG, MAG, BDG, VGT, SH, GLH, GAH, SMJH, PH, AGH, CI, JJ, MAJ, CLK, RAK, JAK, AIK, BK, RK, SHL, LL, CLi, CLo, TLL, FM, CAM, LMM, WM, SCMR, ECM, RM, JM, HM, DLM, ALN, BMN, GN, HN, WCO, BAO, RAO, LO, AJP, MTP, CNP, CP, YP, DP, TJR, VIR, MARid, GAR, SR, ARL, ASS, JS, BS, HSS, ES, JAT, AVVD, HV, MW, YW, JY, HGMW, PE, BC, RR have declared that no competing interests exist. ",

year = "2013",

month = oct,

doi = "10.1371/journal.pgen.1003864",

language = "אנגלית",

volume = "9",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

Davis, LK, Yu, D, Keenan, CL, Gamazon, ER, Konkashbaev, AI, Derks, EM, Neale, BM, Yang, J, Lee, SH, Evans, P, Barr, CL, Bellodi, L, Benarroch, F, Berrio, GB, Bienvenu, OJ, Bloch, MH, Blom, RM, Bruun, RD, Budman, CL, Camarena, B, Campbell, D, Cappi, C, Cardona Silgado, JC, Cath, DC, Cavallini, MC, Chavira, DA, Chouinard, S, Conti, DV, Cook, EH, Coric, V, Cullen, BA, Deforce, D, Delorme, R, Dion, Y, Edlund, CK, Egberts, K, Falkai, P, Fernandez, TV, Gallagher, PJ, Garrido, H, Geller, D, Girard, SL, Grabe, HJ, Grados, MA, Greenberg, BD, Gross-Tsur, V, Haddad, S, Heiman, GA, Hemmings, SMJ, Hounie, AG, Illmann, C, Jankovic, J, Jenike, MA, Kennedy, JL, King, RA, Kremeyer, B, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, JF, Lennertz, L, Liu, C, Lochner, C, Lowe, TL, Macciardi, F, McCracken, JT, McGrath, LM, Mesa Restrepo, SC, Moessner, R, Morgan, J, Muller, H, Murphy, DL, Naarden, AL, Ochoa, WC, Ophoff, RA, Osiecki, L, Pakstis, AJ, Pato, MT, Pato, CN, Piacentini, J, Pittenger, C, Pollak, Y, Rauch, SL, Renner, TJ, Reus, VI, Richter, MA, Riddle, MA, Robertson, MM, Romero, R, Rosàrio, MC, Rosenberg, D, Rouleau, GA, Ruhrmann, S, Ruiz-Linares, A, Sampaio, AS, Samuels, J, Sandor, P, Sheppard, B, Singer, HS, Smit, JH, Stein, DJ, Strengman, E, Tischfield, JA, Valencia Duarte, AV, Vallada, H, Van Nieuwerburgh, F, Veenstra-VanderWeele, J, Walitza, S, Wang, Y, Wendland, JR, Westenberg, HGM, Shugart, YY, Miguel, EC, McMahon, W, Wagner, M, Nicolini, H, Posthuma, D, Hanna, GL, Heutink, P, Denys, D, Arnold, PD, Oostra, BA, Nestadt, G, Freimer, NB, Pauls, DL, Wray, NR, Stewart, SE, Mathews, CA, Knowles, JA, Cox, NJ & Scharf, JM 2013, 'Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture', PLoS Genetics, vol. 9, no. 10, e1003864. https://doi.org/10.1371/journal.pgen.1003864

TY - JOUR

T1 - Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

AU - Davis, Lea K.

AU - Yu, Dongmei

AU - Keenan, Clare L.

AU - Gamazon, Eric R.

AU - Konkashbaev, Anuar I.

AU - Derks, Eske M.

AU - Neale, Benjamin M.

AU - Yang, Jian

AU - Lee, S. Hong

AU - Evans, Patrick

AU - Barr, Cathy L.

AU - Bellodi, Laura

AU - Benarroch, Fortu

AU - Berrio, Gabriel Bedoya

AU - Bienvenu, Oscar J.

AU - Bloch, Michael H.

AU - Blom, Rianne M.

AU - Bruun, Ruth D.

AU - Budman, Cathy L.

AU - Camarena, Beatriz

AU - Campbell, Desmond

AU - Cappi, Carolina

AU - Cardona Silgado, Julio C.

AU - Cath, Danielle C.

AU - Cavallini, Maria C.

AU - Chavira, Denise A.

AU - Chouinard, Sylvain

AU - Conti, David V.

AU - Cook, Edwin H.

AU - Coric, Vladimir

AU - Cullen, Bernadette A.

AU - Deforce, Dieter

AU - Delorme, Richard

AU - Dion, Yves

AU - Edlund, Christopher K.

AU - Egberts, Karin

AU - Falkai, Peter

AU - Fernandez, Thomas V.

AU - Gallagher, Patience J.

AU - Garrido, Helena

AU - Geller, Daniel

AU - Girard, Simon L.

AU - Grabe, Hans J.

AU - Grados, Marco A.

AU - Greenberg, Benjamin D.

AU - Gross-Tsur, Varda

AU - Haddad, Stephen

AU - Heiman, Gary A.

AU - Hemmings, Sian M.J.

AU - Hounie, Ana G.

AU - Illmann, Cornelia

AU - Jankovic, Joseph

AU - Jenike, Michael A.

AU - Kennedy, James L.

AU - King, Robert A.

AU - Kremeyer, Barbara

AU - Kurlan, Roger

AU - Lanzagorta, Nuria

AU - Leboyer, Marion

AU - Leckman, James F.

AU - Lennertz, Leonhard

AU - Liu, Chunyu

AU - Lochner, Christine

AU - Lowe, Thomas L.

AU - Macciardi, Fabio

AU - McCracken, James T.

AU - McGrath, Lauren M.

AU - Mesa Restrepo, Sandra C.

AU - Moessner, Rainald

AU - Morgan, Jubel

AU - Muller, Heike

AU - Murphy, Dennis L.

AU - Naarden, Allan L.

AU - Ochoa, William Cornejo

AU - Ophoff, Roel A.

AU - Osiecki, Lisa

AU - Pakstis, Andrew J.

AU - Pato, Michele T.

AU - Pato, Carlos N.

AU - Piacentini, John

AU - Pittenger, Christopher

AU - Pollak, Yehuda

AU - Rauch, Scott L.

AU - Renner, Tobias J.

AU - Reus, Victor I.

AU - Richter, Margaret A.

AU - Riddle, Mark A.

AU - Robertson, Mary M.

AU - Romero, Roxana

AU - Rosàrio, Maria C.

AU - Rosenberg, David

AU - Rouleau, Guy A.

AU - Ruhrmann, Stephan

AU - Ruiz-Linares, Andres

AU - Sampaio, Aline S.

AU - Samuels, Jack

AU - Sandor, Paul

AU - Sheppard, Brooke

AU - Singer, Harvey S.

AU - Smit, Jan H.

AU - Stein, Dan J.

AU - Strengman, E.

AU - Tischfield, Jay A.

AU - Valencia Duarte, Ana V.

AU - Vallada, Homero

AU - Van Nieuwerburgh, Filip

AU - Veenstra-VanderWeele, Jeremy

AU - Walitza, Susanne

AU - Wang, Ying

AU - Wendland, Jens R.

AU - Westenberg, Herman G.M.

AU - Shugart, Yin Yao

AU - Miguel, Euripedes C.

AU - McMahon, William

AU - Wagner, Michael

AU - Nicolini, Humberto

AU - Posthuma, Danielle

AU - Hanna, Gregory L.

AU - Heutink, Peter

AU - Denys, Damiaan

AU - Arnold, Paul D.

AU - Oostra, Ben A.

AU - Nestadt, Gerald

AU - Freimer, Nelson B.

AU - Pauls, David L.

AU - Wray, Naomi R.

AU - Stewart, S. Evelyn

AU - Mathews, Carol A.

AU - Knowles, James A.

AU - Cox, Nancy J.

AU - Scharf, Jeremiah M.

N1 - Funding Information: The following authors have read the journal's policy and have the following conflicts: CLBu: Currently receiving funding for TS clinical trials from Otsuka Pharmaceutical, JFL: recevies research support from NIH and Grifols, LLC as well royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press, MARic: received honoraria from Lundbeck, and research funding from Great-West Life Assurance Company of Canada and Eli Lilly Canada Ltd, MCR: grant from CNPq (Brazilian National Counsil) and has received research grants and/or consultancy honoraria from Novartis and Shire, DR: received consulting fees for Shire, JMS: received research support, honoraria and travel support from the Tourette Syndrome Association (TSA), DJS: received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Biocodex, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah, and Wyeth, TVF: received research funding from NIMH (K08 MH099424-01), the Simons Foundation, Allison Foundation, and Shire, PS: received research support for this study from the Tourette Syndrome Association (TSA), Tourette Syndrome Foundation of Canada and NIH, DY: received research support from the Tourette Syndrome Association (TSA) and NIH, MMR: received grants from the Tourette's Action-UK, TSA-USA, honoraria from Janssen-Cilag, and book royalties from Wiley - Blackwell, David Fulton/Granada/Taylor Francis, Oxford University Press and Jessica Kingsley Publishers, is a Patron of Tourette's Action (UK), sits on the Medical Advisory Board of the Italian Tourette Syndrome Association and The Tourette Syndrome Foundation of Canada, DAC: NIH/NIMH funding for K01 MH072952 and R34 MH090149, SLR: participated in research funded by Medtronic and Cyberonics, JRW: Past employee of F. Hoffmann-La Roche and current employee of Pfizer, SW: received lecture honoraria from Janssen Cilag, AstraZeneca and Eli Lilly, research funds Swiss National Science Foundation (SNF), Deutsche Forschungsgemeinschaft, EU FP7, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, JV: funding from Seaside Therapeutics, Novartis, Roche Pharmaceuticals, Forest, and SynapDx. Consulting/Advisory Board for Novartis, JTM: Tourette Syndrome Association-Speaker honoraria; Otuska-research grant; Roche-consultant; 1R01MH079487-01A1, JLK: honoraria from Roche, Eli Lilly, and Novartis, PDA: Unrestricted research grant from DNA Genotek SLG, HJG, ML, DLP, SES, NL, JHS, CLBa, LB, FB, GBB, OJB, MHB, RMB, RDB, DC, CC, JCCS, DCC, MCC, SC, DVC, EHC, VC, NJC, BAC, LKD, DDen, DDef, RD, EMD, YD, CKE, KE, PF, NBF, PJG, ERG, HG, MAG, BDG, VGT, SH, GLH, GAH, SMJH, PH, AGH, CI, JJ, MAJ, CLK, RAK, JAK, AIK, BK, RK, SHL, LL, CLi, CLo, TLL, FM, CAM, LMM, WM, SCMR, ECM, RM, JM, HM, DLM, ALN, BMN, GN, HN, WCO, BAO, RAO, LO, AJP, MTP, CNP, CP, YP, DP, TJR, VIR, MARid, GAR, SR, ARL, ASS, JS, BS, HSS, ES, JAT, AVVD, HV, MW, YW, JY, HGMW, PE, BC, RR have declared that no competing interests exist.

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84887265151&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1003864

DO - 10.1371/journal.pgen.1003864

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C2 - 24204291

AN - SCOPUS:84887265151

SN - 1553-7390

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

IS - 10

M1 - e1003864

ER -

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

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