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

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

doi:10.1176/appi.ajp.2014.13101306

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

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

^*Corresponding author for this work

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

122 Scopus citations

Abstract

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identi fication 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. Method: The authors conducted aGWAS 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. Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide signi ficance, 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=2x10^-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). Conclusions: 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,OCDwith co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Original language	English
Pages (from-to)	82-93
Number of pages	12
Journal	American Journal of Psychiatry
Volume	172
Issue number	1
DOIs	https://doi.org/10.1176/appi.ajp.2014.13101306
State	Published - 1 Jan 2015
Externally published	Yes

Funding

Funders	Funder number
National Institute of Mental Health	K23MH085057, R01MH071507, R01MH085321, R13MH073250, K08MH099424, R01MH079494, P50MH094267, K23MH094613, R01MH092293, R25MH077823, U24MH068457, R01MH079489, R01MH090937
National Institute of Neurological Disorders and Stroke	R01NS040024, R01NS037484, R01NS016648, P30NS062691
National Cancer Institute	P01CA089392
National Institute on Drug Abuse	R01DA013423
National Center for Advancing Translational Sciences	KL2TR000431, UL1TR000430, UL1TR000142
Medical Research Council	MR/K01417X/1
European Commission	201550
National Institute on Alcohol Abuse and Alcoholism	U10AA008401
National Human Genome Research Institute	U01HG004446, U01HG004422, U01HG004438

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10.1176/appi.ajp.2014.13101306

Cite this

Yu, D., Mathews, C. A., Scharf, J. M., Neale, B. M., Davis, L. K., Gamazon, E. R., Derks, E. M., Evans, P., Edlund, C. K., Crane, J., Fagerness, J. A., Osiecki, L., Gallagher, P., Gerber, G., Haddad, S., Illmann, C., McGrath, L. M., Mayerfeld, C., Arepalli, S., ... Pauls, D. L. (2015). Cross-disorder genome-wide analyses suggest a complex genetic relationship between tourette's syndrome and OCD. American Journal of Psychiatry, 172(1), 82-93. https://doi.org/10.1176/appi.ajp.2014.13101306

@article{6d51dcf9d517403ba7b1be5b8fc9e85d,

title = "Cross-disorder genome-wide analyses suggest a complex genetic relationship between tourette's syndrome and OCD",

abstract = "Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identi fication 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. Method: The authors conducted aGWAS 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. Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide signi ficance, 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=2x10-4), 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). Conclusions: 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,OCDwith co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.",

author = "Dongmei Yu and Mathews, {Carol A.} and Scharf, {Jeremiah M.} and Neale, {Benjamin M.} and Davis, {Lea K.} and Gamazon, {Eric R.} and Derks, {Eske M.} and Patrick Evans and Edlund, {Christopher K.} and Jacquelyn Crane and Fagerness, {Jesen A.} and Lisa Osiecki and Patience Gallagher and Gloria Gerber and Stephen Haddad and Cornelia Illmann and McGrath, {Lauren M.} and Catherine Mayerfeld and Sampath Arepalli and Cristina Barlassina and Barr, {Cathy L.} and Laura Bellodi and Fortu Benarroch and Berri{\'o}, {Gabriel Bedoya} and Bienvenu, {O. Joseph} and Donald Black and Bloch, {Michael H.} and Helena Brentani and Bruun, {Ruth D.} and Budman, {Cathy L.} and Beatriz Camarena and Campbell, {Desmond D.} and Carolina Cappi and {Cardona Silgado}, {Julio C.} and Cavallini, {Maria C.} and Chavira, {Denise A.} and Sylvain Chouinard and Cook, {Edwin H.} and Cookson, {M. R.} and Vladimir Coric and Bernadette Cullen and Daniele Cusi and Richard Delorme and Damiaan Denys and Yves Dion and Valsama Eapen and Karin Egberts and Peter Falkai and Thomas Fernandez and Eduardo Fournier and Helena Garrido and Daniel Geller and Donald Gilbert and Girard, {Simon L.} and Grabe, {Hans J.} and Grados, {Marco A.} and Greenberg, {Benjamin D.} and Varda Gross-Tsur and Edna Gr{\"u}nblatt and John Hardy and Heiman, {Gary A.} and Hemmings, {Sian M.J.} and Herrera, {Luis D.} and Hezel, {Dianne M.} and Hoekstra, {Pieter J.} and Joseph Jankovic and Kennedy, {James L.} and King, {Robert A.} and Konkashbaev, {Anuar I.} 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 Sara Lupoli and Fabio Macciardi and Wolfgang Maier and Paolo Manunta and Maurizio Marconi and McCracken, {James T.} and {Mesa Restrepo}, {Sandra C.} and Rainald Moessner and Priya Moorjani and Jubel Morgan and Heike Muller and Murphy, {Dennis L.} and Naarden, {Allan L.} and Ochoa, {William Cornejo} and Ophoff, {Roel A.} 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 Tobias Renner 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 Stephan Ruhrmann and Chiara Sabatti and Erika Salvi and Sampaio, {Aline S.} and Jack Samuels and Paul Sandor and Service, {Susan K.} and Brooke Sheppard and Singer, {Harvey S.} and Smit, {Jan H.} and Stein, {Dan J.} and Eric Strengman and Tischfield, {Jay A.} and Maurizio Turiel and {Valencia Duarte}, {Ana V.} and Homero Vallada and Jeremy Veenstra-VanderWeele and Susanne Walitza and John Walkup and Ying Wang and Mike Weale and Robert Weiss and Wendland, {Jens R.} and Westenberg, {Herman G.M.} and Yin Yao and Hounie, {Ana G.} and Miguel, {Euripedes C.} and Humberto Nicolini and Michael Wagner and Andres Ruiz-Linares and Cath, {Danielle C.} and William McMahon and Danielle Posthuma and Oostra, {Ben A.} and Gerald Nestadt and Rouleau, {Guy A.} and Shaun Purcell and Jenike, {Michael A.} and Peter Heutink and Hanna, {Gregory L.} and Conti, {David V.} and Arnold, {Paul D.} and Nelson Freimer and Stewart, {S. Evelyn} and Knowles, {James A.} and Cox, {Nancy J.} and Pauls, {David L.}",

year = "2015",

month = jan,

day = "1",

doi = "10.1176/appi.ajp.2014.13101306",

language = "אנגלית",

volume = "172",

pages = "82--93",

journal = "American Journal of Psychiatry",

issn = "0002-953X",

publisher = "American Psychiatric Association",

number = "1",

}

Yu, D, Mathews, CA, Scharf, JM, Neale, BM, Davis, LK, Gamazon, ER, Derks, EM, Evans, P, Edlund, CK, Crane, J, Fagerness, JA, Osiecki, L, Gallagher, P, Gerber, G, Haddad, S, Illmann, C, McGrath, LM, Mayerfeld, C, Arepalli, S, Barlassina, C, Barr, CL, Bellodi, L, Benarroch, F, Berrió, GB, Bienvenu, OJ, Black, D, Bloch, MH, Brentani, H, Bruun, RD, Budman, CL, Camarena, B, Campbell, DD, Cappi, C, Cardona Silgado, JC, Cavallini, MC, Chavira, DA, Chouinard, S, Cook, EH, Cookson, MR, Coric, V, Cullen, B, Cusi, D, Delorme, R, Denys, D, Dion, Y, Eapen, V, Egberts, K, Falkai, P, Fernandez, T, Fournier, E, Garrido, H, Geller, D, Gilbert, D, Girard, SL, Grabe, HJ, Grados, MA, Greenberg, BD, Gross-Tsur, V, Grünblatt, E, Hardy, J, Heiman, GA, Hemmings, SMJ, Herrera, LD, Hezel, DM, Hoekstra, PJ, Jankovic, J, Kennedy, JL, King, RA, Konkashbaev, AI, Kremeyer, B, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, JF, Lennertz, L, Liu, C, Lochner, C, Lowe, TL, Lupoli, S, Macciardi, F, Maier, W, Manunta, P, Marconi, M, McCracken, JT, Mesa Restrepo, SC, Moessner, R, Moorjani, P, Morgan, J, Muller, H, Murphy, DL, Naarden, AL, Ochoa, WC, Ophoff, RA, Pakstis, AJ, Pato, MT, Pato, CN, Piacentini, J, Pittenger, C, Pollak, Y, Rauch, SL, Renner, T, Reus, VI, Richter, MA, Riddle, MA, Robertson, MM, Romero, R, Rosário, MC, Rosenberg, D, Ruhrmann, S, Sabatti, C, Salvi, E, Sampaio, AS, Samuels, J, Sandor, P, Service, SK, Sheppard, B, Singer, HS, Smit, JH, Stein, DJ, Strengman, E, Tischfield, JA, Turiel, M, Valencia Duarte, AV, Vallada, H, Veenstra-VanderWeele, J, Walitza, S, Walkup, J, Wang, Y, Weale, M, Weiss, R, Wendland, JR, Westenberg, HGM, Yao, Y, Hounie, AG, Miguel, EC, Nicolini, H, Wagner, M, Ruiz-Linares, A, Cath, DC, McMahon, W, Posthuma, D, Oostra, BA, Nestadt, G, Rouleau, GA, Purcell, S, Jenike, MA, Heutink, P, Hanna, GL, Conti, DV, Arnold, PD, Freimer, N, Stewart, SE, Knowles, JA, Cox, NJ & Pauls, DL 2015, 'Cross-disorder genome-wide analyses suggest a complex genetic relationship between tourette's syndrome and OCD', American Journal of Psychiatry, vol. 172, no. 1, pp. 82-93. https://doi.org/10.1176/appi.ajp.2014.13101306

TY - JOUR

T1 - Cross-disorder genome-wide analyses suggest a complex genetic relationship between tourette's syndrome and OCD

AU - Yu, Dongmei

AU - Mathews, Carol A.

AU - Scharf, Jeremiah M.

AU - Neale, Benjamin M.

AU - Davis, Lea K.

AU - Gamazon, Eric R.

AU - Derks, Eske M.

AU - Evans, Patrick

AU - Edlund, Christopher K.

AU - Crane, Jacquelyn

AU - Fagerness, Jesen A.

AU - Osiecki, Lisa

AU - Gallagher, Patience

AU - Gerber, Gloria

AU - Haddad, Stephen

AU - Illmann, Cornelia

AU - McGrath, Lauren M.

AU - Mayerfeld, Catherine

AU - Arepalli, Sampath

AU - Barlassina, Cristina

AU - Barr, Cathy L.

AU - Bellodi, Laura

AU - Benarroch, Fortu

AU - Berrió, Gabriel Bedoya

AU - Bienvenu, O. Joseph

AU - Black, Donald

AU - Bloch, Michael H.

AU - Brentani, Helena

AU - Bruun, Ruth D.

AU - Budman, Cathy L.

AU - Camarena, Beatriz

AU - Campbell, Desmond D.

AU - Cappi, Carolina

AU - Cardona Silgado, Julio C.

AU - Cavallini, Maria C.

AU - Chavira, Denise A.

AU - Chouinard, Sylvain

AU - Cook, Edwin H.

AU - Cookson, M. R.

AU - Coric, Vladimir

AU - Cullen, Bernadette

AU - Cusi, Daniele

AU - Delorme, Richard

AU - Denys, Damiaan

AU - Dion, Yves

AU - Eapen, Valsama

AU - Egberts, Karin

AU - Falkai, Peter

AU - Fernandez, Thomas

AU - Fournier, Eduardo

AU - Garrido, Helena

AU - Geller, Daniel

AU - Gilbert, Donald

AU - Girard, Simon L.

AU - Grabe, Hans J.

AU - Grados, Marco A.

AU - Greenberg, Benjamin D.

AU - Gross-Tsur, Varda

AU - Grünblatt, Edna

AU - Hardy, John

AU - Heiman, Gary A.

AU - Hemmings, Sian M.J.

AU - Herrera, Luis D.

AU - Hezel, Dianne M.

AU - Hoekstra, Pieter J.

AU - Jankovic, Joseph

AU - Kennedy, James L.

AU - King, Robert A.

AU - Konkashbaev, Anuar I.

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 - Lupoli, Sara

AU - Macciardi, Fabio

AU - Maier, Wolfgang

AU - Manunta, Paolo

AU - Marconi, Maurizio

AU - McCracken, James T.

AU - Mesa Restrepo, Sandra C.

AU - Moessner, Rainald

AU - Moorjani, Priya

AU - Morgan, Jubel

AU - Muller, Heike

AU - Murphy, Dennis L.

AU - Naarden, Allan L.

AU - Ochoa, William Cornejo

AU - Ophoff, Roel A.

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

AU - Reus, Victor I.

AU - Richter, Margaret A.

AU - Riddle, Mark A.

AU - Robertson, Mary M.

AU - Romero, Roxana

AU - Rosário, Maria C.

AU - Rosenberg, David

AU - Ruhrmann, Stephan

AU - Sabatti, Chiara

AU - Salvi, Erika

AU - Sampaio, Aline S.

AU - Samuels, Jack

AU - Sandor, Paul

AU - Service, Susan K.

AU - Sheppard, Brooke

AU - Singer, Harvey S.

AU - Smit, Jan H.

AU - Stein, Dan J.

AU - Strengman, Eric

AU - Tischfield, Jay A.

AU - Turiel, Maurizio

AU - Valencia Duarte, Ana V.

AU - Vallada, Homero

AU - Veenstra-VanderWeele, Jeremy

AU - Walitza, Susanne

AU - Walkup, John

AU - Wang, Ying

AU - Weale, Mike

AU - Weiss, Robert

AU - Wendland, Jens R.

AU - Westenberg, Herman G.M.

AU - Yao, Yin

AU - Hounie, Ana G.

AU - Miguel, Euripedes C.

AU - Nicolini, Humberto

AU - Wagner, Michael

AU - Ruiz-Linares, Andres

AU - Cath, Danielle C.

AU - McMahon, William

AU - Posthuma, Danielle

AU - Oostra, Ben A.

AU - Nestadt, Gerald

AU - Rouleau, Guy A.

AU - Purcell, Shaun

AU - Jenike, Michael A.

AU - Heutink, Peter

AU - Hanna, Gregory L.

AU - Conti, David V.

AU - Arnold, Paul D.

AU - Freimer, Nelson

AU - Stewart, S. Evelyn

AU - Knowles, James A.

AU - Cox, Nancy J.

AU - Pauls, David L.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identi fication 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. Method: The authors conducted aGWAS 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. Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide signi ficance, 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=2x10-4), 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). Conclusions: 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,OCDwith co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

AB - Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identi fication 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. Method: The authors conducted aGWAS 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. Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide signi ficance, 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=2x10-4), 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). Conclusions: 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,OCDwith co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

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C2 - 25158072

AN - SCOPUS:84920191001

SN - 0002-953X

VL - 172

SP - 82

EP - 93

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

IS - 1

ER -

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

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