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

LK Davis; DM Yu; CL Keenan; ER Gamazon; AI Konkashbaev; EM Derks; BM Neale; Jiaqi Yang; SH Lee; P Evans; CL Barr; L Bellodi; F Benarroch; GB Berrio; OJ Bienvenu; MH Bloch; RM Blom; RD Bruun; CL Budman; B Camarena; D Campbell; C Cappi; JCC Silgado; DC Cath; MC Cavallini; DA Chavira; S Chouinard; DV Conti; EH Cook; V Coric; BA Cullen; D Deforce; R Delorme; Y Dion; CK Edlund; K Egberts; P Falkai; TV Fernandez; PJ Gallagher; H Garrido; D Geller; SL Girard; HJ Grabe; MA Grados; BD Greenberg; V Gross-Tsur; S Haddad; GA Heiman; SMJ Hemmings; AG Hounie; C Illmann; J Jankovic; MA Jenike; JL Kennedy; RA King; B Kremeyer; R Kurlan; N Lanzagorta; M Leboyer; JF Leckman; L Lennertz; C Liu; C Lochner; TL Lowe; F Macciardi; JT McCracken; LM McGrath; SCM Restrepo; R Moessner; J Morgan; Heike Muller; DL Murphy; AL Naarden; WC Ochoa; RA Ophoff; L Osiecki; AJ Pakstis; MT Pato; CN Pato; J Piacentini; C Pittenger; Y Pollak; SL Rauch; TJ Renner; VI Reus; MA Richter; MA Riddle; MM Robertson; R Romero; MC Rosario; D Rosenberg; GA Rouleau; S Ruhrmann; A Ruiz-Linares; AS Sampaio; J Samuels; P Sandor; B Sheppard; HS Singer; JH Smit; DJ Stein; E Strengman; JA Tischfield; AVV Duarte; H Vallada; F Van Nieuwerburgh; J Veenstra-VanderWeele; S Walitza; Y Wang; JR Wendland; HGM Westenberg; YY Shugart; EC Miguel; W McMahon; M Wagner; H Nicolini; Daniëlle Posthuma; GL Hanna; P Heutink; D Denys; PD Arnold; Ben Oostra; G Nestadt; NB Freimer; DL Pauls; NR Wray; SE Stewart; CA Mathews; JA Knowles; NJ Cox; JM Scharf

doi:10.1371/journal.pgen.1003864

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

LK Davis, DM Yu, CL Keenan, ER Gamazon, AI Konkashbaev, EM Derks, BM Neale, Jiaqi Yang, SH Lee, P Evans, CL Barr, L Bellodi, F Benarroch, GB Berrio, OJ Bienvenu, MH Bloch, RM Blom, RD Bruun, CL Budman, B CamarenaD Campbell, C Cappi, JCC Silgado, DC Cath, MC Cavallini, DA Chavira, S Chouinard, DV Conti, EH Cook, V Coric, BA Cullen, D Deforce, R Delorme, Y Dion, CK Edlund, K Egberts, P Falkai, TV Fernandez, PJ Gallagher, H Garrido, D Geller, SL Girard, HJ Grabe, MA Grados, BD Greenberg, V Gross-Tsur, S Haddad, GA Heiman, SMJ Hemmings, AG Hounie, C Illmann, J Jankovic, MA Jenike, JL Kennedy, RA King, B Kremeyer, R Kurlan, N Lanzagorta, M Leboyer, JF Leckman, L Lennertz, C Liu, C Lochner, TL Lowe, F Macciardi, JT McCracken, LM McGrath, SCM Restrepo, R Moessner, J Morgan, Heike Muller, DL Murphy, AL Naarden, WC Ochoa, RA Ophoff, L Osiecki, AJ Pakstis, MT Pato, CN Pato, J Piacentini, C Pittenger, Y Pollak, SL Rauch, TJ Renner, VI Reus, MA Richter, MA Riddle, MM Robertson, R Romero, MC Rosario, D Rosenberg, GA Rouleau, S Ruhrmann, A Ruiz-Linares, AS Sampaio, J Samuels, P Sandor, B Sheppard, HS Singer, JH Smit, DJ Stein, E Strengman, JA Tischfield, AVV Duarte, H Vallada, F Van Nieuwerburgh, J Veenstra-VanderWeele, S Walitza, Y Wang, JR Wendland, HGM Westenberg, YY Shugart, EC Miguel, W McMahon, M Wagner, H Nicolini, Daniëlle Posthuma, GL Hanna, P Heutink, D Denys, PD Arnold, Ben Oostra, G Nestadt, NB Freimer, DL Pauls, NR Wray, SE Stewart, CA Mathews, JA Knowles, NJ Cox, JM Scharf

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

203 Citations (Scopus)

12 Downloads (Pure)

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
Journal	PLoS Genetics (print)
Volume	9
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1003864
Publication status	Published - 24 Oct 2013

Research programs

EMC MGC-02-96-01
EMC NIHES-04-55-01

Access to Document

10.1371/journal.pgen.1003864Licence: CC BY

Repub_68553_O-A.PDFFinal published version, 637 KBLicence: CC BY

http://hdl.handle.net/1765/68553Licence: CC BY

Cite this

Davis, LK., Yu, DM., 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., ... Scharf, JM. (2013). Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture. PLoS Genetics (print), 9(10). https://doi.org/10.1371/journal.pgen.1003864

@article{3e2d45ecb2c847fe97379b6e8c7d6a44,

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 = "LK Davis and DM Yu and CL Keenan and ER Gamazon and AI Konkashbaev and EM Derks and BM Neale and Jiaqi Yang and SH Lee and P Evans and CL Barr and L Bellodi and F Benarroch and GB Berrio and OJ Bienvenu and MH Bloch and RM Blom and RD Bruun and CL Budman and B Camarena and D Campbell and C Cappi and JCC Silgado and DC Cath and MC Cavallini and DA Chavira and S Chouinard and DV Conti and EH Cook and V Coric and BA Cullen and D Deforce and R Delorme and Y Dion and CK Edlund and K Egberts and P Falkai and TV Fernandez and PJ Gallagher and H Garrido and D Geller and SL Girard and HJ Grabe and MA Grados and BD Greenberg and V Gross-Tsur and S Haddad and GA Heiman and SMJ Hemmings and AG Hounie and C Illmann and J Jankovic and MA Jenike and JL Kennedy and RA King and B Kremeyer and R Kurlan and N Lanzagorta and M Leboyer and JF Leckman and L Lennertz and C Liu and C Lochner and TL Lowe and F Macciardi and JT McCracken and LM McGrath and SCM Restrepo and R Moessner and J Morgan and Heike Muller and DL Murphy and AL Naarden and WC Ochoa and RA Ophoff and L Osiecki and AJ Pakstis and MT Pato and CN Pato and J Piacentini and C Pittenger and Y Pollak and SL Rauch and TJ Renner and VI Reus and MA Richter and MA Riddle and MM Robertson and R Romero and MC Rosario and D Rosenberg and GA Rouleau and S Ruhrmann and A Ruiz-Linares and AS Sampaio and J Samuels and P Sandor and B Sheppard and HS Singer and JH Smit and DJ Stein and E Strengman and JA Tischfield and AVV Duarte and H Vallada and {Van Nieuwerburgh}, F and J Veenstra-VanderWeele and S Walitza and Y Wang and JR Wendland and HGM Westenberg and YY Shugart and EC Miguel and W McMahon and M Wagner and H Nicolini and Dani{\"e}lle Posthuma and GL Hanna and P Heutink and D Denys and PD Arnold and Ben Oostra and G Nestadt and NB Freimer and DL Pauls and NR Wray and SE Stewart and CA Mathews and JA Knowles and NJ Cox and JM Scharf",

year = "2013",

month = oct,

day = "24",

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

language = "English",

volume = "9",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

Davis, LK, Yu, DM, 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, Silgado, JCC, 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, Restrepo, SCM, 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, Rosario, 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, Duarte, AVV, 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, B, 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 (print), vol. 9, no. 10. 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, LK

AU - Yu, DM

AU - Keenan, CL

AU - Gamazon, ER

AU - Konkashbaev, AI

AU - Derks, EM

AU - Neale, BM

AU - Yang, Jiaqi

AU - Lee, SH

AU - Evans, P

AU - Barr, CL

AU - Bellodi, L

AU - Benarroch, F

AU - Berrio, GB

AU - Bienvenu, OJ

AU - Bloch, MH

AU - Blom, RM

AU - Bruun, RD

AU - Budman, CL

AU - Camarena, B

AU - Campbell, D

AU - Cappi, C

AU - Silgado, JCC

AU - Cath, DC

AU - Cavallini, MC

AU - Chavira, DA

AU - Chouinard, S

AU - Conti, DV

AU - Cook, EH

AU - Coric, V

AU - Cullen, BA

AU - Deforce, D

AU - Delorme, R

AU - Dion, Y

AU - Edlund, CK

AU - Egberts, K

AU - Falkai, P

AU - Fernandez, TV

AU - Gallagher, PJ

AU - Garrido, H

AU - Geller, D

AU - Girard, SL

AU - Grabe, HJ

AU - Grados, MA

AU - Greenberg, BD

AU - Gross-Tsur, V

AU - Haddad, S

AU - Heiman, GA

AU - Hemmings, SMJ

AU - Hounie, AG

AU - Illmann, C

AU - Jankovic, J

AU - Jenike, MA

AU - Kennedy, JL

AU - King, RA

AU - Kremeyer, B

AU - Kurlan, R

AU - Lanzagorta, N

AU - Leboyer, M

AU - Leckman, JF

AU - Lennertz, L

AU - Liu, C

AU - Lochner, C

AU - Lowe, TL

AU - Macciardi, F

AU - McCracken, JT

AU - McGrath, LM

AU - Restrepo, SCM

AU - Moessner, R

AU - Morgan, J

AU - Muller, Heike

AU - Murphy, DL

AU - Naarden, AL

AU - Ochoa, WC

AU - Ophoff, RA

AU - Osiecki, L

AU - Pakstis, AJ

AU - Pato, MT

AU - Pato, CN

AU - Piacentini, J

AU - Pittenger, C

AU - Pollak, Y

AU - Rauch, SL

AU - Renner, TJ

AU - Reus, VI

AU - Richter, MA

AU - Riddle, MA

AU - Robertson, MM

AU - Romero, R

AU - Rosario, MC

AU - Rosenberg, D

AU - Rouleau, GA

AU - Ruhrmann, S

AU - Ruiz-Linares, A

AU - Sampaio, AS

AU - Samuels, J

AU - Sandor, P

AU - Sheppard, B

AU - Singer, HS

AU - Smit, JH

AU - Stein, DJ

AU - Strengman, E

AU - Tischfield, JA

AU - Duarte, AVV

AU - Vallada, H

AU - Van Nieuwerburgh, F

AU - Veenstra-VanderWeele, J

AU - Walitza, S

AU - Wang, Y

AU - Wendland, JR

AU - Westenberg, HGM

AU - Shugart, YY

AU - Miguel, EC

AU - McMahon, W

AU - Wagner, M

AU - Nicolini, H

AU - Posthuma, Daniëlle

AU - Hanna, GL

AU - Heutink, P

AU - Denys, D

AU - Arnold, PD

AU - Oostra, Ben

AU - Nestadt, G

AU - Freimer, NB

AU - Pauls, DL

AU - Wray, NR

AU - Stewart, SE

AU - Mathews, CA

AU - Knowles, JA

AU - Cox, NJ

AU - Scharf, JM

PY - 2013/10/24

Y1 - 2013/10/24

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.

U2 - 10.1371/journal.pgen.1003864

DO - 10.1371/journal.pgen.1003864

M3 - Article

C2 - 21204291

SN - 1553-7390

VL - 9

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 10

ER -

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

Abstract

Research programs

Access to Document

Fingerprint

Cite this