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. 2013 Oct;9(10):e1003864.
doi: 10.1371/journal.pgen.1003864. Epub 2013 Oct 24.

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

Lea K Davis  1 Dongmei YuClare L KeenanEric R GamazonAnuar I KonkashbaevEske M DerksBenjamin M NealeJian YangS Hong LeePatrick EvansCathy L BarrLaura BellodiFortu BenarrochGabriel Bedoya BerrioOscar J BienvenuMichael H BlochRianne M BlomRuth D BruunCathy L BudmanBeatriz CamarenaDesmond CampbellCarolina CappiJulio C Cardona SilgadoDanielle C CathMaria C CavalliniDenise A ChaviraSylvain ChouinardDavid V ContiEdwin H CookVladimir CoricBernadette A CullenDieter DeforceRichard DelormeYves DionChristopher K EdlundKarin EgbertsPeter FalkaiThomas V FernandezPatience J GallagherHelena GarridoDaniel GellerSimon L GirardHans J GrabeMarco A GradosBenjamin D GreenbergVarda Gross-TsurStephen HaddadGary A HeimanSian M J HemmingsAna G HounieCornelia IllmannJoseph JankovicMichael A JenikeJames L KennedyRobert A KingBarbara KremeyerRoger KurlanNuria LanzagortaMarion LeboyerJames F LeckmanLeonhard LennertzChunyu LiuChristine LochnerThomas L LoweFabio MacciardiJames T McCrackenLauren M McGrathSandra C Mesa RestrepoRainald MoessnerJubel MorganHeike MullerDennis L MurphyAllan L NaardenWilliam Cornejo OchoaRoel A OphoffLisa OsieckiAndrew J PakstisMichele T PatoCarlos N PatoJohn PiacentiniChristopher PittengerYehuda PollakScott L RauchTobias J RennerVictor I ReusMargaret A RichterMark A RiddleMary M RobertsonRoxana RomeroMaria C RosàrioDavid RosenbergGuy A RouleauStephan RuhrmannAndres Ruiz-LinaresAline S SampaioJack SamuelsPaul SandorBrooke SheppardHarvey S SingerJan H SmitDan J SteinE StrengmanJay A TischfieldAna V Valencia DuarteHomero ValladaFilip Van NieuwerburghJeremy Veenstra-VanderweeleSusanne WalitzaYing WangJens R WendlandHerman G M WestenbergYin Yao ShugartEuripedes C MiguelWilliam McMahonMichael WagnerHumberto NicoliniDanielle PosthumaGregory L HannaPeter HeutinkDamiaan DenysPaul D ArnoldBen A OostraGerald NestadtNelson B FreimerDavid L PaulsNaomi R WrayS Evelyn StewartCarol A MathewsJames A KnowlesNancy J CoxJeremiah M Scharf
Affiliations
Free PMC article

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

Lea K Davis et al. PLoS Genet. .
Free PMC article

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.

Conflict of interest statement

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.

Figures

Figure 1
Figure 1. Tourette Syndrome heritability by chromosome.
Heritability (y-axis) per chromosome is plotted against chromosome length (x-axis). The red line represents heritability regressed on chromosome length and the 95% confidence interval around the slope of the regression model is represented by the red dashed lines. The black line represents the expected heritability per chromosome (based on size) regressed on chromosome length. Chromosomes 2, 5, 11, 12, 16, and 20 fall outside of the 95% confidence interval and appear to account for more heritability than expected based on chromosome length.
Figure 2
Figure 2. Obsessive-compulsive disorder heritability by chromosome.
Heritability (y-axis) per chromosome is plotted against chromosome length (x-axis). The red line represents heritability regressed on chromosome length and the 95% confidence interval around the slope of the regression model is represented by the red dashed lines. The black line represents the expected heritability per chromosome (based on size) regressed on chromosome length. Chromosome 15 is shown in red to highlight its extreme deviation from the expected heritability based on chromosome length. Chromosomes 3, 10, 13, and 17 are also outside of the 95% interval and appear to account for more heritability than expected based on chromosome length.
Figure 3
Figure 3. Heritability by minor allele frequency.
The x-axis represents all minor allele frequency bins tested while the y-axis represents resultant heritability in a given bin. Blue bars indicate TS and red bars indicate OCD. Error bars are shown.

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