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

English version České info

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.

Vyšlo v časopise: Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture. PLoS Genet 9(10): e32767. doi:10.1371/journal.pgen.1003864
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003864

Souhrn

Zdroje

1. ManolioTA, CollinsFS, CoxNJ, GoldsteinDB, HindorffLA, et al. (2009) Finding the missing heritability of complex diseases. Nature 461 : 747–753.

2. ZukO, HechterE, SunyaevSR, LanderES (2012) The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci U S A 109 : 1193–1198.

3. EichlerEE, FlintJ, GibsonG, KongA, LealSM, et al. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11 : 446–450.

4. LeeSH, WrayNR, GoddardME, VisscherPM (2011) Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet 88 : 294–305.

5. YangJ, LeeSH, GoddardME, VisscherPM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88 : 76–82.

6. KleiL, SandersSJ, MurthaMT, HusV, LoweJK, et al. (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3 : 9.

7. KellerMF, SaadM, BrasJ, BettellaF, NicolaouN, et al. (2012) Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease. Hum Mol Genet 21 : 4996–5009.

8. LeeSH, YangJ, GoddardME, VisscherPM, WrayNR (2012) Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics 28 : 2540–2542.

9. MiguelEC, do Rosario-CamposMC, PradoHS, do ValleR, RauchSL, et al. (2000) Sensory phenomena in obsessive-compulsive disorder and Tourette's disorder. J Clin Psychiatry 61 : 150–156; quiz 157.

10. MiguelEC, BaerL, CoffeyBJ, RauchSL, SavageCR, et al. (1997) Phenomenological differences appearing with repetitive behaviours in obsessive-compulsive disorder and Gilles de la Tourette's syndrome. Br J Psychiatry 170 : 140–145.

11. FerraoYA, MiguelE, SteinDJ (2009) Tourette's syndrome, trichotillomania, and obsessive-compulsive disorder: how closely are they related? Psychiatry Res 170 : 32–42.

12. GraybielAM (2008) Habits, rituals, and the evaluative brain. Annu Rev Neurosci 31 : 359–387.

13. HarrisonBJ, PujolJ, CardonerN, DeusJ, AlonsoP, et al. (2013) Brain corticostriatal systems and the major clinical symptom dimensions of obsessive-compulsive disorder. Biol Psychiatry 73 : 321–328.

14. WangL, LeeDY, BaileyE, HartleinJM, GadoMH, et al. (2007) Validity of large-deformation high dimensional brain mapping of the basal ganglia in adults with Tourette syndrome. Psychiatry Res 154 : 181–190.

15. PaulsDL (1992) The genetics of obsessive compulsive disorder and Gilles de la Tourette's syndrome. Psychiatr Clin North Am 15 : 759–766.

16. van GrootheestDS, CathDC, BeekmanAT, BoomsmaDI (2005) Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet 8 : 450–458.

17. MathewsCA, GreenwoodT, WesselJ, AzzamA, GarridoH, et al. (2008) Evidence for a heritable unidimensional symptom factor underlying obsessionality. Am J Med Genet B Neuropsychiatr Genet 147B: 676–685.

18. GradosMA, MathewsCA (2008) Latent class analysis of gilles de la tourette syndrome using comorbidities: clinical and genetic implications. Biol Psychiatry 64 : 219–225.

19. KaterbergH, DelucchiKL, StewartSE, LochnerC, DenysDA, et al. (2010) Symptom dimensions in OCD: item-level factor analysis and heritability estimates. Behav Genet 40 : 505–517.

20. van GrootheestDS, CathD, HottengaJJ, BeekmanAT, BoomsmaDI (2009) Genetic factors underlie stability of obsessive-compulsive symptoms. Twin Res Hum Genet 12 : 411–419.

21. KiddKK, HeimbuchRC, RecordsMA, OehlertG, WebsterRL (1980) Familial stuttering patterns are not related to one measure of severity. J Speech Hear Res 23 : 539–545.

22. KiddKK, PrusoffBA, CohenDJ (1980) Familial pattern of Gilles de la Tourette syndrome. Arch Gen Psychiatry 37 : 1336–1339.

23. KanoY, OhtaM, NagaiY, PaulsDL, LeckmanJF (2001) A family study of Tourette syndrome in Japan. Am J Med Genet 105 : 414–421.

24. PaulsDL, RaymondCL, StevensonJM, LeckmanJF (1991) A family study of Gilles de la Tourette syndrome. Am J Hum Genet 48 : 154–163.

25. HebebrandJ, KlugB, FimmersR, SeuchterSA, Wettke-SchaferR, et al. (1997) Rates for tic disorders and obsessive compulsive symptomatology in families of children and adolescents with Gilles de la Tourette syndrome. J Psychiatr Res 31 : 519–530.

26. PriceRA, KiddKK, CohenDJ, PaulsDL, LeckmanJF (1985) A twin study of Tourette syndrome. Arch Gen Psychiatry 42 : 815–820.

27. BoltonD, RijsdijkF, O'ConnorTG, PerrinS, EleyTC (2007) Obsessive-compulsive disorder, tics and anxiety in 6-year-old twins. Psychol Med 37 : 39–48.

28. LichtensteinP, CarlstromE, RastamM, GillbergC, AnckarsaterH (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167 : 1357–1363.

29. O'RourkeJA, ScharfJM, YuD, PaulsDL (2009) The genetics of Tourette syndrome: a review. J Psychosom Res 67 : 533–545.

30. ScharfJM, YuD, MathewsCA, NealeBM, StewartSE, et al. (2012) Genome-wide association study of Tourette's syndrome. Mol Psychiatry 18 (6) 721–8.

31. StewartSE, YuD, ScharfJM, NealeBM, FagernessJA, et al. (2012) Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 18 (7) 788–98.

32. PattersonN, PriceAL, ReichD (2006) Population structure and eigenanalysis. PLoS Genet 2: e190.

33. KarnoM, GoldingJM, SorensonSB, BurnamMA (1988) The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry 45 : 1094–1099.

34. KhalifaN, von KnorringAL (2003) Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Dev Med Child Neurol 45 : 315–319.

35. WangHS, KuoMF (2003) Tourette's syndrome in Taiwan: an epidemiological study of tic disorders in an elementary school at Taipei County. Brain Dev 25 Suppl 1: S29–31.

36. LanziG, ZambrinoCA, TermineC, PalestraM, Ferrari GinevraO, et al. (2004) Prevalence of tic disorders among primary school students in the city of Pavia, Italy. Arch Dis Child 89 : 45–47.

37. WangK, LiM, HakonarsonH (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38: e164.

38. GamazonER, BadnerJA, ChengL, ZhangC, ZhangD, et al. (2012) Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry 18 (3) 340–6.

39. ElbeinSC, KernPA, RasouliN, Yao-BorengasserA, SharmaNK, et al. (2011) Global gene expression profiles of subcutaneous adipose and muscle from glucose-tolerant, insulin-sensitive, and insulin-resistant individuals matched for BMI. Diabetes 60 : 1019–1029.

40. ElbeinSC, GamazonER, DasSK, RasouliN, KernPA, et al. (2012) Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture? Am J Hum Genet 91 : 466–477.

41. JohnsonWE, LiC, RabinovicA (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8 : 118–127.

42. LeekJT, StoreyJD (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3 : 1724–1735.

43. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 : 559–575.

44. LiY, WillerCJ, DingJ, ScheetP, AbecasisGR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34 : 816–834.

45. LiY, WillerC, SannaS, AbecasisG (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10 : 387–406.

46. NestadtG, SamuelsJ, RiddleM, BienvenuOJ3rd, LiangKY, et al. (2000) A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 57 : 358–363.

47. HannaGL, HimleJA, CurtisGC, GillespieBW (2005) A family study of obsessive-compulsive disorder with pediatric probands. Am J Med Genet B Neuropsychiatr Genet 134B: 13–19.

48. LeeSH, HaroldD, NyholtDR, GoddardME, ZondervanKT, et al. (2013) Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum Mol Genet 22 : 832–841.

49. Scharf JM, Pauls D (2007) Genetics of tic disorders. In: D.L. R, M. CJ, R.E. P, R. KB, editors. Principles and Pracitices of Medical Genetics. 5th ed. New York: Elsevier. pp. 2737–2754.

50. Consortium C-DGotPG (2013) Genetic relationships between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45 (9) 984–94.

51. YangJ, ManolioTA, PasqualeLR, BoerwinkleE, CaporasoN, et al. (2011) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43 : 519–525.

52. ShugartYY, SamuelsJ, WillourVL, GradosMA, GreenbergBD, et al. (2006) Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol Psychiatry 11 : 763–770.

53. RossJ, BadnerJ, GarridoH, SheppardB, ChaviraDA, et al. (2011) Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD. Hum Genet 130 : 795–805.

54. ShaoY, CuccaroML, HauserER, RaifordKL, MenoldMM, et al. (2003) Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet 72 : 539–548.

55. DelahantyRJ, KangJQ, BruneCW, KistnerEO, CourchesneE, et al. (2011) Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry 16 : 86–96.

56. DoornbosM, Sikkema-RaddatzB, RuijvenkampCA, DijkhuizenT, BijlsmaEK, et al. (2009) Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 52 : 108–115.

57. NestadtG, WangY, GradosMA, RiddleMA, GreenbergBD, et al. (2012) Homeobox genes in obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 159B: 53–60.

58. SwedoSE, LeonardHL, GarveyM, MittlemanB, AllenAJ, et al. (1998) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155 : 264–271.

59. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43 : 969–976.

60. Gamazon E, Im H, Liu C, Nicolae D, Cox N (2012) The convergence of functional genomics, heritability estimation, and polygenic modeling: Emerging spectrum of alleleic variation in bipolar disorder. arXiv:submit/0682261.

61. DavisLK, GamazonER, Kistner-GriffinE, BadnerJA, LiuC, et al. (2012) Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci. Mol Autism 3 : 3.