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Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture

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., Camarena B., Campbell D., Cappi C., Cardona Silgado J. C., Cath D. C., Cavallini M. C., Chavira D. A., Chouinard S., Conti D. V., Cook E. H., Coric V., Cullen B. A., Deforce D., Delorme R., Dion Y., Edlund C. K., Egberts K., Falkai P., Fernandez T. V., Gallagher P. J., Garrido H., Geller D., Girard Simon, Grabe H. J., Grados M. A., Greenberg B. D., Gross-Tsur V., Haddad S., Heiman G. A., Hemmings S. M.J., Hounie A. G., Illmann C., Jankovic J., Jenike M. A., Kennedy J. L., King R. A., Kremeyer B., Kurlan R., Lanzagorta N., Leboyer M., Leckman J. F., Lennertz L., Liu C., Lochner C., Lowe T. L., Macciardi F., McCracken J. T., McGrath L. M., Mesa Restrepo S. C., Moessner R., Morgan J., Muller H., Murphy D. L., Naarden A. L., Ochoa W. C., Ophoff R. A., Osiecki L., Pakstis A. J., Pato M. T., Pato C. N., Piacentini J., Pittenger C., Pollak Y., Rauch S. L., Renner T. J., Reus V. I., Richter M. A., Riddle M. A., Robertson M. M., Romero R., Rosario M. C., Rosenberg D., Rouleau G. A., Ruhrmann S., Ruiz-Linares A., Sampaio A. S., Samuels J., Sandor P., Sheppard B., Singer H. S., Smit J. H., Stein D. J., Strengman E., Tischfield J. A., Valencia Duarte A. V., Vallada H., Van Nieuwerburgh F., Veenstra-Vanderweele J., Walitza S., Wang Y., Wendland J. R., Westenberg H. G.M., Shugart Y. Y., Miguel E. C., McMahon W., Wagner M., Nicolini H., Posthuma D., Hanna G. L., Heutink P., Denys D., Arnold P. D., Oostra B. A., Nestadt G., Freimer N. B., Pauls D. L., Wray N. R., Stewart S. E., Mathews C. A., Knowles J. A., Cox N. J. et Scharf J. M.. (2013). Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PloS Genetics, 9, (10), e1003864.

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URL officielle: http://dx.doi.org/doi:10.1371/journal.pgen.1003864

Résumé

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.

Type de document:Article publié dans une revue avec comité d'évaluation
ISSN:1553-7404 (Electronic) 1553-7390 (Linking)
Volume:9
Numéro:10
Pages:e1003864
Version évaluée par les pairs:Oui
Date:2013
Sujets:Sciences de la santé > Sciences médicales > Génétique
Département, module, service et unité de recherche:Départements et modules > Département des sciences fondamentales
Mots-clés:Tourette syndrome, obsessive-compulsive disorder, genetics, heridity, single nucleotide polymorphisms, SNPs, heritable quantitative traits
Déposé le:29 août 2019 23:56
Dernière modification:29 août 2019 23:56
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