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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.

SUBMITTER: Davis LK 

PROVIDER: S-EPMC3812053 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Davis Lea K LK   Yu Dongmei D   Keenan Clare L CL   Gamazon Eric R ER   Konkashbaev Anuar I AI   Derks Eske M EM   Neale Benjamin M BM   Yang Jian J   Lee S Hong SH   Evans Patrick P   Barr Cathy L CL   Bellodi Laura L   Benarroch Fortu F   Berrio Gabriel Bedoya GB   Bienvenu Oscar J OJ   Bloch Michael H MH   Blom Rianne M RM   Bruun Ruth D RD   Budman Cathy L CL   Camarena Beatriz B   Campbell Desmond D   Cappi Carolina C   Cardona Silgado Julio C JC   Cath Danielle C DC   Cavallini Maria C MC   Chavira Denise A DA   Chouinard Sylvain S   Conti David V DV   Cook Edwin H EH   Coric Vladimir V   Cullen Bernadette A BA   Deforce Dieter D   Delorme Richard R   Dion Yves Y   Edlund Christopher K CK   Egberts Karin K   Falkai Peter P   Fernandez Thomas V TV   Gallagher Patience J PJ   Garrido Helena H   Geller Daniel D   Girard Simon L SL   Grabe Hans J HJ   Grados Marco A MA   Greenberg Benjamin D BD   Gross-Tsur Varda V   Haddad Stephen S   Heiman Gary A GA   Hemmings Sian M J SM   Hounie Ana G AG   Illmann Cornelia C   Jankovic Joseph J   Jenike Michael A MA   Kennedy James L JL   King Robert A RA   Kremeyer Barbara B   Kurlan Roger R   Lanzagorta Nuria N   Leboyer Marion M   Leckman James F JF   Lennertz Leonhard L   Liu Chunyu C   Lochner Christine C   Lowe Thomas L TL   Macciardi Fabio F   McCracken James T JT   McGrath Lauren M LM   Mesa Restrepo Sandra C SC   Moessner Rainald R   Morgan Jubel J   Muller Heike H   Murphy Dennis L DL   Naarden Allan L AL   Ochoa William Cornejo WC   Ophoff Roel A RA   Osiecki Lisa L   Pakstis Andrew J AJ   Pato Michele T MT   Pato Carlos N CN   Piacentini John J   Pittenger Christopher C   Pollak Yehuda Y   Rauch Scott L SL   Renner Tobias J TJ   Reus Victor I VI   Richter Margaret A MA   Riddle Mark A MA   Robertson Mary M MM   Romero Roxana R   Rosàrio Maria C MC   Rosenberg David D   Rouleau Guy A GA   Ruhrmann Stephan S   Ruiz-Linares Andres A   Sampaio Aline S AS   Samuels Jack J   Sandor Paul P   Sheppard Brooke B   Singer Harvey S HS   Smit Jan H JH   Stein Dan J DJ   Strengman E E   Tischfield Jay A JA   Valencia Duarte Ana V AV   Vallada Homero H   Van Nieuwerburgh Filip F   Veenstra-Vanderweele Jeremy J   Walitza Susanne S   Wang Ying Y   Wendland Jens R JR   Westenberg Herman G M HG   Shugart Yin Yao YY   Miguel Euripedes C EC   McMahon William W   Wagner Michael M   Nicolini Humberto H   Posthuma Danielle D   Hanna Gregory L GL   Heutink Peter P   Denys Damiaan D   Arnold Paul D PD   Oostra Ben A BA   Nestadt Gerald G   Freimer Nelson B NB   Pauls David L DL   Wray Naomi R NR   Stewart S Evelyn SE   Mathews Carol A CA   Knowles James A JA   Cox Nancy J NJ   Scharf Jeremiah M JM  

PLoS genetics 20131024 10

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 o  ...[more]

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