Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette's Syndrome and OCD
Carregando...
Citações na Scopus
111
Tipo de produção
article
Data de publicação
2015
Título da Revista
ISSN da Revista
Título do Volume
Editora
AMER PSYCHIATRIC PUBLISHING, INC
Autores
YU, Dongmei
MATHEWS, Carol A.
SCHARF, Jeremiah M.
NEALE, Benjamin M.
DAVIS, Lea K.
GAMAZON, Eric R.
DERKS, Eske M.
EVANS, Patrick
EDLUND, Christopher K.
CRANE, Jacquelyn
Citação
AMERICAN JOURNAL OF PSYCHIATRY, v.172, n.1, p.82-93, 2015
Resumo
Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
Palavras-chave
Referências
- Bloch MH, 2006, MOL PSYCHIATR, V11, P622, DOI 10.1038/sj.mp.4001823
- Bolton D, 2007, PSYCHOL MED, V37, P39, DOI 10.1017/S0033291706008816
- Cavallini MC, 1999, AM J MED GENET, V88, P38, DOI 10.1002/(SICI)1096-8628(19990205)88:1<38::AID-AJMG7>3.0.CO;2-#
- Como Peter G, 2005, Adv Neurol, V96, P249
- Altshuler D, 2010, NATURE, V467, P1061, DOI 10.1038/nature09534
- Davis LK, 2013, PLOS GENET, V9, DOI 10.1371/journal.pgen.1003864
- do Rosario-Campos MC, 2005, AM J MED GENET B, V136B, P92, DOI 10.1002/ajmg.b.30149
- Dudbridge F, 2008, GENET EPIDEMIOL, V32, P227, DOI 10.1002/gepi.20297
- Ercan-Sencicek AG, 2010, NEW ENGL J MED, V362, P1901, DOI 10.1056/NEJMoa0907006
- Grados MA, 2008, BIOL PSYCHIAT, V64, P219, DOI 10.1016/j.biopsych.2008.01.019
- Howie BN, 2009, PLOS GENET, V5, DOI 10.1371/journal.pgen.1000529
- Kovas Y, 2006, TRENDS COGN SCI, V10, P198, DOI 10.1016/j.tics.2006.03.001
- LECKMAN JF, 1994, ANXIETY, V1, P208
- March JS, 2007, BIOL PSYCHIAT, V61, P344, DOI 10.1016/j.biopsych.2006.09.035
- Mathews CA, 2011, J AM ACAD CHILD PSY, V50, P46, DOI 10.1016/j.jaac.2010.10.004
- Miguel EC, 2000, J CLIN PSYCHIAT, V61, P150
- O'Roak BJ, 2010, MOL PSYCHIATR, V15, P447, DOI 10.1038/mp.2009.105
- O'Rourke JA, 2009, J PSYCHOSOM RES, V67, P533, DOI 10.1016/j.jpsychores.2009.06.006
- Pauls DL, 2008, AM J MED GENET C, V148C, P133, DOI 10.1002/ajmg.c.30168
- PAULS DL, 1986, ARCH GEN PSYCHIAT, V43, P1180
- PAULS DL, 1992, PSYCHIAT CLIN N AM, V15, P759
- Pe'er I, 2008, GENET EPIDEMIOL, V32, P381, DOI 10.1002/gepi.20303
- Price AL, 2006, NAT GENET, V38, P904, DOI 10.1038/ng1847
- Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011, NAT GENET, V43, P977
- Purcell S, 2007, AM J HUM GENET, V81, P559, DOI 10.1086/519795
- Purcell SM, 2009, NATURE, V460, P748, DOI 10.1038/nature08185
- Rauch S L, 2001, Adv Neurol, V85, P207
- Scharf JM, 2010, NEUROLOGY, V74, P1564, DOI 10.1212/WNL.0b013e3181e24161
- Scharf JM, 2013, MOL PSYCHIATR, V18, P721, DOI 10.1038/mp.2012.69
- Sheppard DM, 1999, CLIN PSYCHOL REV, V19, P531, DOI 10.1016/S0272-7358(98)00059-2
- Stewart SE, 2013, MOL PSYCHIATR, V18, P788, DOI 10.1038/mp.2012.85
- Sundaram SK, 2010, NEUROLOGY, V74, P1583, DOI 10.1212/WNL.0b013e3181e0f147
- The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, 2011, NAT GENET, V43, P969, DOI 10.1038/ng.940
- Willer CJ, 2010, BIOINFORMATICS, V26, P2190, DOI 10.1093/bioinformatics/btq340
- Zhang DD, 2010, AM J HUM GENET, V86, P411, DOI 10.1016/j.ajhg.2010.02.005