Sex differences in the genetic architecture of obsessive-compulsive disorder

Imagem de Miniatura
Arquivos
art_KHRAMTSOVA_Sex_differences_in_the_genetic_architecture_of_obsessivecompulsive_2019.PDF (2.11 MB)
Citações na Scopus
37
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY
Autores
KHRAMTSOVA, Ekaterina A.
HELDMAN, Raphael
DERKS, Eske M.
YU, Dongmei
DAVIS, Lea K.
STRANGER, Barbara E.
ARNOLD, Paul D.
ASKLAND, Kathleen D.
BARLASSINA, Cristina
BELLODI, Laura
Citação
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, v.180, n.6, Special Issue, p.351-364, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex-dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex-combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD.
Palavras-chave
genetics, genome-wide association study, obsessive compulsive disorder, sex differences, sex-specific analysis, sex-specific genetic architecture
URI
https://observatorio.fm.usp.br/handle/OPI/33554
Referências
  1. Adams HHH, 2016, NAT NEUROSCI, V19, P1569, DOI 10.1038/nn.4398
  2. Aguet F, 2017, NATURE, V550, P204, DOI 10.1038/nature24277
  3. Anttila V, 2018, SCIENCE, V360, P1313, DOI 10.1126/science.aap8757
  4. Arnold PD, 2018, MOL PSYCHIATR, V23, P1181, DOI 10.1038/mp.2017.154
  5. Barban N, 2016, NAT GENET, V48, P1462, DOI 10.1038/ng.3698
  6. BELLODI L, 1992, PSYCHIAT RES, V42, P111, DOI 10.1016/0165-1781(92)90075-E
  7. Boileau Bernard, 2011, Dialogues Clin Neurosci, V13, P401
  8. Boraska V, 2014, MOL PSYCHIATR, V19, P1085, DOI 10.1038/mp.2013.187
  9. BROWN MB, 1975, BIOMETRICS, V31, P987, DOI 10.2307/2529826
  10. Bulik-Sullivan B, 2015, NAT GENET, V47, P1236, DOI 10.1038/ng.3406
  11. Bulik-Sullivan BK, 2015, NAT GENET, V47, P291, DOI 10.1038/ng.3211
  12. Cappi C, 2016, TRANSL PSYCHIAT, V6, DOI 10.1038/tp.2016.30
  13. Carapetis JR, 1999, ARCH DIS CHILD, V80, P353, DOI 10.1136/adc.80.4.353
  14. Clarke TK, 2017, MOL PSYCHIATR, V22, P1376, DOI 10.1038/mp.2017.153
  15. Davis LK, 2013, PLOS GENET, V9, DOI 10.1371/journal.pgen.1003864
  16. de Leeuw CA, 2015, PLOS COMPUT BIOL, V11, DOI 10.1371/journal.pcbi.1004219
  17. de Mathis MA, 2011, REV BRAS PSIQUIATR, V33, P390, DOI 10.1590/S1516-44462011000400014
  18. Delaneau O, 2013, NAT METHODS, V10, P5, DOI 10.1038/nmeth.2307
  19. den Braber A, 2016, TRANSL PSYCHIAT, V6, DOI 10.1038/tp.2015.223
  20. Duncan LE, 2018, MOL PSYCHIATR, V23, P666, DOI 10.1038/mp.2017.77
  21. FLAMENT MF, 1990, J CHILD PSYCHOL PSYC, V31, P363, DOI 10.1111/j.1469-7610.1990.tb01575.x
  22. Furberg H, 2010, NAT GENET, V42, P441, DOI 10.1038/ng.571
  23. Furtado M, 2015, PSYCHIAT RES, V229, P37, DOI 10.1016/j.psychres.2015.05.036
  24. Furtado M, 2015, PSYCHIAT RES, V229, P27, DOI 10.1016/j.psychres.2015.06.009
  25. Gao F, 2015, J HERED, V106, P666, DOI 10.1093/jhered/esv059
  26. Goodman WK, 2006, PSYCHIAT CLIN N AM, V29, P445, DOI 10.1016/j.psc.2006.02.003
  27. Graybiel AM, 2000, NEURON, V28, P343, DOI 10.1016/S0896-6273(00)00113-6
  28. Hammerschlag AR, 2017, NAT GENET, V49, P1584, DOI 10.1038/ng.3888
  29. Han B, 2011, AM J HUM GENET, V88, P586, DOI 10.1016/j.ajhg.2011.04.014
  30. Hartiala JA, 2016, NAT COMMUN, V7, DOI 10.1038/ncomms10558
  31. Heneka MT, 2015, NAT IMMUNOL, V16, P229, DOI 10.1038/ni.3102
  32. Hibar DP, 2017, NAT COMMUN, V8, DOI 10.1038/ncomms13624
  33. Hibar DP, 2015, NATURE, V520, P224, DOI 10.1038/nature14101
  34. Hou CD, 2005, STAT PROBABIL LETT, V73, P179, DOI 10.1016/j.spl.2004.11.028
  35. Howie B, 2011, G3-GENES GENOM GENET, V1, P457, DOI 10.1534/g3.111.001198
  36. Kantarci OH, 2006, NEUROLOGY, V67, P305, DOI 10.1212/01.wnl.0000225070.13682.11
  37. Kawikova I, 2007, BIOL PSYCHIAT, V61, P273, DOI 10.1016/j.biopsych.2006.06.012
  38. Kessler RC, 2005, ARCH GEN PSYCHIAT, V62, P593, DOI 10.1001/archpsyc.62.6.593
  39. Khramtsova EA, 2017, BIOINFORMATICS, V33, P432, DOI 10.1093/bioinformatics/btw641
  40. Kim Y, 2014, TRANSL PSYCHIAT, V4, DOI 10.1038/tp.2014.96
  41. Klein SL, 2016, NAT REV IMMUNOL, V16, P626, DOI 10.1038/nri.2016.90
  42. Kruse LM, 2012, J BONE JOINT SURG AM, V94A, P1485, DOI 10.2106/JBJS.K.01450
  43. LEONARD HL, 1992, ADV NEUROL, V58, P83
  44. Liu LY, 2012, HUM GENET, V131, P353, DOI 10.1007/s00439-011-1081-y
  45. Lochner C, 2004, EUR NEUROPSYCHOPHARM, V14, P105, DOI 10.1016/S0924-977X(03)00063-4
  46. Locke AE, 2015, NATURE, V518, P197, DOI 10.1038/nature14177
  47. Marazziti D, 1999, BIOL PSYCHIAT, V46, P810, DOI 10.1016/S0006-3223(98)00371-0
  48. Marsh SE, 2016, P NATL ACAD SCI USA, V113, pE1316, DOI 10.1073/pnas.1525466113
  49. Martin J., 2017, GENETIC INVESTIGATIO, DOI [10.1101/154088, DOI 10.1101/154088]
  50. Martin J, 2018, BIOL PSYCHIAT, V83, P1044, DOI 10.1016/j.biopsych.2017.11.026
  51. Mattheisen M, 2015, MOL PSYCHIATR, V20, P337, DOI 10.1038/mp.2014.43
  52. MIGUEL EC, 1995, J NEUROPSYCH CLIN N, V7, P507
  53. Mitra I, 2016, PLOS GENET, V12, DOI 10.1371/journal.pgen.1006425
  54. Murphy TK, 2012, J PEDIATR-US, V160, P314, DOI 10.1016/j.jpeds.2011.07.012
  55. Neale BM, 2010, J AM ACAD CHILD PSY, V49, P884, DOI 10.1016/j.jaac.2010.06.008
  56. Nestadt G, 2000, ARCH GEN PSYCHIAT, V57, P358, DOI 10.1001/archpsyc.57.4.358
  57. Nestadt G, 2010, PSYCHIAT CLIN N AM, V33, P141, DOI 10.1016/j.psc.2009.11.001
  58. Okbay A, 2016, NAT GENET, V48, P624, DOI 10.1038/ng.3552
  59. Okbay A, 2016, NATURE, V533, P539, DOI 10.1038/nature17671
  60. Orozco G, 2012, INT J EPIDEMIOL, V41, P1376, DOI 10.1093/ije/dys104
  61. Otowa T, 2016, MOL PSYCHIATR, V21, P1485, DOI 10.1038/mp.2016.11
  62. Pers TH, 2015, BIOINFORMATICS, V31, P418, DOI 10.1093/bioinformatics/btu655
  63. Pittenger C, 2011, PHARMACOL THERAPEUT, V132, P314, DOI 10.1016/j.pharmthera.2011.09.006
  64. Price AL, 2006, NAT GENET, V38, P904, DOI 10.1038/ng1847
  65. Purcell S, 2007, AM J HUM GENET, V81, P559, DOI 10.1086/519795
  66. Rahmioglu N, 2015, HUM MOL GENET, V24, P1185, DOI 10.1093/hmg/ddu516
  67. Raj T, 2014, SCIENCE, V344, P519, DOI 10.1126/science.1249547
  68. Randall JC, 2013, PLOS GENET, V9, DOI 10.1371/journal.pgen.1003500
  69. Ripke S, 2014, NATURE, V511, P421, DOI 10.1038/nature13595
  70. Ruscio AM, 2010, MOL PSYCHIATR, V15, P53, DOI 10.1038/mp.2008.94
  71. Scharf JM, 2013, MOL PSYCHIATR, V18, P721, DOI 10.1038/mp.2012.69
  72. Schumann G, 2016, P NATL ACAD SCI USA, V113, P14372, DOI 10.1073/pnas.1611243113
  73. Singh SK, 2016, MEDICINE, V95, DOI 10.1097/MD.0000000000005300
  74. Sklar P, 2011, NAT GENET, V43, P977, DOI 10.1038/ng.943
  75. Slattery MJ, 2004, J CLIN PSYCHIAT, V65
  76. Snider LA, 2004, MOL PSYCHIATR, V9, P900, DOI 10.1038/sj.mp.4001542
  77. Stewart SE, 2013, MOL PSYCHIATR, V18, P788, DOI 10.1038/mp.2012.85
  78. Sullivan PF, 2013, MOL PSYCHIATR, V18, P497, DOI 10.1038/mp.2012.21
  79. Swedo S. E., 2012, RES SUBGROUP CLIN SY
  80. SWEDO SE, 1989, ARCH GEN PSYCHIAT, V46, P335
  81. Swedo SE, 1998, AM J PSYCHIAT, V155, P264
  82. Taylor KC, 2013, BMC GENET, V14, DOI 10.1186/1471-2156-14-33
  83. Torres AR, 2005, REV BRAS PSIQUIATR, V27, P237, DOI 10.1590/S1516-44462005000300015
  84. van Grootheest DS, 2005, TWIN RES HUM GENET, V8, P450, DOI 10.1375/183242705774310060
  85. Watanabe K, 2017, NAT COMMUN, V8, DOI 10.1038/s41467-017-01261-5
  86. WEISSMAN MM, 1994, J CLIN PSYCHIAT, V55, P5
  87. Willer CJ, 2010, BIOINFORMATICS, V26, P2190, DOI 10.1093/bioinformatics/btq340
  88. Winkler TW, 2015, PLOS GENET, V11, DOI 10.1371/journal.pgen.1005378
  89. Yang JA, 2011, AM J HUM GENET, V88, P76, DOI 10.1016/j.ajhg.2010.11.011
  90. Yu DM, 2015, AM J PSYCHIAT, V172, P82, DOI 10.1176/appi.ajp.2014.13101306
  91. Zhuang Joanna J, 2009, BMC Proc, V3 Suppl 7, pS90

Coleções
Artigos e Materiais de Revistas Científicas - FM/MPS
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/21
Artigos e Materiais de Revistas Científicas - LIM/23