Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants

Human Molecular Genetics

Volumn 24, Issue 16, 2015, Pages 4674-4685

  Duan, Jubao ^a,b   Sanders, Alan R ^a,b   Moy, Winton ^a,b   Drigalenko, Eugene I ^c   Brown, Eric C ^a   Freda, Jessica ^a   Leites, Catherine ^a   Göring, Harald H H ^c   Gejman, Pablo V ^a,b   Levinson, D F ^d   Shi, J ^d   Buccola, N G ^d   Mowry, B J ^d   Freedman, R ^d   Olincy, A ^d   Amin, F ^d   Black, D W ^d   Silverman, J M ^d   Byerley, W F ^d   Svrakic, D M ^d   Cloninger, C ^d   more..

^a NORTHSHORE UNIVERSITY HEALTHSYSTEM   (United States)

^b UNIVERSITY OF CHICAGO   (United States)

^c SOUTHWEST FOUNDATION FOR BIOMEDICAL RESEARCH   (United States)

^d Molecular Genetics of Schizophrenia (MGS) Collaboration   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANAPHASE PROMOTING COMPLEX SUBUNIT 10; DNA; LIM DOMAINS CONTAINING 1; LIM PROTEIN; SEMAPHORIN; SEMAPHORIN 6A; TRANSCRIPTOME; UNCLASSIFIED DRUG;

ADULT; ALLELE; ARID1B GENE; ARTICLE; CHST11 GENE; CONTROLLED STUDY; DENDRITE; DEVELOPMENTAL DISORDER; DNA SEQUENCE; EPIGENETICS; EXON; FARS2 GENE; FEMALE; FRAMESHIFT MUTATION; FUNCTIONAL GENOMICS; GENE; GENE DELETION; GENE DOSAGE; GENE DUPLICATION; GENE EXPRESSION; GENE SEQUENCE; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; HUMAN CELL; KIAA1586 GENE; MOLECULAR PATHOLOGY; MOTONEURON; NCOA7 GENE; NERVE CELL GROWTH; NEURODEVELOPMENTAL DISORDER; NEUROLOGIC DISEASE; OAS2 GENE; PRIORITY JOURNAL; RNA ANALYSIS; RNA SEQUENCE; RNA STABILITY; SCFD2 GENE; SCHIZOPHRENIA; STOP CODON; TIFA GENE; TRANSCRIPTOME OUTLIER ANALYSIS; TRIB3 GENE; UQCR10 GENE; WHOLE GENOME SEQUENCING; GENETIC EPIGENESIS; GENETIC PREDISPOSITION; GENETIC VARIATION; GENETICS; MALE; METABOLISM;

EPIGENESIS, GENETIC; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; HUMANS; MALE; SCHIZOPHRENIA; TRANSCRIPTOME;

EID: 84939522785     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddv199     Document Type: Article

References (73)

1. McGuffin, P., Farmer, A.E., Gottesman, I.I., Murray, R.M. and Reveley, A.M. (1984) Twin concordance for operationally defined schizophrenia. Confirmation of familiality and heritability. Arch. Gen. Psychiatry, 41, 541-545.
2. Shi, J., Levinson, D.F., Duan, J., Sanders, A.R., Zheng, Y., Pe'er, I., Dudbridge, F., Holmans, P.A., Whittemore, A.S., Mowry, B.J. et al. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature, 460, 753-757.
3. International Schizophrenia ConsortiumPurcell, S.M., Wray, N.R., Stone, J.L., Visscher, P.M., O'Donovan, M.C., Sullivan, P.F. and Sklar, P. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460, 748-752.
4. Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P., Mors, O., Mortensen, P.B. et al. (2009) Common variants conferring risk of schizophrenia. Nature, 460, 744-747.
5. Schizophrenia Psychiatric Genome-Wide Association Study Consortium. (2011) Genome-wide association study identifies five new schizophrenia loci. Nat. Genet., 43, 969-976.
6. Lee, S.H., DeCandia, T.R., Ripke, S. and Yang, J., Schizophrenia Psychiatric Genome-Wide Association Study Consortium, International Schizophrenia Consortium, Molecular Genetics of Schizophrenia Consortium, Sullivan, P.F., Goddard, M.E., Keller, M.C. et al. (2012) Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet., 44, 247-250.
7. Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421-427.
8. Ripke, S., O'Dushlaine, C., Chambert, K., Moran, J.L., Kahler, A.K., Akterin, S., Bergen, S.E., Collins, A.L., Crowley, J.J., Fromer, M. et al. (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet., 45, 1150-1159.
9. International Schizophrenia Consortium. (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237-241.
10. Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E. et al. (2008) Large recurrent microdeletions associated with schizophrenia. Nature, 455, 232-236.
11. Levinson, D.F., Duan, J., Oh, S., Wang, K., Sanders, A.R., Shi, J., Zhang, N., Mowry, B.J., Olincy, A., Amin, F. et al. (2011) Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am. J. Psychiatry, 168, 302-316.
12. Gottesman, I.I. and Shields, J. (1967) A polygenic theory of schizophrenia. Proc. Natl. Acad. Sci. USA, 58, 199-205.
13. Purcell, S.M., Moran, J.L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O'Dushlaine, C., Chambert, K., Bergen, S.E., Kahler, A. et al. (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature, 506, 185-190.
14. Fromer, M., Pocklington, A.J., Kavanagh, D.H., Williams, H.J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D.M. et al. (2014) De novomutations in schizophrenia implicate synaptic networks. Nature, 506, 179-184.
15. Consortium, G.T. (2013) The Genotype-Tissue Expression (GTEx) project. Nat. Genet., 45, 580-585.
16. Luo, R., Sanders, S.J., Tian, Y., Voineagu, I., Huang, N., Chu, S.H., Klei, L., Cai, C., Ou, J., Lowe, J.K. et al. (2012) Genomewide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. Am. J. Hum. Genet., 91, 38-55.
17. Efron, B. (1979) Bootstrap methods: another look at the jackknife. Ann. Stat., 7, 1-26.
18. Duan, J., Shi, J., Ge, X., Dolken, L., Moy, W., He, D., Shi, S., Sanders, A.R., Ross, J. and Gejman, P.V. (2013) Genome-wide survey of interindividual differences of RNA stability in human lymphoblastoid cell lines. Scientific Reports, 3, 1318.
19. Kervestin, S. and Jacobson, A. (2012) NMD: a multifaceted response to premature translational termination. Nat. Rev. Mol. Cell. Biol., 13, 700-712.
20. Chang, Y.F., Imam, J.S. and Wilkinson, M.F. (2007) The nonsense-mediated decay RNA surveillance pathway. Annu. Rev. Biochem., 76, 51-74.
21. Zhuang, B., Su, Y.S. and Sockanathan, S. (2009) FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron, 61, 359-372.
22. Sun, L.O., Jiang, Z., Rivlin-Etzion, M., Hand, R., Brady, C.M., Matsuoka, R.L., Yau, K.W., Feller, M.B. and Kolodkin, A.L. (2013) On and offretinal circuit assembly by divergent molecular mechanisms. Science, 342, 1241974.
23. Kang, H.J., Kawasawa, Y.I., Cheng, F., Zhu, Y., Xu, X., Li, M., Sousa, A.M., Pletikos, M., Meyer, K.A., Sedmak, G. et al. (2011) Spatio-temporal transcriptome of the human brain. Nature, 478, 483-489.
24. Cooper, G.M., Coe, B.P., Girirajan, S., Rosenfeld, J.A., Vu, T.H., Baker, C., Williams, C., Stalker, H., Hamid, R., Hannig, V. et al. (2011) A copy number variation morbidity map of developmental delay. Nat. Genet., 43, 838-846.
25. Lim, E.T., Raychaudhuri, S., Sanders, S.J., Stevens, C., Sabo, A., MacArthur, D.G., Neale, B.M., Kirby, A., Ruderfer, D.M., Fromer, M. et al. (2013) Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron, 77, 235-242.
26. Grundberg, E., Small, K.S., Hedman, A.K., Nica, A.C., Buil, A., Keildson, S., Bell, J.T., Yang, T.P., Meduri, E., Barrett, A. et al. (2012) Mapping cis-and trans-regulatory effects across multiple tissues in twins. Nat. Genet., 44, 1084-1089.
27. Bottini, N., De Luca, D., Saccucci, P., Fiumara, A., Elia, M., Porfirio, M.C., Lucarelli, P. and Curatolo, P. (2001) Autism: evidence of association with adenosine deaminase genetic polymorphism. Neurogenetics, 3, 111-113.
28. Boison, D., Singer, P., Shen, H.Y., Feldon, J. and Yee, B.K. (2012) Adenosine hypothesis of schizophrenia-opportunities for pharmacotherapy. Neuropharmacology, 62, 1527-1543.
29. Shen, H.Y., Singer, P., Lytle, N., Wei, C.J., Lan, J.Q., Williams-Karnesky, R.L., Chen, J.F., Yee, B.K. and Boison, D. (2012) Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia. J. Clin. Invest., 122, 2567-2577.
30. Fenelon, K., Mukai, J., Xu, B., Hsu, P.K., Drew, L.J., Karayiorgou, M., Fischbach, G.D., Macdermott, A.B. and Gogos, J.A. (2011) Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc. Natl. Acad. Sci. USA, 108, 4447-4452.
31. Stark, K.L., Xu, B., Bagchi, A., Lai, W.S., Liu, H., Hsu, R., Wan, X., Pavlidis, P., Mills, A.A., Karayiorgou, M. et al. (2008) Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet., 40, 751-760.
32. Xu, B., Hsu, P.K., Stark, K.L., Karayiorgou, M. and Gogos, J.A. (2013) Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell, 152, 262-275.
33. Insel, T.R. (2010) Rethinking schizophrenia. Nature, 468, 187-193.
34. Owen, M.J., O'Donovan, M.C., Thapar, A. and Craddock, N. (2011) Neurodevelopmental hypothesis of schizophrenia. Br. J. Psychiatry, 198, 173-175.
35. Cristino, A.S., Williams, S.M., Hawi, Z., An, J.Y., Bellgrove, M. A., Schwartz, C.E., Costa Lda, F. and Claudianos, C. (2014) Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system. Mol. Psychiatry, 19, 294-301.
36. Talkowski, M.E., Rosenfeld, J.A., Blumenthal, I., Pillalamarri, V., Chiang, C., Heilbut, A., Ernst, C., Hanscom, C., Rossin, E., Lindgren, A.M. et al. (2012) Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell, 149, 525-537.
37. Montgomery, S.B., Lappalainen, T., Gutierrez-Arcelus, M. and Dermitzakis, E.T. (2011) Rare and common regulatory variation in population-scale sequenced human genomes. PLoS Genet., 7, e1002144.
38. Zeng, Y., Wang, G., Yang, E., Ji, G., Brinkmeyer-Langford, C.L. and Cai, J.J. (2015) Aberrant gene expression in humans. PLoS Genet., 11, e1004942.
39. Kong, A., Frigge, M.L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S.A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A. et al. (2012) Rate of de novo mutations and the importance of father's age to disease risk. Nature, 488, 471-475.
40. Handsaker, R.E., Van Doren, V., Berman, J.R., Genovese, G., Kashin, S., Boettger, L.M. and McCarroll, S.A. (2015) Large multiallelic copy number variations in humans. Nat. Genet., 26, doi: 10.1038/ng.3200.
41. Ward, L.D. and Kellis, M. (2012) Interpreting noncoding genetic variation in complex traits and human disease. Nat. Biotechnol., 30, 1095-1106.
42. Ritchie, G.R., Dunham, I., Zeggini, E. and Flicek, P. (2014) Functional annotation of noncoding sequence variants. Nat. Methods, 11, 294-296.
43. Tylee, D.S., Kawaguchi, D.M. and Glatt, S.J. (2013) On the outside, looking in: a reviewand evaluation of the comparability of blood and brain '-omes'. Am. J. Med. Genet. B Neuropsychiatr. Genet., 162B, 595-603.
44. Rollins, B., Martin, M.V., Morgan, L. and Vawter, M.P. (2010) Analysis of whole genome biomarker expression in blood and brain. Am. J. Med. Genet. B Neuropsychiatr. Genet., 153B, 919-936.
45. Schadt, E.E., Monks, S.A., Drake, T.A., Lusis, A.J., Che, N., Colinayo, V., Ruff, T.G., Milligan, S.B., Lamb, J.R., Cavet, G. et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature, 422, 297-302.
46. Yan, H., Yuan, W., Velculescu, V.E., Vogelstein, B. and Kinzler, K.W. (2002) Allelic variation in human gene expression. Science, 297, 1143.
47. Cheung, V.G., Conlin, L.K., Weber, T.M., Arcaro, M., Jen, K.Y., Morley, M. and Spielman, R.S. (2003) Natural variation in human gene expression assessed in lymphoblastoid cells. Nat. Genet., 33, 422-425.
48. Gretarsdottir, S., Thorleifsson, G., Reynisdottir, S.T., Manolescu, A., Jonsdottir, S., Jonsdottir, T., Gudmundsdottir, T., Bjarnadottir, S.M., Einarsson, O.B., Gudjonsdottir, H.M. et al. (2003) The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet., 35, 131-138.
49. Dixon, A.L., Liang, L., Moffatt, M.F., Chen, W., Heath, S., Wong, K.C., Taylor, J., Burnett, E., Gut, I., Farrall, M. et al. (2007) A genome-wide association study of global gene expression. Nat. Genet., 39, 1202-1207.
50. Emilsson, V., Thorleifsson, G., Zhang, B., Leonardson, A.S., Zink, F., Zhu, J., Carlson, S., Helgason, A., Walters, G.B., Gunnarsdottir, S. et al. (2008) Genetics of gene expression and its effect on disease. Nature, 452, 423-428.
51. Ioannidis, J.P., Allison, D.B., Ball, C.A., Coulibaly, I., Cui, X., Culhane, A.C., Falchi, M., Furlanello, C., Game, L., Jurman, G. et al. (2009) Repeatability of published microarray gene expression analyses. Nat. Genet., 41, 149-155.
52. van Heerden, J.H., Conesa, A., Stein, D.J., Montaner, D., Russell, V. and Illing, N. (2009) Parallel changes in gene expression in peripheral bloodmononuclear cells and the brain aftermaternal separation in the mouse. BMC Res. Notes, 2, 195.
53. DeLisi, L.E. and Crow, T.J. (1986) Is schizophrenia a viral or immunologic disorder? Psychiatr. Clin. North Am., 9, 115-132.
54. Knuesel, I., Chicha, L., Britschgi, M., Schobel, S.A., Bodmer, M., Hellings, J.A., Toovey, S. and Prinssen, E.P. (2014) Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol., 10, 643-660.
55. Brown, A.S. and Derkits, E.J. (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am. J. Psychiatry, 167, 261-280.
56. Eaton, W.W., Pedersen, M.G., Nielsen, P.R. and Mortensen, P.B. (2010) Autoimmune diseases, bipolar disorder, and nonaffective psychosis. Bipolar Disord., 12, 638-646.
57. Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium. (2015) Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci., 18, 199-209.
58. Sanders, A.R., Goring, H.H.H., Duan, J., Drigalenko, E.I., Moy, W., Freda, J., He, D. and Shi, J., MGS and Gejman, P.V. (2013) Transcriptome study of differential expression in schizophrenia. Hum. Mol. Genet., 22, 5001-5014.
59. Londin, E.R., Keller, M.A., D'Andrea, M.R., Delgrosso, K., Ertel, A., Surrey, S. and Fortina, P. (2011) Whole-exome sequencing of DNA from peripheral blood mononuclear cells (PBMC) and EBV-transformed lymphocytes from the same donor. BMC Genomics, 12, 464.
60. Nickles, D., Madireddy, L., Yang, S., Khankhanian, P., Lincoln, S., Hauser, S.L., Oksenberg, J.R. and Baranzini, S.E. (2012) In depth comparison of an individual's DNA and its lymphoblastoid cell line using whole genome sequencing. BMC Genomics, 13, 477.
61. Shirley, M.D., Baugher, J.D., Stevens, E.L., Tang, Z., Gerry, N., Beiswanger, C.M., Berlin, D.S. and Pevsner, J. (2012) Chromosomal variation in lymphoblastoid cell lines. Hum. Mutat., 33, 1075-1086.
62. Caliskan, M., Cusanovich, D.A., Ober, C. and Gilad, Y. (2011) The effects of EBV transformation on gene expression levels and methylation profiles. Hum Mol Genet, 20, 1643-1652.
63. Raychaudhuri, S., Korn, J.M. and McCarroll, S.A., International Schizophrenia Consortium, Altshuler, D., Sklar, P., Purcell, S. and Daly, M.J. (2010) Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet., 6, e1001097.
64. Kirov, G., Grozeva, D., Norton, N., Ivanov, D., Mantripragada, K.K. and Holmans, P., International Schizophrenia Consortium, Wellcome Trust Case Control Consortium, Craddock, N., Owen, M.J. et al. (2009) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum. Mol. Genet., 18, 1497-1503.
65. Rees, E., Kirov, G., Sanders, A., Walters, J.T., Chambert, K.D., Shi, J., Szatkiewicz, J., O'Dushlaine, C., Richards, A.L., Green, E.K. et al. (2014) Evidence that duplications of 22q11.2 protect against schizophrenia. Mol. Psychiatry, 19, 37-40.
66. Sanders, A.R., Levinson, D.F., Duan, J., Dennis, J.M., Li, R., Kendler, K.S., Rice, J.P., Shi, J., Mowry, B.J., Amin, F. et al. (2010) The Internet-based MGS2 control sample: self report of mental illness. Am. J. Psychiatry, 167, 854-865.
67. Trapnell, C., Roberts, A., Goff, L., Pertea, G., Kim, D., Kelley, D.R., Pimentel, H., Salzberg, S.L., Rinn, J.L. and Pachter, L. (2012) Differential gene and transcript expression analysis of RNA-seq experimentswithTopHat and Cufflinks. Nat. Protoc., 7, 562-578.
68. Anders, S. and Huber, W. (2010) Differential expression analysis for sequence count data. Genome Biol., 11, R106.
69. Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. and Wold, B. (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods, 5, 621-628.
70. Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G. and Durbin, R. and Genome Project Data Processing Subgroup. (2009) The sequence alignment/map format and SAMtools. Bioinformatics, 25, 2078-2079.
71. O'Roak, B.J., Vives, L., Fu, W., Egertson, J.D., Stanaway, I.B., Phelps, I.G., Carvill, G., Kumar, A., Lee, C., Ankenman, K. et al. (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrumdisorders. Science, 338, 1619-1622.
72. Sanders, A.R., Duan, J., Levinson, D.F., Shi, J., He, D., Hou, C., Burrell, G.J., Rice, J.P., Nertney, D.A., Olincy, A. et al. (2008) No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am. J. Psychiatry, 165, 497-506.
73. Shi, S., Leites, C., He, D., Schwartz, D., Moy, W., Shi, J. and Duan, J. (2014) MicroRNA-9 and microRNA-326 regulate human dopamine D2 receptor expression and the micro-RNA-mediated expression regulation is altered by a genetic variant. J. Biol. Chem., 289, 13434-13444.