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Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity

Molecular Psychiatry volume 22, pages 760–773 (2017)Cite this article

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Abstract

Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted P<0.1). In depression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO analysis suggests lower expression of genes involved in oligodendrocyte differentiation, regulation of glutamatergic neurotransmission, and oxytocin receptor expression in both suicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) in depression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood–brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorders.

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References

  1. Brent DA, Oquendo M, Birmaher B, Greenhill L, Kolko D, Stanley B et al. Familial pathways to early-onset suicide attempt: risk for suicidal behavior in offspring of mood-disordered suicide attempters. Arch Gen Psychiatry 2002; 59: 801–807.

    Article  PubMed  Google Scholar 

  2. Mann JJ, Brent DA, Arango V . The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology 2001; 24: 467–477.

    Article  CAS  PubMed  Google Scholar 

  3. Fiori LM, Turecki G . Gene expression profiling of suicide completers. Eur Psychiatry 2010; 25: 287–290.

    Article  CAS  PubMed  Google Scholar 

  4. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 2012; 18: 1413–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tochigi M, Iwamoto K, Bundo M, Sasaki T, Kato N, Kato T . Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains. Neurosci Res 2008; 60: 184–191.

    Article  CAS  PubMed  Google Scholar 

  6. Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA et al. Gene expression profiling in postmortem prefrontal cortex of major depressive disorder. J Neurosci 2007; 27: 13329–13340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aston C, Jiang L, Sokolov BP . Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol Psychiatry 2005; 10: 309–322.

    Article  CAS  PubMed  Google Scholar 

  8. Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, ffrench-Mullen J et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry 2009; 14: 175–189.

    Article  CAS  PubMed  Google Scholar 

  9. Sequeira A, Klempan T, Canetti L, ffrench-Mullen J, Benkelfat C, Rouleau GA et al. Patterns of gene expression in the limbic system of suicides with and without major depression. Mol Psychiatry 2007; 12: 640–655.

    Article  CAS  PubMed  Google Scholar 

  10. Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 2009; 4: e6585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Okoniewski MJ, Miller CJ . Hybridization interactions between probesets in short oligo microarrays lead to spurious correlations. BMC Bioinformatics 2006; 7: 276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Royce TE, Rozowsky JS, Gerstein MB . Toward a universal microarray: prediction of gene expression through nearest-neighbor probe sequence identification. Nucleic Acids Res 2007; 35: e99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang Z, Gerstein M, Snyder M . RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 2009; 10: 57–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li HD, Menon R, Omenn GS, Guan Y . The emerging era of genomic data integration for analyzing splice isoform function. Trends Genet 2014; 30: 340–347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schmauss C . Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing. Neuroscientist 2003; 9: 237–242.

    Article  CAS  PubMed  Google Scholar 

  16. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 2012; 7: 562–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nagalakshmi U, Wang Z, Waern K, Shou C, Raha D, Gerstein M et al. The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 2008; 320: 1344–1349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B . Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008; 5: 621–628.

    Article  CAS  PubMed  Google Scholar 

  19. Anders S, Reyes A, Huber W . Detecting differential usage of exons from RNA-seq data. Genome Res 2012; 22: 2008–2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bredemeier K, Miller IW . Executive function and suicidality: a systematic qualitative review. Clin Psychol Rev 2015; 40: 170–183.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Watkins HB, Meyer TD . Is there an empirical link between impulsivity and suicidality in bipolar disorders? A review of the current literature and the potential psychological implications of the relationship. Bipolar Disord 2013; 15: 542–558.

    Article  PubMed  Google Scholar 

  22. Desmyter S, van Heeringen C, Audenaert K . Structural and functional neuroimaging studies of the suicidal brain. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 796–808.

    Article  CAS  PubMed  Google Scholar 

  23. van Heeringen K, Mann JJ . The neurobiology of suicide. Lancet Psychiatry 2014; 1: 63–72.

    Article  PubMed  Google Scholar 

  24. Klempan TA, Rujescu D, Mérette C, Himmelman C, Sequeira A, Canetti L et al. Profiling brain expression of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene in suicide. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 934–943.

    Article  CAS  PubMed  Google Scholar 

  25. Kelly TM, Mann JJ . Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatr Scand 1996; 94: 337–343.

    Article  CAS  PubMed  Google Scholar 

  26. Sibille E, Arango V, Galfalvy HC, Pavlidis P, Erraji-Benchekroun L, Ellis SP et al. Gene expression profiling of depression and suicide in human prefrontal cortex. Neuropsychopharmacology 2004; 29: 351–361.

    Article  CAS  PubMed  Google Scholar 

  27. Love MI, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15: 550.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Erraji-Benchekroun L, Underwood MD, Arango V, Galfalvy H, Pavlidis P, Smyrniotopoulos P et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol Psychiatry 2005; 57: 549–558.

    Article  CAS  PubMed  Google Scholar 

  29. Lawrence M, Huber W, Pagès H, Aboyoun P, Carlson M, Gentleman R et al. Software for computing and annotating genomic ranges. PLoS Comput Biol 2013; 9: e1003118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pfaffl MW . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29: e45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee HK, Braynen W, Keshav K, Pavlidis P . ErmineJ: tool for functional analysis of gene expression data sets. BMC Bioinformatics 2005; 6: 269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gillis J, Pavlidis P . The impact of multifunctional genes on "guilt by association" analysis. PLoS One 2011; 6: e17258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yi M, Zhao Y, Jia L, He M, Kebebew E, Stephens RM . Performance comparison of SNP detection tools with illumina exome sequencing data—an assessment using both family pedigree information and sample-matched SNP array data. Nucleic Acids Res 2014; 42: e101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297–1303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011; 43: 491–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 2012; 6: 80–92.

    Article  CAS  Google Scholar 

  37. Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM et al. Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift. Front Genet 2012; 3: 35.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Serafini G, Pompili M, Hansen KF, Obrietan K, Dwivedi Y, Shomron N et al. The involvement of microRNAs in major depression, suicidal behavior, and related disorders: a focus on miR-185 and miR-491-3p. Cell Mol Neurobiol 2014; 34: 17–30.

    Article  CAS  PubMed  Google Scholar 

  39. Rajkowska G . Cell pathology in mood disorders. Semin Clin Neuropsychiatry 2002; 7: 281–292.

    Article  PubMed  Google Scholar 

  40. Ongür D, Drevets WC, Price JL . Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998; 95: 13290–13295.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gray AL, Hyde TM, Deep-Soboslay A, Kleinman JE, Sodhi MS . Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry 2015; 20: 1057–1068.

    Article  CAS  PubMed  Google Scholar 

  42. Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP . Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003; 31: e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B, Dembinska-Kiec A . Evidence for potential functionality of nuclearly-encoded humanin isoforms. Genomics 2009; 94: 247–256.

    Article  CAS  PubMed  Google Scholar 

  44. Nishimoto I, Matsuoka M, Niikura T . Unravelling the role of Humanin. Trends Mol Med 2004; 10: 102–105.

    Article  CAS  PubMed  Google Scholar 

  45. Lee C, Yen K, Cohen P . Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab 2013; 24: 222–228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Labonté B, Suderman M, Maussion G, Lopez JP, Navarro-Sánchez L, Yerko V et al. Genome-wide methylation changes in the brains of suicide completers. Am J Psychiatry 2013; 170: 511–520.

    Article  PubMed  Google Scholar 

  47. Sequeira A, Gwadry FG, Ffrench-Mullen JM, Canetti L, Gingras Y, Casero RA et al. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Arch Gen Psychiatry 2006; 63: 35–48.

    Article  CAS  PubMed  Google Scholar 

  48. Pantazatos SP, Andrews SJ, Dunning-Broadbent J, Pang J, Huang YY, Arango V et al. Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 (SAT1) gene in major depression and suicide. Neurobiol Dis 2015; 79: 123–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lopez JP, Fiori LM, Gross JA, Labonte B, Yerko V, Mechawar N et al. Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int J Neuropsychopharmacol 2014; 17: 23–32.

    Article  CAS  PubMed  Google Scholar 

  50. Semple BD, Kossmann T, Morganti-Kossmann MC . Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 2010; 30: 459–473.

    Article  CAS  PubMed  Google Scholar 

  51. Harada A, Sekido N, Akahoshi T, Wada T, Mukaida N, Matsushima K . Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol 1994; 56: 559–564.

    Article  CAS  PubMed  Google Scholar 

  52. Dunn AJ, Swiergiel AH, de Beaurepaire R . Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev 2005; 29: 891–909.

    Article  CAS  PubMed  Google Scholar 

  53. Müller N, Ackenheil M . Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 1–33.

    Article  PubMed  Google Scholar 

  54. Hiles SA, Baker AL, de Malmanche T, Attia J . A meta-analysis of differences in IL-6 and IL-10 between people with and without depression: exploring the causes of heterogeneity. Brain Behav Immun 2012; 26: 1180–1188.

    Article  CAS  PubMed  Google Scholar 

  55. Podlipný J, Hess Z, Vrzalová J, Rosolová H, Beran J, Petrlová B . Lower serum levels of interleukin-6 in a population sample with symptoms of depression than in a population sample without symptoms of depression. Physiol Res 2010; 59: 121–126.

    PubMed  Google Scholar 

  56. Janelidze S, Suchankova P, Ekman A, Erhardt S, Sellgren C, Samuelsson M et al. Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels. Acta Psychiatr Scand 2014; 131: 269–278.

    Article  CAS  PubMed  Google Scholar 

  57. Pandey GN, Rizavi HS, Ren X, Fareed J, Hoppensteadt DA, Roberts RC et al. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res 2012; 46: 57–63.

    Article  PubMed  Google Scholar 

  58. Galfalvy H, Zalsman G, Huang YY, Murphy L, Rosoklija G, Dwork AJ et al. A pilot genome wide association and gene expression array study of suicide with and without major depression. World J Biol Psychiatry 2011; 14: 574–582.

    Article  PubMed  Google Scholar 

  59. Mostafavi S, Battle A, Zhu X, Potash JB, Weissman MM, Shi J et al. Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing. Mol Psychiatry 2013; 19: 1267–1274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N . Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun 2014; 42: 50–59.

    Article  CAS  PubMed  Google Scholar 

  61. Black C, Miller BJ . Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients. Biol Psychiatry 2015; 78: 28–37.

    Article  CAS  PubMed  Google Scholar 

  62. Ducasse D, Olié E, Guillaume S, Artéro S, Courtet P . A meta-analysis of cytokines in suicidal behavior. Brain Behav Immun 2015; 46: 203–211.

    Article  CAS  PubMed  Google Scholar 

  63. Isung J, Aeinehband S, Mobarrez F, Mårtensson B, Nordström P, Asberg M et al. Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters. Transl Psychiatry 2012; 2: e196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Janelidze S, Ventorp F, Erhardt S, Hansson O, Minthon L, Flax J et al. Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters. Psychoneuroendocrinology 2013; 38: 853–862.

    Article  CAS  PubMed  Google Scholar 

  65. Rezaie P, Trillo-Pazos G, Everall IP, Male DK . Expression of beta-chemokines and chemokine receptors in human fetal astrocyte and microglial co-cultures: potential role of chemokines in the developing CNS. Glia 2002; 37: 64–75.

    Article  CAS  PubMed  Google Scholar 

  66. Chintawar S, Cayrol R, Antel J, Pandolfo M, Prat A . Blood-brain barrier promotes differentiation of human fetal neural precursor cells. Stem Cells 2009; 27: 838–846.

    Article  PubMed  Google Scholar 

  67. Wake H, Moorhouse AJ, Nabekura J . Functions of microglia in the central nervous system—beyond the immune response. Neuron Glia Biol 2011; 7: 47–53.

    Article  PubMed  Google Scholar 

  68. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 2014; 17: 400–406.

    Article  CAS  PubMed  Google Scholar 

  69. Torres-Platas SG, Nagy C, Wakid M, Turecki G, Mechawar N . Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry 2015; 21: 509–515.

    Article  CAS  PubMed  Google Scholar 

  70. Rajkowska G, Stockmeier CA . Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 2013; 14: 1225–1236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C et al. Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Mol Psychiatry 2015; 20: 320–328.

    Article  CAS  PubMed  Google Scholar 

  72. Choi SS, Lee HJ, Lim I, Satoh J, Kim SU . Human astrocytes: secretome profiles of cytokines and chemokines. PLoS One 2014; 9: e92325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Barres BA . The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 2008; 60: 430–440.

    Article  CAS  PubMed  Google Scholar 

  74. Shinozaki Y, Nomura M, Iwatsuki K, Moriyama Y, Gachet C, Koizumi S . Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission. Sci Rep 2014; 4: 4329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [¹¹C]PBR28 PET study. Brain Behav Immun 2013; 33: 131–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA 2015; 112: 12468–12473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Schnieder TP, Trencevska I, Rosoklija G, Stankov A, Mann JJ, Smiley J et al. Microglia of prefrontal white matter in suicide. J Neuropathol Exp Neurol 2014; 73: 880–890.

    Article  PubMed  Google Scholar 

  78. Dimberg A . Chemokines in angiogenesis. Curr Top Microbiol Immunol 2010; 341: 59–80.

    CAS  PubMed  Google Scholar 

  79. Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 2012; 72: 562–571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Almeida OP, Ford AH, Flicker L, Hankey GJ, Yeap BB, Clancy P et al. Angiogenesis inhibition and depression in older men. J Psychiatry Neurosci 2014; 39: 200–205.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kurkinen M, Taylor A, Garrels JI, Hogan BL . Cell surface-associated proteins which bind native type IV collagen or gelatin. J Biol Chem 1984; 259: 5915–5922.

    CAS  PubMed  Google Scholar 

  82. Wang H, Parry S, Macones G, Sammel MD, Kuivaniemi H, Tromp G et al. A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans. Proc Natl Acad Sci USA 2006; 103: 13463–13467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S et al. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet 2010; 86: 389–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hedstrom L . An overview of serine proteases. Curr Protoc Protein Sci 2002 Chapter 21: Unit 21.10.

  85. van Hinsbergh VW, Engelse MA, Quax PH . Pericellular proteases in angiogenesis and vasculogenesis. Arterioscler Thromb Vasc Biol 2006; 26: 716–728.

    Article  CAS  PubMed  Google Scholar 

  86. Takatsu H, Baba K, Shima T, Umino H, Kato U, Umeda M et al. ATP9B, a P4-ATPase (a putative aminophospholipid translocase), localizes to the trans-Golgi network in a CDC50 protein-independent manner. J Biol Chem 2011; 286: 38159–38167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Muthusamy BP, Natarajan P, Zhou X, Graham TR . Linking phospholipid flippases to vesicle-mediated protein transport. Biochim Biophys Acta 2009; 1791: 612–619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Folmer DE, Elferink RP, Paulusma CC . P4 ATPases—lipid flippases and their role in disease. Biochim Biophys Acta 2009; 1791: 628–635.

    Article  CAS  PubMed  Google Scholar 

  89. CONVERGE consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 2015; 523: 588–591.

    Article  CAS  PubMed Central  Google Scholar 

  90. Sullivan PF . Genetics of disease: associations with depression. Nature 2015; 523: 539–540.

    Article  CAS  PubMed  Google Scholar 

  91. Morris SE, Cuthbert BN . Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior. Dialogues Clin Neurosci 2012; 14: 29–37.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was funded by NIMH 5R01MH082041-05 (PI: JJM), a Paul Janssen Translational Neuroscience Postdoctoral Fellowship (to SPP) and an NIMH K01MH108721 (PI: SPP). Collection and psychiatric characterization of brain samples was supported by MH40210 (PI: VA), MH062185 (PI: JJM) and MH064168 (PI: AJD). We thank Hanga Galfalvy for helpful comments and suggestions regarding data analysis, Peter L Nagy, Jane Dunning-Broadbent, Stuart J Andrews and Jiuhong Pang for contributions to RNA sequencing, data processing, interpretation and analysis, and John Repass at ARG Genetics for conducting qPCR validation experiments.

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  1. Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, , New York, NY, USA

    S P Pantazatos, Y-Y Huang, G B Rosoklija, V Arango & J J Mann

  2. Department of Psychiatry, Columbia University, New York, NY, USA

    S P Pantazatos, Y-Y Huang, G B Rosoklija, A J Dwork, V Arango & J J Mann

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  1. S P Pantazatos
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The authors have no relevant conflicts of interest to report. JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene.

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Pantazatos, S., Huang, YY., Rosoklija, G. et al. Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity. Mol Psychiatry 22, 760–773 (2017). https://doi.org/10.1038/mp.2016.130

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