Skip to main content Accessibility help
×
Home

An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome

  • Shiqiang Cheng (a1), Fanglin Guan (a2), Mei Ma (a1), Lu Zhang (a1), Bolun Cheng (a1), Xin Qi (a1), Chujun Liang (a1), Ping Li (a1), Om Prakash Kafle (a1), Yan Wen (a1) and Feng Zhang (a1)...

Abstract

Background.

Psychiatric disorders are a group of complex psychological syndromes with high prevalence. Recent studies observed associations between altered plasma proteins and psychiatric disorders. This study aims to systematically explore the potential genetic relationships between five major psychiatric disorders and more than 3,000 plasma proteins.

Methods.

The genome-wide association study (GWAS) datasets of attention deficiency/hyperactive disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) were driven from the Psychiatric GWAS Consortium. The GWAS datasets of 3,283 human plasma proteins were derived from recently published study, including 3,301 study subjects. Linkage disequilibrium score (LDSC) regression analysis were conducted to evaluate the genetic correlations between psychiatric disorders and each of the 3,283 plasma proteins.

Results.

LDSC observed several genetic correlations between plasma proteins and psychiatric disorders, such as ADHD and lysosomal Pro-X carboxypeptidase (p value = 0.015), ASD and extracellular superoxide dismutase (Cu-Zn; p value = 0.023), BD and alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 6 (p value = 0.007), MDD and trefoil factor 1 (p value = 0.011), and SCZ and insulin-like growth factor-binding protein 6 (p value = 0.011). Additionally, we detected four common plasma proteins showing correlation evidence with both BD and SCZ, such as tumor necrosis factor receptor superfamily member 1B (p value = 0.012 for BD, p value = 0.011 for SCZ).

Conclusions.

This study provided an atlas of genetic correlations between psychiatric disorders and plasma proteome, providing novel clues for pathogenetic and biomarkers, therapeutic studies of psychiatric disorders.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome
      Available formats
      ×

Copyright

This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

Feng Zhang, E-mail: fzhxjtu@mail.xjtu.edu.cn

Footnotes

Hide All
*

Shiqiang Cheng and Fanglin Guan contributed equally to this work.

Footnotes

References

Hide All
[1]American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Arlington, VA: American Psychiatric Publishing, 2013.
[2]Andrade, LH, Caraveoanduaga, JJ, Berglund, P, Bijl, RV, Kessler, RC, Demler, O, et al.Cross-national comparisons of the prevalences and correlates of mental disorders. Bull World Health Organ. 2000;78:413425.
[3]Costello, EJ, Egger, H, Angold, A. 10-Year research update review: the epidemiology of child and adolescent psychiatric disorders: I. Methods and public health burden. J Am Acad Child Adolesc Psychiatry. 2005;44(10):972986.
[4]Arango, C, Diazcaneja, CM, Mcgorry, PD, Rapoport, JL, Sommer, IEC, Vorstman, J, et al.Preventive strategies for mental health. Lancet Psychiatry. 2018;5(7):591604.
[5]Lichtenstein, P, Yip, BH, Björk, C, Pawitan, Y, Cannon, TD, Sullivan, PF, et al.Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373(9659):234239.
[6]McGuffin, P, Rijsdijk, F, Andrew, M, Sham, P, Katz, R, Cardno, A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003;60(5):497502.
[7]Smoller, JW, Kendler, KS, Craddock, NJ, Lee, PH, Neale, BM, Nurnberger, JI, et al.Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):13711379.
[8]Bipolar Disorder Genome Study (BiGS) Consortium, McMahon, FJ, Akula, N, Schulze, TG, Muglia, P, Tozzi, F, et al.Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet. 2010;42:128.
[9]Keyes, KM, Eaton, NR, Krueger, RF, Mclaughlin, KA, Wall, MM, Grant, BF, et al.Childhood maltreatment and the structure of common psychiatric disorders. Br J Psychiatry. 2012;200(2):107115.
[10]McGuffin, P, Owen, MJ, Gottesman, II. Psychiatric genetics and genomics II. UK: Oxford University Press, 2002.
[11]Freitag, CM. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry. 2006;12:2.
[12]Gratacòs, M, Costas, J, de Cid, R, Bayés, M, González, JR, Baca-García, E, et al.Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment. Am J Med Genet B. 2009;150B(6):808816.
[13]Sun, BB, Maranville, JC, Peters, JE, Stacey, D, Staley, JR, Blackshaw, J, et al.Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):7379.
[14]Chan, MK, Gottschalk, MG, Haenisch, F, Tomasik, J, Ruland, T, Rahmoune, H, et al.Applications of blood-based protein biomarker strategies in the study of psychiatric disorders. Progr Neurobiol. 2014;122:4572.
[15]Ganz, P, Heidecker, B, Hveem, K, Jonasson, C, Kato, S, Segal, MR, et al.Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. 2016;315(23):25322541.
[16]Chan, KC, Lucas, DA, Hise, D, Schaefer, CF, Xiao, Z, Janini, GM, et al.Analysis of the human serum proteome. Clin Proteomics. 2004;1(2):101225.
[17]Anderson, NL. The clinical plasma proteome: a survey of clinical assays for proteins in plasma and serum. Clin Chem. 2010;56(2):177185.
[18]Hye, A, Lynham, S, Thambisetty, M, Causevic, M, Campbell, J, Byers, HL, et al.Proteome-based plasma biomarkers for Alzheimer’s disease. Brain. 2006;129(11):30423050.
[19]Sussulini, A, Dihazi, H, Banzato, CEM, Arruda, MAZ, Stühmer, W, Ehrenreich, H, et al.Apolipoprotein A-I as a candidate serum marker for the response to lithium treatment in bipolar disorder. Proteomics. 2011;11(2):261269.
[20]Dimas, AS, Deutsch, S, Stranger, BE, Montgomery, SB, Borel, C, Attar-Cohen, H, et al.Common regulatory variation impacts gene expression in a cell type-dependent manner. Science. 2009;325(5945):12461250.
[21]Hernandez, DG, Nalls, MA, Moore, M, Chong, S, Dillman, A, Trabzuni, D, et al.Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain. Neurobiol Dis. 2012;47(1):2028.
[22]Foss, EJ, Radulovic, D, Shaffer, SA, Ruderfer, DM, Bedalov, A, Goodlett, DR, et al.Genetic basis of proteome variation in yeast. Nat Genet. 2007;39:1369.
[23]Bulik-Sullivan, BK, Loh, PR, Finucane, HK, Ripke, S, Yang, J, Schizophrenia Working Group of the Psychiatric Genomics Consortium, et al.LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47:291.
[24]Lee, JJ, Chow, CC. LD score regression as an estimator of confounding and genetic correlations in genome-wide association studies. bioRxiv. 2017;234815.
[25]Bulik-Sullivan, B, Finucane, HK, Anttila, V, Gusev, A, Day, FR, Loh, PR, et al.An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47(11):12361241.
[26]Duncan, LE, Ratanatharathorn, A, Aiello, AE, Almli, LM, Amstadter, AB, Ashley-Koch, AE, et al.Largest GWAS of PTSD (N = 20,070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. 2017;23:666.
[27]Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, et al.Discovery of the first genome-wide significant risk loci for ADHD. bioRxiv. 2017;145581.
[28]Anney, RJL, Ripke, S, Anttila, V, Grove, J, Holmans, P, Huang, H, et al.Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism. 2017;8(1):21.
[29]Ruderfer, DM, Ripke, S, McQuillin, A, Boocock, J, Stahl, EA, Pavlides, JMW, et al.Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173(7):1705.e161715.e16.
[30]Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, et al.Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50(5):668681.
[31]Schork, AJ, Won, H, Appadurai, V, Nudel, R, Gandal, M, Delaneau, O, et al.A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment. Nat Neurosci. 2019;22:353361.
[32]Angelantonio, ED, Thompson, SG, Kaptoge, S, Moore, C, Walker, MP, Armitage, J, et al.Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors. Lancet. 2017;390(10110):23602371.
[33]Astle, WJ, Elding, H, Jiang, T, Allen, D, Ruklisa, D, Mann, AL, et al.The allelic landscape of human blood cell trait variation and links to common complex disease. Cell. 2016;167(5):1415.e191429.e19.
[34]Bulik-Sullivan, B, Finucane, HK, Anttila, V, Gusev, A, Day, FR, Consortium, R, et al.An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236.
[35]Shi, H, Kichaev, G, Pasaniuc, B. Contrasting the genetic architecture of 30 complex traits from summary association data. Am J Hum Genet. 2016;99(1):139153.
[36]Chamberlain, RS, Herman, BH. A novel biochemical model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism. Biol Psychiatry. 1990;28(9):773793.
[37]Leboyer, M, Bouvard, MP, Recasens, C, Philippe, A, Guilloudbataille, M, Bondoux, D, et al.Difference between plasma N- and C-terminally directed beta-endorphin immunoreactivity in infantile autism. Am J Psychiatry. 1994;151(12):17971801.
[38]Sandman, CA, Hetrick, WP, Taylor, D, Chiczdemet, A. Dissociation of POMC peptides after self-injury predicts responses to centrally acting opiate blockers. Am J Mental Retard. 1997;102(2):182199.
[39]Cazzullo, AG, Musetti, MC, Musetti, L, Bajo, S, Sacerdote, P, Panerai, A. β-Endorphin levels in peripheral blood mononuclear cells and long-term naltrexone treatment in autistic children. Eur Neuropsychopharmacol. 1999;9(4):361366.
[40]Sandman, CA, Spence, MA, Smith, . Proopiomelanocortin (POMC) disregulation and response to opiate blockers. Mental Retardat Dev Disabil Res Rev. 1999;5(4):314321.
[41]Sandman, CA, Touchette, P, Marion, S, Lenjavi, M, Chicz-Demet, A. Disregulation of proopiomelanocortin and contagious maladaptive behavior. Regul Peptid. 2002;108(2):179185.
[42]Tilleman, H, Hakim, V, Novikov, O, Liser, K, Nashelsky, L, Di Salvio, M, et al.Bmp5/7 in concert with the mid-hindbrain organizer control development of noradrenergic locus coeruleus neurons. Mol Cell Neurosci. 2010;45(1):111.
[43]Goridis, C, Rohrer, H. Specification of catecholaminergic and serotonergic neurons. Nat Rev Neurosci. 2002;3:531.
[44]Ordway, GA, Szebeni, A, Chandley, MJ, Stockmeier, CA, Xiang, L, Newton, SS, et al.Low gene expression of bone morphogenetic protein 7 in brainstem astrocytes in major depression. Int J Neuropsychopharmacol. 2012;15(7):855868.
[45]Braff, DL, Grillon, C, Geyer, MA. Gating and habituation of the startle reflex in schizophrenic patients. Archiv Gen Psychiatry. 1992;49(3):206215.
[46]Hakak, Y, Walker, JR, Li, C, Wong, WH, Davis, KL, Buxbaum, JD, et al.Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci U S A. 2001;98(8):47464751.
[47]Kim, HJ, Miron, VE, Dukala, D, Proia, RL, Ludwin, SK, Traka, M, et al.Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. FASEB J. 2011;25(5):15091518.
[48]Contos, JJA, Ishii, I, Fukushima, N, Kingsbury, MA, Ye, X, Kawamura, S, et al.Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2). Mol Cell Biol. 2002;22(19):69216929.
[49]Maceyka, M, Harikumar, KB, Milstien, S, Spiegel, S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 2012;22(1):5060.
[50]Ho, MC, Nassan, M, Balwinder, S, Colby, C, McElroy, S, Frye, M, et al.F125. Genome-wide association study of anti-epileptic drug mood stabilizer response in bipolar disorder patients. Biol Psychiatry. 2018;83(9):S286.
[51]Mitsuhiro, T, Annie-Claire, D, Isabelle, D, Nicolas de, T. Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction. J Neurosurg. 1994;80(6):10631073.
[52]Fontaine, V, Mohandsaid, S, Hanoteau, N, Fuchs, C, Pfizenmaier, K, Eisel, ULM. Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci. 2002;22(7):17.
[53]Bruce, AJ, Boling, W, Kindy, MS, Peschon, J, Kraemer, PJ, Carpenter, MK, et al.Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med. 1996;2(7):788794.
[54]Till, A, Rosenstiel, P, Krippnerheidenreich, A, Mascheretticroucher, S, Croucher, PJP, Schafer, H, et al.The Met-196 Arg variation of human tumor necrosis factor receptor 2 (TNFR2) affects TNF-α-induced apoptosis by impaired NF-κB signaling and target gene expression. J Biol Chem. 2005;280(7):59946004.
[55]Thabet, S, Ben Nejma, M, Zaafrane, F, Gaha, L, Ben Salem, K, Romdhane, A, et al.Association of the Met-196-Arg variation of human tumor necrosis factor receptor 2 (TNFR2) with paranoid schizophrenia. J Mol Neurosci. 2011;43(3):358363.
[56]Hoseth, EZ, Ueland, T, Dieset, I, Birnbaum, R, Shin, JH, Kleinman, JE, et al.A study of TNF pathway activation in schizophrenia and bipolar disorder in plasma and brain tissue. Schizophr Bull. 2017;43(4):881890.
[57]Doganavsargil-Baysal, O, Cinemre, B, Aksoy, UM, Akbas, H, Metin, O, Fettahoglu, C, et al.Levels of TNF-α, soluble TNF receptors (sTNFR1, sTNFR2), and cognition in bipolar disorder. Hum Psychopharmacol Clin Exp. 2013;28(2):160167.

Keywords

An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome

  • Shiqiang Cheng (a1), Fanglin Guan (a2), Mei Ma (a1), Lu Zhang (a1), Bolun Cheng (a1), Xin Qi (a1), Chujun Liang (a1), Ping Li (a1), Om Prakash Kafle (a1), Yan Wen (a1) and Feng Zhang (a1)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.

An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome

  • Shiqiang Cheng (a1), Fanglin Guan (a2), Mei Ma (a1), Lu Zhang (a1), Bolun Cheng (a1), Xin Qi (a1), Chujun Liang (a1), Ping Li (a1), Om Prakash Kafle (a1), Yan Wen (a1) and Feng Zhang (a1)...
Submit a response

Comments

No Comments have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *