Skip to main content

Association of the leucine-7 to proline-7 variation in the signal sequence of neuropeptide Y with major depression

  • Pernille Koefoed (a1) (a2) (a3), David P.D. Woldbye (a1) (a3), Thomas v. O. Hansen (a2), Lene F. Eplov (a4), Søren H. Christiansen (a1), Ole Mors (a5), Lars V. Kessing (a3), Thomas Werge (a6), Katja Kaipio (a7), Ullamari Pesonen (a7), Thomas Fahmy (a3), Erling Mellerup (a1), Klaus D. Jakobsen (a6) (a8), Elsebeth S. Hansen (a3), Gitte M. Knudsen (a9), Jens D. Bukh (a3), Camilla Bock (a3), Camilla Lindberg (a1), Ann S. Kristensen (a5), Henrik Dam (a3), Merete Nordentoft (a3), Thomas D. Als (a5), August G. Wang (a10), Ulrik Gether (a11), Jens F. Rehfeld (a2) and Tom G. Bolwig (a1)...

Objective: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression.

Method: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro.

Results: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5%, n = 593; p = 0.009; odds ratio, OR: 1.46) as compared to ethnically matched controls (3.8%, n = 2912), while schizophrenia patients (4.1%, n = 503) did not differ. In vitro, the Pro7 substitution appeared to be associated with reduced levels of NPY without affecting its mRNA level.

Conclusion: The Leu7Pro variation may increase the risk of major depression, possibly by affecting the biosynthesis of NPY.

Corresponding author
Pernille Koefoed, Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen & Mental Health Centre Copenhagen, Rigshospitalet O-6102, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. Tel.: +45 3545 6113; Fax: +45 3539 3546; E-mail:
Hide All
1.Kessing LV.Gender differences in patients presenting with a single depressive episode according to ICD-10. Soc Psychiatry Psychiatr Epidemiol 2005;40:197201.
2.Levinson DF.The genetics of depression: a review. Biol Psychiatry 2006;60:8492.
3.Redrobe JP, Dumont Y, Quirion R.Neuropeptide Y (NPY) and depression: from animal studies to the human condition. Life Sci 2002;71:29212937.
4.Husum H, Vasquez PA, Mathe AA.Changed concentrations of tachykinins and neuropeptide Y in brain of a rat model of depression: lithium treatment normalizes tachykinins. Neuropsychopharmacology 2001;24:183191.
5.Mathé AA, Jimenez PA, Theodorsson E, Stenfors C.Neuropeptide Y, neurokinin A and neurotensin in brain regions of Fawn-Hooded “depressed”, Wistar, and Sprague-Dawley rats. Effects of electroconvulsive stimuli. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:529546.
6.Jimenez-Vasquez PA, Mathé AA, Thomas JD, Riley EP, Ehlers CL.Early maternal separation alters neuropeptide Y concentrations in selected brain regions in adult rats. Brain Res Dev Brain Res 2001;131:149152.
7.Caberlotto L, Fuxe K, Overstreet DH, Gerrard P, Hurd YL.Alterations in neuropeptide Y and Y1 receptor mRNA expression in brains from an animal model of depression: region specific adaptation after fluoxetine treatment. Brain Res Mol Brain Res 1998;59:5865.
8.Heilig M, Wahlestedt C, Ekman R, Widerlöv E.Antidepressant drugs increase the concentration of neuropeptide Y (NPY)-like immunoreactivity in the rat brain. Eur J Pharmacol 1988;147:465467.
9.Mathé AA, Jousisto-Hanson J, Stenfors C, Theodorsson E.Effect of lithium on tachykinins, calcitonin gene-related peptide, and neuropeptide Y in rat brain. J Neurosci Res 1990;26:233237.
10.Stenfors C, Theodorsson E, Mathé AA.Effect of repeated electroconvulsive treatment on regional concentrations of tachykinins, neurotensin, vasoactive intestinal polypeptide, neuropeptide Y, and galanin in rat brain. J Neurosci Res 1989;24:445450.
11.Christensen DZ, Olesen MV, Kristiansen H, Mikkelsen JD, Woldbye DPD.Unaltered neuropeptide Y (NPY)-stimulated [35S]GTPγS binding suggests a net increase in NPY signalling after repeated electroconvulsive seizures in mice. J Neurosci Res 2006;84:12821291.
12.Mikkelsen JD, Woldbye DPD.Accumulated increase in neuropeptide Y and somatostatin gene expression of the rat in response to repeated electroconvulsive stimulation. J Psychiatr Res 2006;40:153159.
13.Husum H, Mikkelsen JD, Hogg S, Mathé AA.Mørk A.Involvement of hippocampal neuropeptide Y in mediating the chronic actions of lithium, electroconvulsive stimulation and citalopram. Neuropharmacology 2000;39:14631473.
14.Redrobe JP, Dumont Y, Fournier A, Quirion R.The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 2002;26: 615624.
15.Heilig M, Zachrisson O, Thorsell A et al. Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar depression: preliminary evidence for association with preproNPY gene polymorphism. J Psychiatr Res 2004;38:113121.
16.Widerlöv E, Lindstrom LH, Wahlestedt C, Ekman R.Neuropeptide Y and peptide YY as possible cerebrospinal fluid markers for major depression and schizophrenia, respectively. J Psychiatr Res 1988;22:6979.
17.Bannon AW, Seda J, Carmouche M et al. Behavioral characterization of neuropeptide Y knockout mice. Brain Res 2000;868:7987.
18.Sørensen G, Lindberg C, Wörtwein G, Bolwig TG, Woldbye DPD.Different roles for neuropeptide Y Y1 and Y5 receptors in anxiety and sedation. J Neurosci Res 2004; 77:723729.
19.Zhou Z, Zhu G, Hariri AR et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 2008;452:9971001.
20.Karvonen MK, Pesonen U, Koulu M et al. Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. Nat Med 1998;4:14341437.
21.Okubo T, Harada S.Polymorphism of the neuropeptide Y gene: an association study with alcohol withdrawal. Alcohol Clin Exp Res 2001;25(6 Suppl):59S62S.
22.Itokawa M, Arai M, Kato S et al. Association between a novel polymorphism in the promotor region of the neuropeptide Y gene and schizophrenia in humans. Neurosci Lett 2003;347:202204.
23.Mottagui-Tabar S, Prince JA, Wahlestedt C, Zhu G, Goldman D, Heilig M.A novel single nucleotide polymorphism of the neuropeptides Y (NPY) gene associated with alcohol dependence. Alcohol Clin Exp Res 2005;29: 702707.
24.Niskanen L, Karvonen MK, Valve R et al. Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene is associated with enhanced carotid atherosclerosis in elderly patients with type 2 diabetes and control subjects. J Clin Endocrinol Metab 2000;85:22662269.
25.Niskanen L, Voutilainen-Kaunisto R, Terasvirta M et al. Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene is associated with retinopathy in type 2 diabetes. Exp Clin Endocrinol Diabetes 2000;108:235236.
26.Lappalainen J, Kranzler HR, Malison R et al. A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch Gen Psychiatry 2002;59:825831.
27.Kauhanen J, Karvonen MK, Pesonen U et al. Neuropeptide Y polymorphism and alcohol consumption in middle-aged men. Am J Med Genet 2000;93:117121.
28.Sjöholm lk, Melas PA, Forsell Y, Lavebratt C.PreproNPY Pro7 protects against depression despite exposure to environmental risk factors. J Affect Disord 2009;118: 124130.
29.Bosker FJ, Hartman CA, Nolte IM et al. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry 2011;16: 516532.
30.Kessing LV, Jørgensen OS.Apolipoprotein E-ε4 frequency in affective disorder. Biol Psychiatry 1999;45: 430434.
31.Mellerup E, Bennike B, Bolwig T et al. Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients. Acta Psychiatr Scand 2001;103:229233.
32.Haugboel S, Pinborg LH, Arfan HM et al. Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. Eur J Nucl Med Mol Imaging 2007;34:910915.
33.Jørgensen T, Borch-Johnsen K, Thomsen TF et al. A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur J Cardiovasc Prev Rehabil 2003;10:377386.
34.Lindberg C, Koefoed P, Hansen ES et al. No association between the – 399 C>T polymorphism of the neuropeptide Y gene and schizophrenia, unipolar depression or panic disorder in a Danish population. Acta Psychiatr Scand 2006; 113:5458.
35.Koefoed P, Hansen TVO, Woldbye DPD et al. An intron 1 polymorphism in the CCK-A receptor gene associated with schizophrenia in males. Acta Psychiatr Scand 2009; 120:281287.
36.Hansen T, Olsen L, Lindow M et al. Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One 2007;12:e873.
37.Rehfeld JF.Radioimmunochemical analysis of neuropeptides based on general characteristics of the analyte. Trends Analyt Chem 1989;8:102106.
38.Hällström T, Damström-Thakker K, Forsell Y, Lundberg I, Tinghög P. The Part study. A population based study of mental health in the Stockholm county: study design. 2003. [accessed on April 2011].
39.Ding B.Distribution of the NPY 1128C allele frequency in different populations. J Neural Transm 2003;110: 11991204.
40.Domschke K, Dannlowski U, Hohoff C et al. Neuropeptide Y (NPY) gene: impact on emotional processing and treatment response in anxious depression. Eur Neuropsychopharmacol 2010;20:301309.
41.Mickey BJ, Zhou Z, Heitzeg MM et al. Emotion processing, major depression, and functional genetic variation of neuropeptide Y. Arch Gen Psychiatry 2011;68:158166.
42.Hegde RS, Bernstein HD.The surprising complexity of signal sequences. Trends Biochem Sci 2006;31:563571.
43.Fitches AC, Appleby R, Lane DA, De SV, Leone G, Olds RJ.Impaired cotranslational processing as a mechanism for type I antithrombin deficiency. Blood 1998;92: 46714676.
44.Lanza F, De La Salle C, Baas MJ et al. A Leu7Pro mutation in the signal peptide of platelet glycoprotein (GP)IX in a case of Bernard-Soulier syndrome abolishes surface expression of the GPIb-V-IX complex. Br J Haematol 2002;118:260266.
45.Pidasheva S, Canaff L, Simonds WF, Marx SJ, Hendy GN.Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia. Hum Mol Genet 2005;14:16791690.
46.Ding B, Kull B, Liu Z et al. Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: possible mode of function. Regul Pept 2005;127:4553.
47.Mitchell GC, Wang Q, Ramamoorthy P, Whim MD. A common single nucleotide polymorphism alters the synthesis and secretion of neuropeptide Y. J Neurosci 2008;28: 1442814434.
48.Kallio J, Pesonen U, Jaakola U, Karvonen MK, Helenius H, Koulu M.Changes in diurnal sympathoadrenal balance and pituitary hormone secretion in subjects with Leu7Pro. J Clin Endocrinol Metab 2003;88:32783283.
49.Jaakkola U, Kuusela T, Jartti T et al. The Leu7Pro polymorphism of preproNPY is associated with decreased insulin secretion, delayed ghrelin suppression, and increased cardiovascular responsiveness to norepinephrine during oral glucose tolerance test. J Clin Endocrinol Metab 2005;90: 36463652.
50.Kallio J, Pesonen U, Kaipio K et al. Altered intracellular processing and release of neuropeptides Y due to leucine 7 to proline 7 polymorphism in the signal peptide of preproneuropeptide Y in humans. FASEB J 2001;15: 12421244.
51.Heilig M.The NPY system in stress, anxiety and depression. Neuropeptides 2004;38:213224.
52.Ishida H, Shirayama Y, Iwata M et al. Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor. Hippocampus 2007;17:271280.
53.Nikisch G, Agren H, Eap CB, Czernik A, Baumann P, Mathé AA.Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram. Int J Neuropsychopharmacol 2005;8: 403410.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
  • URL: /core/journals/acta-neuropsychiatrica
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 1
Total number of PDF views: 34 *
Loading metrics...

Abstract views

Total abstract views: 175 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 11th December 2017. This data will be updated every 24 hours.