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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:


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