title: Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in European Populations.
abstract: Despite high heritability, little success was achieved in mapping genetic determinants of depression-related traits by means of genome-wide association studies.
  
  
  
  To identify genes associated with depressive symptomology, we performed a gene-based association analysis of nonsynonymous variation captured using exome-sequencing and exome-chip genotyping in a genetically isolated population from the Netherlands (n = 1999). Finally, we reproduced our significant findings in an independent population-based cohort (n = 1604).
  
  
  
  We detected significant association of depressive symptoms with a gene NKPD1 (p = 3.7 × 10-08). Nonsynonymous variants in the gene explained 0.9% of sex- and age-adjusted variance of depressive symptoms in the discovery study, which is translated into 3.8% of the total estimated heritability (h2= 0.24). Significant association of depressive symptoms with NKPD1 was also observed (n = 1604; p = 1.5 × 10-03) in the independent replication sample despite little overlap with the discovery cohort in the set of nonsynonymous genetic variants observed in the NKPD1 gene. Meta-analysis of the discovery and replication studies improved the association signal (p = 1.0 × 10-09).
  
  
  
  Our study suggests that nonsynonymous variation in the gene NKPD1 affects depressive symptoms in the general population. NKPD1 is predicted to be involved in the de novo synthesis of sphingolipids, which have been implicated in the pathogenesis of depression.
authors.affiliation: Departments of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: n.amin@erasmusmc.nl.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Nadezhda M
authors.initials: NM
authors.lastname: Belonogova
authors.affiliation: Departments of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Olivera
authors.initials: O
authors.lastname: Jovanova
authors.affiliation: Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Rutger W W
authors.initials: RW
authors.lastname: Brouwer
authors.affiliation: Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Jeroen G J
authors.initials: JG
authors.lastname: van Rooij
authors.affiliation: Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Mirjam C G N
authors.initials: MC
authors.lastname: van den Hout
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Gulnara R
authors.initials: GR
authors.lastname: Svishcheva
authors.affiliation: Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kraaij
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zorkoltseva
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Anatoly V
authors.initials: AV
authors.lastname: Kirichenko
authors.affiliation: Departments of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Departments of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Departments of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia; Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia.
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Axenovich
authors.affiliation: Departments of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D003863:Depression / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D059472:Exome; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009426:Netherlands; D043583:Nucleoside-Triphosphatase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C000621988:NKPD1 protein, human; D043583:Nucleoside-Triphosphatase
keywords: CESD; Depressive symptoms; Exome sequencing; MDD; Major depression; NKPD1