Background: Despite high heritability, little success was achieved in mapping genetic determinants of depression-related traits by means of genome-wide association studies. Methods: 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). Results: 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 (h 2 = 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). Conclusions: 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.

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Keywords CESD, Depressive symptoms, Exome sequencing, Major depression, MDD, NKPD1
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Journal Biological Psychiatry
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/201413 - European Network for Genetic and Genomic Epidemiology (ENGAGE)
Amin, N, Belonogova, N.M, Story-Jovanova, O, Brouwer, R.W.W, Van Rooij, J, van den hout, M.C.G.N, … van Duijn, C.M. (2017). Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in the European Populations. Biological Psychiatry, 81(8), 702–707. doi:10.1016/j.biopsych.2016.08.008