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.

Additional Metadata
Keywords CESD, Depressive symptoms, Exome sequencing, Major depression, MDD, NKPD1
Persistent URL dx.doi.org/10.1016/j.biopsych.2016.08.008, hdl.handle.net/1765/93789
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)
Citation
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