Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms

N. Amin, O. Jovanova, H Adams, A Dehghan, M. Kavousi, Meike W. Vernooij, R. P. Peeters, F. M.S. De Vrij, S. J. Van Der Lee, J. G.J. Van Rooij, E. M. Van Leeuwen, Layal Chaker, A. Demirkan, A Hofman, R. W.W. Brouwer, R. Kraaij, K. Willems Van DIjk, T Hankemeier, W. F.J. Van Ijcken, André G. UitterlindenW. J. Niessen, Oscar H. Franco, S. A. Kushner, M A Ikram, H Tiemeier, C. M. Van Duijn

    Research output: Contribution to journalArticleScientificpeer-review

    30 Citations (Scopus)

    Abstract

    Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10 -08, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10 -03, β=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 1 -02) and a higher risk of Alzheimer's disease (odds ration=2.01; P-value=2.8 × 10 -02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

    Original languageEnglish
    Pages (from-to)537-543
    Number of pages7
    JournalMolecular Psychiatry
    Volume22
    Issue number4
    DOIs
    Publication statusPublished - 1 Apr 2017

    Fingerprint Dive into the research topics of 'Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms'. Together they form a unique fingerprint.

  • Cite this

    Amin, N., Jovanova, O., Adams, H., Dehghan, A., Kavousi, M., Vernooij, M. W., Peeters, R. P., De Vrij, F. M. S., Van Der Lee, S. J., Van Rooij, J. G. J., Van Leeuwen, E. M., Chaker, L., Demirkan, A., Hofman, A., Brouwer, R. W. W., Kraaij, R., Willems Van DIjk, K., Hankemeier, T., Van Ijcken, W. F. J., ... Van Duijn, C. M. (2017). Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. Molecular Psychiatry, 22(4), 537-543. https://doi.org/10.1038/mp.2016.101