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

Molecular Psychiatry volume 22, pages 537–543 (2017)Cite this article

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A Corrigendum to this article was published on 09 August 2016

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.

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Acknowledgements

Erasmus Rucphen family study: The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the program ‘Quality of Life and Management of the Living Resources’ of the 5th Framework Programme (number QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing analysis in ERF was supported by the ZonMw grant (project 91111025). Metabolomics was partly funded by BBMRI-NL. We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, J Vergeer for the supervision of the laboratory work and P Snijders for his help in data collection. NA is supported by the Netherlands Brain Foundation (project number F2013(1)-28). FMSdV was supported by the Netherlands Brain Foundation (grant number FS2012(1)-39). Rotterdam study: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of the exome sequencing data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, The Netherlands. The Exome Sequencing data set was funded by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) sponsored Netherlands Consortium for Healthy Aging (NCHA; project number 050-060-810), by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC and by the and by a Complementation Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl; project number CP2010-41). Metabolomics assessment was funded by the Rainbow Project 4 of BBMRI-NL. We thank Mr Pascal Arp, Ms Mila Jhamai and Mr Marijn Verkerk for their help in creating the RS-Exome Sequencing database.

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Author notes

  1. H Tiemeier and C M van Duijn: These authors have contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology, Genetic Epidemiology Unit, Erasmus MC, Rotterdam, The Netherlands

    N Amin, S J van der Lee, E M van Leeuwen, A Demirkan & C M van Duijn

  2. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands

    O Jovanova, H H H Adams, A Dehghan, M Kavousi, M W Vernooij, R P Peeters, L Chaker, A Hofman, A G Uitterlinden, O H Franco, M A Ikram & H Tiemeier

  3. Department of Radiology, Erasmus MC, Rotterdam, The Netherlands

    H H H Adams, M W Vernooij & M A Ikram

  4. Rotterdam Thyroid Center, Erasmus MC, Rotterdam, The Netherlands

    R P Peeters & L Chaker

  5. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

    R P Peeters, J G J van Rooij, L Chaker, R Kraaij & A G Uitterlinden

  6. Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands

    F M S de Vrij & S A Kushner

  7. Department of Human Genetics, Leiden University Medical Center, RC Leiden, The Netherlands

    A Demirkan & K Willems van Dijk

  8. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

    A Hofman

  9. Department of Cell Biology, Center for Biomics, Erasmus MC, Rotterdam, The Netherlands

    R W W Brouwer & W F J van Ijcken

  10. Division of Endocrinology, Department of Medicine, Leiden University Medical Center, RC Leiden, The Netherlands

    K Willems van Dijk

  11. Division of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

    T Hankemeier

  12. The Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands

    T Hankemeier

  13. Departments of Radiology and Medical Informatics, Erasmus MC, Rotterdam, The Netherlands

    W J Niessen

  14. Department of Imaging Physics, Delft University of Technology, Delft, The Netherlands

    W J Niessen

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  1. N Amin
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Correspondence to N Amin.

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Amin, N., Jovanova, O., Adams, H. et al. Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. Mol Psychiatry 22, 537–543 (2017). https://doi.org/10.1038/mp.2016.101

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