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

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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

Journal Article (2017)

Author(s)

N. Amin (Erasmus MC)

O. Jovanova (Erasmus MC)

H Adams (Erasmus MC)

A Dehghan (Erasmus MC)

M. Kavousi (Erasmus MC)

Meike W. Vernooij (Erasmus MC)

R. P. Peeters (Erasmus MC)

F. M.S. De Vrij (Erasmus MC)

S. J. Van Der Lee (Erasmus MC)

J. G.J. Van Rooij (TU Delft - ImPhys/Quantitative Imaging, Erasmus MC)

E. M. Van Leeuwen (Erasmus MC)

Layal Chaker (Erasmus MC)

A. Demirkan (Leiden University Medical Center, Erasmus MC)

A Hofman (Erasmus MC)

R. W.W. Brouwer (Erasmus MC)

R. Kraaij (Erasmus MC)

K. Willems Van DIjk (Leiden University Medical Center)

T Hankemeier (Universiteit Leiden)

W. F.J. Van Ijcken (Erasmus MC)

André G. Uitterlinden (Erasmus MC)

W. J. Niessen (Erasmus MC, Biomedical Imaging Group Rotterdam, TU Delft - ImPhys/Quantitative Imaging)

Oscar H. Franco (Erasmus MC)

S. A. Kushner (Erasmus MC)

M A Ikram (Erasmus MC)

H Tiemeier (Erasmus MC)

C. M. Van Duijn (Erasmus MC)

DOI related publication

https://doi.org/10.1038/mp.2016.101 Final published version

To reference this document use

https://resolver.tudelft.nl/uuid:61cdbc0e-85dc-4bda-acb7-fe8f3f5f34f6

More Info

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Publication Year

2017

Language

English

Issue number

4

Volume number

22

Pages (from-to)

537-543

Downloads counter

422

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.