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. H.H. Adams, A. Dehghan, M. Kavousi, M. W. Vernooij, R. P. Peeters, F. M.S. De Vrij, S. J. Van Der Lee, J. G.J. Van Rooij, E. M. Van Leeuwen, L. Chaker, A. Demirkan, A. Hofman, R. W.W. Brouwer, R. Kraaij, K. Willems Van DIjk, T. Hankemeier, W. F.J. Van Ijcken, A. G. Uitterlinden & 6 others W. J. Niessen, O. H. Franco, S. A. Kushner, M. A. Ikram, H. Tiemeier, C. M. Van Duijn

Research output: Contribution to journalArticleAcademicpeer-review

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

Cite this

Amin, N., Jovanova, O., Adams, H. H. H., Dehghan, A., Kavousi, M., Vernooij, M. W., ... 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
Amin, N. ; Jovanova, O. ; Adams, H. H.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. ; Uitterlinden, A. G. ; Niessen, W. J. ; Franco, O. H. ; Kushner, S. A. ; Ikram, M. A. ; Tiemeier, H. ; Van Duijn, C. M. / Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. In: Molecular Psychiatry. 2017 ; Vol. 22, No. 4. pp. 537-543.
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title = "Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms",
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.",
author = "N. Amin and O. Jovanova and Adams, {H. H.H.} and A. Dehghan and M. Kavousi and Vernooij, {M. W.} and Peeters, {R. P.} and {De Vrij}, {F. M.S.} and {Van Der Lee}, {S. J.} and {Van Rooij}, {J. G.J.} and {Van Leeuwen}, {E. M.} and L. Chaker and A. Demirkan and A. Hofman and Brouwer, {R. W.W.} and R. Kraaij and {Willems Van DIjk}, K. and T. Hankemeier and {Van Ijcken}, {W. F.J.} and Uitterlinden, {A. G.} and Niessen, {W. J.} and Franco, {O. H.} and Kushner, {S. A.} and Ikram, {M. A.} and H. Tiemeier and {Van Duijn}, {C. M.}",
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Amin, N, Jovanova, O, Adams, HHH, Dehghan, A, Kavousi, M, Vernooij, MW, Peeters, RP, De Vrij, FMS, Van Der Lee, SJ, Van Rooij, JGJ, Van Leeuwen, EM, Chaker, L, Demirkan, A, Hofman, A, Brouwer, RWW, Kraaij, R, Willems Van DIjk, K, Hankemeier, T, Van Ijcken, WFJ, Uitterlinden, AG, Niessen, WJ, Franco, OH, Kushner, SA, Ikram, MA, Tiemeier, H & Van Duijn, CM 2017, 'Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms' Molecular Psychiatry, vol. 22, no. 4, pp. 537-543. https://doi.org/10.1038/mp.2016.101

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. / Amin, N.; Jovanova, O.; Adams, H. H.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.; Uitterlinden, A. G.; Niessen, W. J.; Franco, O. H.; Kushner, S. A.; Ikram, M. A.; Tiemeier, H.; Van Duijn, C. M.

In: Molecular Psychiatry, Vol. 22, No. 4, 01.04.2017, p. 537-543.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms

AU - Amin, N.

AU - Jovanova, O.

AU - Adams, H. H.H.

AU - Dehghan, A.

AU - Kavousi, M.

AU - Vernooij, M. W.

AU - Peeters, R. P.

AU - De Vrij, F. M.S.

AU - Van Der Lee, S. J.

AU - Van Rooij, J. G.J.

AU - Van Leeuwen, E. M.

AU - Chaker, L.

AU - Demirkan, A.

AU - Hofman, A.

AU - Brouwer, R. W.W.

AU - Kraaij, R.

AU - Willems Van DIjk, K.

AU - Hankemeier, T.

AU - Van Ijcken, W. F.J.

AU - Uitterlinden, A. G.

AU - Niessen, W. J.

AU - Franco, O. H.

AU - Kushner, S. A.

AU - Ikram, M. A.

AU - Tiemeier, H.

AU - Van Duijn, C. M.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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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U2 - 10.1038/mp.2016.101

DO - 10.1038/mp.2016.101

M3 - Article

VL - 22

SP - 537

EP - 543

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

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ER -