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 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=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.
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Amin
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Jovanova
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: H H H
authors.initials: HH
authors.lastname: Adams
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Kavousi
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M W
authors.initials: MW
authors.lastname: Vernooij
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Rotterdam Thyroid Center, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Peeters
authors.affiliation: Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: F M S
authors.initials: FM
authors.lastname: de Vrij
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: S J
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: J G J
authors.initials: JG
authors.lastname: van Rooij
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Rotterdam Thyroid Center, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Chaker
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Demirkan
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Center for Biomics, Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: R W W
authors.initials: RW
authors.lastname: Brouwer
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Kraaij
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.|Division of Endocrinology, Department of Medicine, Leiden University Medical Center, RC Leiden, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Willems van Dijk
authors.affiliation: Leiden Academic Center for Drug Research, Division of Analytical Biosciences, Leiden University, Leiden, The Netherlands.|The Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Hankemeier
authors.affiliation: Center for Biomics, Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: W F J
authors.initials: WF
authors.lastname: van Ijcken
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Departments of Radiology and Medical Informatics, Erasmus MC, Rotterdam, The Netherlands.|Department of Imaging Physics, Delft University of Technology, Delft, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Niessen
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: O H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Kushner
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: H
authors.identifier: 0000-0002-4395-1397
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics; D008076:Cholesterol, HDL / Q000235:genetics; D003863:Depression / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005091:Exons; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D008076:Cholesterol, HDL; C410382:LIPG protein, human; D008049:Lipase