Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype–phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as t...

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Published inMolecular psychiatry Vol. 19; no. 2; pp. 228 - 234
Main Authors Luykx, J J, Bakker, S C, Lentjes, E, Neeleman, M, Strengman, E, Mentink, L, DeYoung, J, de Jong, S, Sul, J H, Eskin, E, van Eijk, K, van Setten, J, Buizer-Voskamp, J E, Cantor, R M, Lu, A, van Amerongen, M, van Dongen, E P A, Keijzers, P, Kappen, T, Borgdorff, P, Bruins, P, Derks, E M, Kahn, R S, Ophoff, R A
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.02.2014
Nature Publishing Group
Subjects
3',5'-Cyclic-AMP Phosphodiesterases - genetics
631/208/205/2138
692/699/476/377
Adult
Anesthesiology
Behavioral Sciences
Biogenic Monoamines - cerebrospinal fluid
Biological and medical sciences
Biological Psychology
Brain research
Central nervous system
Cerebrospinal fluid
Chromosomes, Human, Pair 11
Dopamine
Female
Gene Expression
Genes
Genetic diversity
Genetic Loci
Genetic Variation
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genotypes
Genotyping Techniques
Glutamic acid receptors
Homovanillic Acid - cerebrospinal fluid
Humans
Hydroxyindoleacetic Acid - cerebrospinal fluid
Identification and classification
Intensive care
Linear Models
Male
Medical sciences
Medicine
Medicine & Public Health
Membrane Proteins - genetics
Mental depression
Mental disorders
Mental Disorders - genetics
Metabolism
Metabolites
Methoxyhydroxyphenylglycol - cerebrospinal fluid
Monoamines
mRNA
Nervous system
Neural transmission
Neurosciences
original-article
Pain management
Pharmacotherapy
Phenotypes
Polymorphism
Polymorphism, Single Nucleotide
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Quantitative genetics
Quantitative trait loci
Schizophrenia
Serotonin
Signal transduction
Susceptibility
Testing
Los Angeles California
Netherlands
California
United States > US
monoamine
cerebrospinal fluid
genome-wide association study
Human
Metabolite
Monoamine
Cerebrospinal fluid
SSTR1
CSMD1
PDE9A
Online AccessGet full text
ISSN1359-4184
1476-5578
1476-5578
DOI10.1038/mp.2012.183

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Abstract Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype–phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P =4.92 × 10 −8 ), located 20 kb from SSTR1 , a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted =5.6 × 10 −7 ; P corrected =0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1 , a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
AbstractList Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized beta =0.32, P=4.92 10 super(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A ( beta =0.21; P sub(unadjusted)=5.6 10 super(-7); P sub(corrected)=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotypephenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β = 0.32, P = 4.92 x [10.sup.-8]), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β = 0.21; [P.sub.unadjusted] = 5.6 x [10.sup.-7]; [P.sub.corrected] = 0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at C5MD7, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes. Molecular Psychiatry (2014) 19, 228-234; doi:10.1038/mp.2012.183; published online 15 January 2013 Keywords: cerebrospinal fluid; CSMD7; genome-wide association study; monoamine; PDE9A; SSTR1 rs11221522 11 129 0.22 rs1881744 12 47.8 0.10 4.60 x [10.sup.-7] -0.24 TP53AIP1/ 7.76 x [10.sup.-6] 0.23 SNORA64.2 2.92 + 74.9 +
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype–phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P =4.92 × 10 −8 ), located 20 kb from SSTR1 , a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted =5.6 × 10 −7 ; P corrected =0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1 , a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype–phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10−8), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; Punadjusted=5.6 × 10−7; Pcorrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotypephenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β = 0.32, P = 4.92 x [10.sup.-8]), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β = 0.21; [P.sub.unadjusted] = 5.6 x [10.sup.-7]; [P.sub.corrected] = 0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at C5MD7, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized [beta]=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A ([beta]=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Audience Academic
Author Lu, A
Keijzers, P
Bruins, P
Eskin, E
Kahn, R S
Neeleman, M
Borgdorff, P
Mentink, L
de Jong, S
van Setten, J
Bakker, S C
Buizer-Voskamp, J E
van Amerongen, M
Cantor, R M
Sul, J H
van Eijk, K
Kappen, T
van Dongen, E P A
Luykx, J J
DeYoung, J
Strengman, E
Derks, E M
Ophoff, R A
Lentjes, E
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https://www.ncbi.nlm.nih.gov/pubmed/23319000$$D View this record in MEDLINE/PubMed
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Keywords monoamine
cerebrospinal fluid
genome-wide association study
Human
Metabolite
Monoamine
Cerebrospinal fluid
SSTR1
CSMD1
PDE9A
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Snippet Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype–phenotype correlations. Metabolic traits...
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits...
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotypephenotype correlations. Metabolic traits...
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StartPage 228
SubjectTerms 3',5'-Cyclic-AMP Phosphodiesterases - genetics
631/208/205/2138
692/699/476/377
Adult
Anesthesiology
Behavioral Sciences
Biogenic Monoamines - cerebrospinal fluid
Biological and medical sciences
Biological Psychology
Brain research
Central nervous system
Cerebrospinal fluid
Chromosomes, Human, Pair 11
Dopamine
Female
Gene Expression
Genes
Genetic diversity
Genetic Loci
Genetic Variation
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genotypes
Genotyping Techniques
Glutamic acid receptors
Homovanillic Acid - cerebrospinal fluid
Humans
Hydroxyindoleacetic Acid - cerebrospinal fluid
Identification and classification
Intensive care
Linear Models
Male
Medical sciences
Medicine
Medicine & Public Health
Membrane Proteins - genetics
Mental depression
Mental disorders
Mental Disorders - genetics
Metabolism
Metabolites
Methoxyhydroxyphenylglycol - cerebrospinal fluid
Monoamines
mRNA
Nervous system
Neural transmission
Neurosciences
original-article
Pain management
Pharmacotherapy
Phenotypes
Polymorphism
Polymorphism, Single Nucleotide
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Quantitative genetics
Quantitative trait loci
Schizophrenia
Serotonin
Signal transduction
Susceptibility
Testing
Title Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid
URI https://link.springer.com/article/10.1038/mp.2012.183
https://www.ncbi.nlm.nih.gov/pubmed/23319000
https://www.proquest.com/docview/1491273769
https://www.proquest.com/docview/2645770407
https://www.proquest.com/docview/1492704586
https://www.proquest.com/docview/1496882690
Volume 19
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