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Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.
MedLine Citation:
PMID:  23319000     Owner:  NLM     Status:  Publisher    
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.Molecular Psychiatry advance online publication, 15 January 2013; doi:10.1038/mp.2012.183.
J J Luykx; S C Bakker; E Lentjes; M Neeleman; E Strengman; L Mentink; J Deyoung; S de Jong; J H Sul; E Eskin; K van Eijk; J van Setten; J E Buizer-Voskamp; R M Cantor; A Lu; M van Amerongen; E P A van Dongen; P Keijzers; T Kappen; P Borgdorff; P Bruins; E M Derks; R S Kahn; R A Ophoff
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  Molecular psychiatry     Volume:  -     ISSN:  1476-5578     ISO Abbreviation:  Mol. Psychiatry     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9607835     Medline TA:  Mol Psychiatry     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1] Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
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