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

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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Luykx JJ,Bakker SC,Lentjes E,Neeleman M,Strengman E,Mentink L,DeYoung J,de Jong S,Sul JH,Eskin E,van Eijk K,van Setten J,Buizer-Voskamp JE,Cantor RM,Lu A,van Amerongen M,van Dongen EP,Keijzers P,Kappen T,Borgdorff P

doi

10.1038/mp.2012.183

subject

Has Abstract

pub_date

2014-02-01 00:00:00

pages

228-34

issue

2

eissn

1359-4184

issn

1476-5578

pii

mp2012183

journal_volume

19

pub_type

杂志文章

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