a1 Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, Bethesda, MD, USA
a2 Section on Neuroimaging in Mood and Anxiety Disorders, National Institute of Mental Health, Bethesda, MD, USA
a3 Clinical Neuroimaging Laboratory, Department of Psychiatry, National University of Ireland, Galway, Ireland
a4 Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
a5 Laboratory of Molecular Pathophysiology, Mood & Anxiety Program, National Institute of Mental Health, National Institutes of Health, Department of Health & Human Services, Bethesda, MD, USA
In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [11C]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [11C]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [11C]DASB BPND in thalamus and three markers in a region spanning the 3′ untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression.
(Received April 14 2009)
(Revised September 22 2009)
(Accepted October 29 2009)
(Online publication January 05 2010)
c1 Address for correspondence: G. Laje, M.D., M.H.Sc., Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, 35 Convent Drive, Rm 1A207, Bethesda, MD 20892-3719, USA. Tel.: 301 496 7730 Fax: 301 402 9081 Email: firstname.lastname@example.org
* These authors contributed equally to this work.