Archiver > GENEALOGY-DNA > 2010-03 > 1268707676

From: "Don Jackson" <>
Subject: [DNA] Too soon for genotyping as and aid in deciding therapeuticmodialities?
Date: Mon, 15 Mar 2010 21:47:56 -0500

Summary and Comment

Genetic Variant Influences Extinction Learning

A single-nucleotide polymorphism affects anxiety-related behavior in both
mice and humans.

Outcomes from extinction therapy for anxiety (Biol Psychiatry 2009; 66:636)
have been associated with a polymorphism at codon 66 of the gene for
brain-derived neurotrophic factor (BDNF) that leads to a valine (Val) to
methionine (Met) substitution (Val66Met). In mice, presence of the Met
allele was associated with slower extinction of fear, which was rescued by
D-cycloserine. D-cycloserine, which acts at the glycine site of the
N-methyl-D-aspartate receptor (J Neurosci 2009; 29:4056), has been used to
augment the treatment of anxiety in humans (
<>; JW Psychiatry Jan
14 2008). To build on these data, researchers performed animal and human

Mice with knocked-in human Val or Met alleles were conditioned to fear
(i.e., an adverse stimulus was supplied with a neutral cue) and then
underwent fear extinction (the neutral cue occurred without the adverse
stimulus). Fear conditioning did not differ among Val homozygotes, Met
homozygotes, and heterozygotes. Met homozygotes showed significantly poorer
extinction (i.e., longer periods of freezing behaviors on late trials) than
Val homozygotes, and heterozygotes performed midway between the other two

The researchers also genotyped 72 people, who underwent a
conditioning/extinction paradigm with functional magnetic resonance imaging
(fMRI) of fear circuitry - the ventromedial prefrontal cortex (PFC) and
amygdala regions. Because 5 subjects were homozygous for Met, that group was
combined with the heterozygote group. Fear conditioning did not differ
between Met carriers and Val homozygotes. Met carriers had significantly
impaired extinction (i.e., higher skin conductance in late trials) compared
with Val homozygotes and had greater amygdala activation and lower
ventromedial PFC activation on fMRI.

Comment: These findings add to the growing body of work on the role of Val
and Met variants of the BDNF gene in anxiety states and extinction
phenomena. It appears to be time for BDNF Val66Met genotyping to become part
of research into anxiety therapies. Is it too soon for clinical genotyping
as an aid in deciding on therapeutic modalities?

Barbara Geller, MD

Published in <>; Journal Watch Psychiatry March
15, 2010


Soliman F et al. A genetic variant BDNF polymorphism alters extinction
learning in both mouse and human. Science 2010 Feb 12; 327:863.

=327/5967/863> Original article (Subscription may be required)

=MED> Medline abstract (Free)

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