The study showed that healthy adults who carry TCF4 variants
and who smoke process acoustic stimuli in a similarly deficient way as
adults with schizophrenia. And the impact is stronger the more the
person smokes.
The research was published online March 26 in Proceedings of the National Academy of Science.
"Smoking might be a relevant risk factor for schizophrenia and should
be considered when genetic risk factors of psychiatric disorders are
assessed," first author Boris B. Quednow, PhD, from University Hospital
of Psychiatry Zurich in Switzerland, told Medscape Medical News.
In addition, "a set of markers, including smoking,
electrophysiological parameters, and genes, might help to identify and
predict subtypes of schizophrenia, which may lead us also to new
treatment options," he said.
Gene-Behavior Interactions
A combination of genetic and environmental factors is thought to play
a role in the development of schizophrenia. Several polymorphisms in
the TCF4 gene have been shown to increase the risk for schizophrenia, particularly TCF4
rs996076. This variant is associated with impaired sensorimotor
gating measured by prepulse inhibition — an established endophenotype of
schizophrenia.
Dr. Quednow and colleagues therefore investigated whether TCF4
polymorphisms also affect another proposed endophenotype of
schizophrenia, namely, sensory gating assessed by P50 suppression of the
auditory evoked potential.
They used electroencephalography to see how 1821 healthy adults process simple acoustic stimuli (a sequence of similar clicks).
Given that smoking is highly prevalent in schizophrenia and affects
sensory gating, they also assessed smoking behavior, cotinine plasma
concentrations, exhaled carbon monoxide, and the Fagerström Test for
Nicotine Dependence (FTND). Of the 1821 study participants, 1023 had
never smoked, and 798 were smokers.
"As predicted, healthy subjects carrying the schizophrenia risk alleles of TCF4
polymorphisms displayed worse pre-attentional filter functions
(similar as schizophrenia patients) as measured by P50 suppression of
the auditory evoked potential," said Dr. Quednow.
Dose-Dependent Effect
"Interestingly," he added, "the gene effect was more pronounced" in
smokers; participants who had never smoked did not show a
deteriorating effect by the risk alleles on filter functions. Heavy
smokers, with an FTND score of 4 or higher, showed stronger gene effects
on P50 suppression than light smokers.
"We conclude, if smoking can modulate the impact of a schizophrenia
risk allele on early information processing, it might also modulate the
risk for schizophrenia per se. However, smoking has not been
investigated as a modulating factor in genetic studies of schizophrenia
so far," Dr. Quednow noted.
The researchers point out that studies are needed to explore whether
nicotine use itself might enhance the risk for schizophrenia, as
suggested by longitudinal studies showing that beyond cannabis and
alcohol use, early use of tobacco increases the risk for psychosis.
It is possible, they write, that an extended endophenotype, including
electrophysiological gating measures such as P50 suppression, smoking
behavior, and risk genes, such as TCF4, "may be suitable as an early indicator of a developing psychosis."
"We would like to explore if smoking also changes the effect of other
genes on endophenotypes of psychiatric disorders," said Dr. Quednow.
The study was supported by the German
Research Foundation as part of the priority program Nicotine: Molecular
and Physiological Effects in Central Nervous System. The authors have
disclosed no relevant financial relationships.
PNAS. Published online March 26, 2012. Abstract
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