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NIAAA Press Office
Scientists at the
National Institutes of Health’s (NIH) National
Institute on Alcohol Abuse and Alcoholism (NIAAA)
have identified a previously unknown gene variant
that doubles an individual’s risk for
obsessive-compulsive disorder (OCD). The new
functional variant, or allele, is a component of
the serotonin transporter gene (SERT), site of
action for the selective serotonin reuptake
inhibitors (SSRIs) that are today’s mainstay
medications for OCD, other anxiety disorders, and
depression.
“Improved
knowledge of SERT's role in OCD raises the
possibility of improved screening, treatment, and
medications development for that disorder,”
said Ting-Kai Li, M.D., Director, National
Institute on Alcohol Abuse and Alcoholism. “It
also provides an important clue to the
neurobiologic basis of OCD and the compulsive
behaviors often seen in other psychiatric diseases,
including alcohol dependence.”
Approximately 2
percent of U.S. adults (3.3 million people) have
OCD, the fourth most prevalent mental health
disorder in the United States. Individuals with OCD
have intrusive, disturbing thoughts or images
(obsessions) and perform rituals (compulsions) to
prevent or banish those thoughts. Many other
individuals demonstrate obsessive-compulsive
behaviors that do not meet OCD diagnostic criteria
but alter the individuals’ lives.
Drs. David Goldman,
Chief, and Xianzhang Hu, Research Scientist, in
NIAAA’s Laboratory of Neurogenetics discovered
the linkage aided by new functional analyses of the
SERT genetic variant. The researchers first
compared the genotypes of 169 OCD patients to those
of 253 controls in a large U.S. patient population*
and found that the OCD patients were twice as
likely to have the variant. Then they studied
transmission and non-transmission of the variant in
a Canadian population** of 175 OCD parent-child
trios (two healthy parents and a child with OCD)
and found that the risk variant was twice as likely
to be transmitted from a parent to a child with
OCD. Specifically, of 86 informative trios, 48
children carried the new risk variant and 26 did
not.
“Whereas most
genetic diseases are caused by variations that lead
to reduced gene function, we found that a common
SERT variant that increases SERT activity also
increases risk for OCD,” said Dr. Goldman. The
same research team previously identified a rare
gain-of- function variant at a different location
in SERT. It, too, is linked to OCD but has been
studied only in two families with a severe,
treatment-resistant form of the disease. “That
earlier study suggested that we should test the
common gain-of-function variant for OCD
linkage,” Goldman said.
The new variant is
located at a well-recognized site in the SERT gene.
Also known as HTTLPR, the site is the most heavily
studied polymorphic site (those that may display
differing DNA sequences) in psychiatric genetics.
For years, HTTLPR has been known to have two
variants — S and L — that alter
expression of the SERT gene and are common across
all human populations. The loss-of-function S
variant exerts a small effect on a person’s
risk for anxiety, depression, and suicidality,
especially in response to environmental stressors.
The S allele exerts a larger effect on the
intermediate neurobiology of anxiety and
depression, specifically, by disrupting the
structure and functional coupling of key brain
regions. The gain-of-function L allele, on the
other hand, enhances SERT activity and functional
coupling. The current study differentiates the L
variant into two — LA and LG — and shows
that LA exerts a greater influence on SERT
expression.
“The
gain-of-function L alleles appear to inhibit
connections between emotion and repetitive
behaviors and such executive brain functions as
task-switching,” Goldman said. “These
neurobiology relationships should be further tested
in combined genetic-neuroimaging
studies.”
"Serotonin
Transporter Promoter Gain-of-Function Genotypes Are
Linked to Obsessive-Compulsive Disorder" appears in
the current online version of the American Journal
of Human Genetics at www.ajhg.org.
It will be published in the May 2006 print issue
(Volume 78, Number 5).
For an interview with
Dr. Goldman, please contact the NIAAA Press Office:
301/443-3860.
The National
Institute on Alcohol Abuse and Alcoholism, part of
the National Institutes of Health, is the primary
U.S. agency for conducting and supporting research
on the causes, consequences, prevention, and
treatment of alcohol abuse, alcoholism, and alcohol
problems and disseminates research findings to
general, professional, and academic audiences.
Additional alcohol research information and
publications are available at www.niaaa.nih.gov.
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* Obsessive
Compulsive Disorder Case Control Study, conducted
by Dennis Murphy, M.D., Laboratory of Clinical
Science, National Institute of Mental Health,
National Institutes of Health
** The Toronto OCD
Parent/Child Trio Study, conducted by James L.
Kennedy, M.D. , Department of Psychiatry, Centre
for Addiction and Mental Health, University of
Toronto
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