A new approach to investigating hard-to-find chromosomal abnormalities
has identified 33 genes associated with autism and related disorders, 22
for the first time. Several of these genes also appear to be altered in
different ways in individuals with psychiatric disorders such as
schizophrenia, symptoms of which may begin in adolescence or adulthood.
Results of the study by a multi-institutional research team will appear
in the April 27 issue of Cell and have been released online.
"By sequencing the genomes of a group of children with
neurodevelopmental abnormalities, including autism, who were also known
to have abnormal chromosomes, we identified the precise points where the
DNA strands are disrupted and segments exchanged within or between
chromosomes. As a result, we were able to discover a series of genes
that have a strong individual impact on these disorders," says James
Gusella, PhD, director of the Massachusetts General Hospital Center for
Human Genetic Research (MGH CHGR) and senior author of the Cell paper.
"We also found that many of these genes play a role in diverse clinical
situations -- from severe intellectual disability to adult-onset
schizophrenia -- leading to the conclusion that these genes are very
sensitive to even subtle perturbations."
Physicians evaluating children with neurodevelopmental abnormalities
often order tests to examine their chromosomes, but while these tests
can detect significant abnormalities in chromosomal structure, they
typically cannot identify a specific gene as being disrupted. Structural
variants known as balanced chromosome abnormalities (BCAs) -- in which
DNA segments are moved into different locations in the same chromosome
or exchanged with segments in other chromosomes, leaving the overall
size of the chromosomes unchanged -- are known to be significantly more
common in individuals with autism spectrum disorders than in a control
population. Several years ago Gusella and Cynthia Morton, PhD, of
Brigham and Women's Hospital initiated the Developmental Genome Anatomy
Project to identify developmentally important genes by investigating
BCAs, but the task of identifying specific chromosome breakpoints has
been slow and laborious.
To get a clearer view of the potential impact of BCAs on autism, the
research team took advantage of a new approach developed by Michael
Talkowski, PhD, of the MGH CHGR, lead author of the Cell paper,
which allows the sequencing of an individual's entire genome in a way
that detects the breakpoints of BCAs. The whole procedure can be
accomplished in less than two weeks rather than the many months
previously required. Screening the genomes of 38 individuals diagnosed
with autism or other neurodevelopmental disorders found chromosomal
breakpoints and rearrangements in non-protein-coding regions that
disrupted 33 genes, only 11 of which previously had been suspected in
these disorders.
As they compiled their results, the researchers were struck by how
many of the BCA-disrupted genes they identified had been associated with
psychiatric disorders in previous studies. To test their observation,
they examined data from the largest genome-wide association study in
schizophrenia to date -- in collaboration with Mark Daly, PhD, also of
the MGH CHGR who led that study -- and found that a significant number
of the BCA-disrupted genes identified in the current study were
associated with schizophrenia when altered by more subtle variants that
are common in the population.
"The theory that schizophrenia is a neurodevelopmental disorder has
long been hypothesized, but we are just now beginning to uncover
specific portions of the genetic underpinnings that may support that
theory," says Talkowski. "We also found that different gene variations
-- deletion, duplication or inactivation -- can result in very similar
effects, while two similar changes at the same site might have very
different neurodevelopmental manifestations. We suspected that the
genetic causes of autism and other neurodevelopmental abnormalities are
complex and likely to involve many genes, and our data support this."
Adds Gusella, who is the Bullard Professor of Neurogenetics at
Harvard Medical School, "Our results suggest that many genes and
pathways are important to normal brain development and that perturbation
of some can lead to a great variety of developmental or psychiatric
conditions, warranting extensive further study. We're hoping to
investigate how these gene disruptions alter other genes and pathways
and how prevalent these rearrangements are in the general population.
This is a first step in what will be a long journey toward understanding
genes underlying the pathophysiology of neurodevelopmental and
psychiatric disorders and developing new clinical treatments."
Researchers from 15 institutions in three countries -- including
Massachusetts General Hospital, the Broad Institute, Brigham and Women's
Hospital and Harvard Medical School -- collaborated with Talkowski,
Gusella, Morton and Daly on the investigation. Support for the study
includes grants from the National Institutes of Health, the Simons
Foundation Autism Research Initiative and Autism Speaks.
Journal Reference:
- Michael E. Talkowski, Jill A. Rosenfeld, Ian Blumenthal, Vamsee Pillalamarri, Colby Chiang, Adrian Heilbut, Carl Ernst, Carrie Hanscom, Elizabeth Rossin, Amelia M. Lindgren, Shahrin Pereira, Douglas Ruderfer, Andrew Kirby, Stephan Ripke, David J. Harris, Ji-Hyun Lee, Kyungsoo Ha, Hyung-Goo Kim, Benjamin D. Solomon, Andrea L. Gropman, Diane Lucente, Katherine Sims, Toshiro K. Ohsumi, Mark L. Borowsky, Stephanie Loranger, Bradley Quade, Kasper Lage, Judith Miles, Bai-Lin Wu, Yiping Shen, Benjamin Neale, Lisa G. Shaffer, Mark J. Daly, Cynthia C. Morton, James F. Gusella. Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries. Cell, 2012; DOI: 10.1016/j.cell.2012.03.028
Courtesy: ScienceDaily
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