Autism-cholesterol link
New research reveals a subtype of autism associated with lipid
abnormalities

Date:
August 17, 2020
Source:
Harvard Medical School
Summary:
A new study identifies a subtype of autism arising from a cluster
of genes that regulate cholesterol metabolism and brain development.



FULL STORY ========================================================================== Researchers at Harvard Medical School, Massachusetts Institute
of Technology and Northwestern University have identified a subtype
of autism arising from a cluster of genes that regulate cholesterol
metabolism and brain development.


==========================================================================
The researchers say their findings, published Aug. 10 in Nature Medicine,
can inform both the design of precision-targeted therapies for this
specific form of autism and enhance screening efforts to diagnose
autism earlier.

The team identified the shared molecular roots between lipid dysfunction
and autism through DNA analysis of brain samples -- findings that
they then confirmed by examining medical records of individuals with
autism. Indeed, both children with autism and their parents had pronounced alterations in lipid blood, the analysis showed.

The results of the study, the researchers said, raise many questions; key
among them are: Just how do lipid alterations drive neurodevelopmental dysfunction and could normalizing lipid metabolism affect disease
outcomes? The new findings set the stage for future studies to answer
these questions and others.

"Our results are a striking illustration of the complexity of autism
and the fact that autism encompasses many different conditions that
each arise from different causes -- genetic, environmental or both,"
said study senior investigator Isaac Kohane, chair of the Department
of Biomedical Informatics in the Blavatnik Institute at Harvard Medical
School. "Identifying the roots of dysfunction in each subtype is critical
to designing both treatments and screening tools for correct and timely diagnosis -- that is the essence of precision medicine." A Google map of
autism Autism and autism-spectrum disorders, estimated to affect one in
54 children in the United States, are among the most complex heritable conditions. Thousands of gene variants, both rare and common, have been implicated in autism, likely through an intricate and not-well understood interplay between genetic and environmental factors - - both before and
after birth.



==========================================================================
The new study findings not only underscore this complexity but also
demonstrate the critical importance of defining the various subtypes
of the condition and developing treatments that target subtype-specific anomalies.

Achieving a meaningful level of specificity in the study of a vastly
complex disorder such as autism, however, is not easy. To do so, the researchers used a novel approach based on the interlacing of multiple
layers of data, including whole exome sequencing, patterns of protein expression, medical records and health insurance claims.

"Think of a Google map and how it overlays various types of information
on top of one another -- cities, streets, parcels, land use, electrical
grids, elevations -- for a more detailed representation," said Yuan Luo,
who co-led the study with Alal Eran, a Harvard Medical School lecturer
on pediatrics at Boston Children's Hospital.

"This is what we did with our data to get a complete view of genes that
have multiple regulatory functions and are implicated in autism," said
Luo, who started working on the research while at MIT's Computer Science
& Artificial Intelligence Lab and continued the work at Northwestern University, where he is now associate professor of preventive medicine
at the Feinberg School of Medicine.

The team started out by analyzing patterns of gene expression from
brain samples contained in two large national brain banks, focusing
on genes that work in tandem during prenatal and postnatal brain
development. Because autism is four times more common in males than
females, they further focused on genes that had the largest male-to-female differences during development. Within those, they homed in on exons --
the protein-coding parts of genes -- to seek out mutations that occurred
more often in patients with autism. Through this progressive zooming
in, the researchers identified a previously unrecognize node of shared
function -- a cluster of exons regulating both neurodevelopment and
fat metabolism.



========================================================================== Protein to person To confirm whether the molecular link between autism
and lipid metabolism was borne out in actual patients, the team turned
to two vast clinical record repositories. In one that contained more than
2.7 million records of patients seen at Boston Children's, including more
than 25, o00 children with autism, the researchers identified notable
lipid alterations in children with autism, including changes in levels
of their bad cholesterol (LDL), good cholesterol (HDL) and triglycerides.

The other dataset contained medical records of more than 34 million
individuals seen at multiple U.S. medical institutions. Of those,
more than 80,700 individuals had diagnoses of autism. Overall, 6.5
percent of those who had an autism diagnosis also had abnormal lipid
levels. Individuals with autism were nearly twice as likely to have
abnormal lipid tests results as those without autism. There was also
a pronounced familial link. Mothers with lipid abnormalities were 16
percent more likely to have a child with autism than mothers without
lipid abnormalities. The risk for having a child with autism among
fathers with lipid abnormalities was 13 percent greater than in males
with normal lipid levels. And within families with more than one child, children diagnosed with autism were 76 percent more likely to have
abnormal lipid profiles than their siblings.

Among individuals with autism and abnormal lipid levels on their blood
work, conditions such as epilepsy, sleep disorders and attention deficit hyperactivity disorder were markedly more common than among those without elevated lipid levels -- a finding that suggests dyslipidemia may alter neurodevelopment in general, the researchers said. Individuals with
autism and dyslipidemia were also more likely to have certain hormonal
and metabolic conditions including anemia, hypothyroidism and vitamin
D deficiency.

The autism-dyslipidemia link persisted even when the researchers
accounted for the possible influence of drugs commonly used in people
with autism, some of which are known to affect lipid levels. In fact,
lipid abnormalities were more common among people with autism who were
not taking such medications.

The newly found link offers a molecular explanation to the
well-established observation that a mutation in a gene involved in
cholesterol metabolism is also found in people with Rett syndrome, a neurodevelopmental disorder closely related to autism. Another striking observation that may be explained by the newly found link is that between
50 and 88 percent of children born with Smith- Lemli-Opitz syndrome,
caused by a defect in cholesterol synthesis, also have autism.

The researchers say their approach -- based on integrating multiple data modalities -- could be adapted to other similarly genetically complex conditions as a way to precision-profile subtypes of disease.

For example, the ability to identify disease subtypes in cancer in the
past two decades has propelled the field of oncology forward and led to
the development of many targeted cancer treatments, researchers said.

"Our findings can help design precision-targeted treatments that home in
on the specific defect underlying the development of dyslipidemia-related autism," Kohane said. "Conceptually, this is the same framework that
we can apply in complex inherited neurodevelopmental disorders like
autism and beyond. Our multimodal approach combining multiple types
of data demonstrates that this is not only possible but imminent." Co-investigators on the study included Nathan Palmer, Paul Avillach,
Ami Levy- Moonshine and Peter Szolovits.

The work was supported by the National Institute of Health (grants 1R21LM012618, 5UL1TR001422, P50MH106933, U01HG007530, OT3OD025466,
OT3HL142480, U54HG007963, 1U01TR002623-01 and 1U54HD090255-01), Israeli Ministry of Science and Technology (grant 17708), and Precision Link
Biobank for Health Discovery at Boston Children's. Palmer received
funding support from Aetna Life Insurance.


========================================================================== Story Source: Materials provided by Harvard_Medical_School. Original
written by Ekaterina Pesheva. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Yuan Luo, Alal Eran, Nathan Palmer, Paul Avillach, Ami
Levy-Moonshine,
Peter Szolovits, Isaac S. Kohane. A multidimensional precision
medicine approach identifies an autism subtype characterized
by dyslipidemia.

Nature Medicine, 2020; DOI: 10.1038/s41591-020-1007-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200817191733.htm

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