GENES & CELLS
DNA diversity data offer disease clues
Exome studies give insights into schizophrenia, heart conditions
BY TINA HESMAN SAEY
A large study of human genetic variation finds more than 7 million spots
where one person’s DNA can differ from
another’s. Analyses of such variants, compiled from cataloging the genes of more
than 60,000 people, are already offering
doctors insights into diseases such as
schizophrenia and some heart conditions.
Researchers from the Exome Aggregation Consortium first presented their
analysis of the ExAC database online
at bioRxiv.org last year (SN: 12/12/15,
p. 8). Now, the project is getting its official debut in the Aug. 18 Nature.
An exome consists of only the protein-producing genes in a person’s genetic
instruction book, or genome. Scientists
pooled exome data from 60,706 people
from nearly two dozen studies around
the world, nearly 10 times as much data as
any previous study of human genetic variation. The people were far more racially
and ethnically diverse than those in any
previous study and included people with
various diseases as well as healthy people.
Any one person carries tens of thousands of DNA variants, geneticist Daniel
MacArthur of Massachusetts General
Hospital in Boston said in a news briefing. The ExAC team found that, on
average, one in every eight DNA bases
(the chemical building blocks of DNA)
differs among people. In total, the team
recorded over 7. 4 million variants, most
of them changes in single DNA bases.
Even before they presented their own
analysis, ExAC researchers released the
data in 2014 for other scientists to use.
Already, these data have contributed to
the day-to-day interpretation of genetic
information in the clinic, says Eliezer Van
Allen, a medical oncologist at Harvard
Medical School. “It gives a new look into
the drivers of human genetic diversity.”
A companion study reported August
17 in Nature Genetics, for instance, found
that, on average, people have 0.81 missing
genes and 1.75 extra copies of genes. The
analysis echoed previous studies in show-
ing that people with schizophrenia are
more likely to have deleted or duplicated
genes, often genes important in the brain.
Now, the challenge is to figure out
what all of the variations mean.
Two separate studies suggest that
ExAC data could give a clearer picture of
the gene changes that contribute to heart
conditions known as cardiomyopathies.
Scientists over the last 10 years have
amassed a number of rare variants linked
to heart diseases. “There was always a lot
of doubt cast about whether these [vari-ants] were real or not,” says geneticist
Roddy Walsh of Imperial College London.
Walsh and colleagues used ExAC data
and data from 7,855 cardiomyopathy
patients to reevaluate the likelihood that
a particular variant would cause a heart
problem. Finding a variant in patients
that is rarely seen in people without the
disease suggests the variant could be the
cause. But if the variant appears just as
often in people that don’t have cardio-
myopathies, it is unlikely to cause disease.
Of the people in ExAC, 11. 7 percent
carry variants linked to hypertrophic
cardiomyopathy, Walsh’s team reports
August 17 in Genetics in Medicine. That’s
far more people than expected for a rare
inherited condition, which strikes about
one in 500 people. Those data and other
evidence suggest that many of the vari-
ants implicated in the disease are benign.
ExAC data alone can’t rule out a
potentially disease-causing variant,
says Benjamin Meder, a cardiologist at
Heidelberg University Hospital in
Germany. Researchers don’t know the
full medical history of ExAC volunteers.
Some may have undetected cardio-
myopathy; others may have been mis-
diagnosed as having the disease, he says.
It’s important to clearly define who has a
disease and who doesn’t before conduct-
ing genetic studies. “This paper does it the
wrong way around,” Meder says. Still, he
says, ExAC offers some valuable insights
into the genetics of heart problems.
Misdiagnosing a genetic disease can
affect entire families, says Isaac Kohane,
a biomedical informaticist at Harvard
Medical School. For instance, people
related to a youngster who collapses on
the basketball court and is found to carry
a rare variant associated with a heart con-
dition may also be screened for the vari-
ant. Relatives carrying the variant may be
treated for a condition they don’t have.
Misdiagnosis is more likely for African-
Americans, Kohane and colleagues report
in the Aug. 18 New England Journal of
Medicine. Five variants previously associ-
ated with hypertrophic cardiomyopathy
are too common to cause a rare genetic
disorder, Kohane’s team found. Of black
Americans, 2. 9 to 27. 1 percent carried
at least one copy of the variants; 0.02 to
2. 9 percent of white Americans had one.
Kohane’s team now says these vari-
ants are benign. The mistake could have
been avoided if researchers had included
even a few black Americans in their stud-
ies. Kohane’s team calculates that the
ExAC data, with its genetic diversity,
could rule out many benign variants,
including ones carried by as little as
0.1 percent of the population. s
Copy count A genetic analysis of more
than 60,000 people found that, on average,
each person has 0.81 deleted genes (yellow)
and 1.75 duplicated genes (blue). But some
people may be missing or have extra copies of
up to 10 or more genes, which may put them
at risk for diseases such as schizophrenia.
SOURCE: D. RUDERFER ET AL/NATURE GENETICS 2016
Number of genes deleted or
duplicated per individual
Proportion of people with missing
or extra copies of genes