People often ask, is Parkinson’s disease (PD) genetic?
If one of my parents has Parkinson’s, am I more at risk? In rare cases, the
answer is black-and-white: a specific inherited genetic change, or mutation,
causes Parkinson’s directly.
But for most people, genetics plays a more complex
role, influencing their risk for Parkinson’s but not directly causing the
disease.
In the past decade or so, genetics has become one of
the most exciting areas of Parkinson’s research, leading to a startling
realization: most cases of Parkinson’s likely have a genetic component. And
today, that grey area — the continuum of risk for Parkinson’s — is coming into
sharper focus.
The Parkinson’s Disease Foundation (PDF), a division
of the Parkinson’s Foundation, has invested heavily in genetics research,
through our fellowship and career development awards to individuals, and grants
to teams at our Research Centers.
The genetic discoveries made by our teams are leading
to fundamental insights into the causes of Parkinson’s and ideas for how to
better treat the disease. The reasoning goes like this: if we understand which
genes are linked to PD, we can find ways to change their activity. For example,
if a gene contributes to PD by being overactive (e.g., encoding for an
overactive enzyme), a drug that shuts it down might help PD, even in those
without the gene mutation. Additionally, long-term studies of genes, some of
which we have supported, are influencing the design of clinical trials and
helping us to understand why different people experience the disease
differently.
This research, in turn, paves the way to personalized
therapies. Here are some highlights.
Genetics Upends Our View of Parkinson’s
Today, scientists agree that genetic and environmental
factors both play a role in causing Parkinson’s. However, as recently as the
1990s, few scientists suspected a role for genes. One who did was Roger
Duvoisin, M.D., the first research fellow funded by PDF (to date, we have
supported 150). In 1997, Dr. Duvoisin and colleagues broke open the field with
the discovery of the first gene linked to PD: alpha- synuclein. Mutations in
this gene cause PD throughout multiple generations in the rare families who carry
them.
Dr. Duvoisin’s finding spurred an intense search for
more PD genes. Studies of families affected by PD quickly led to the discovery
of another gene, LRRK2 (leucine-rich repeat kinase 2) in 2004 and the
realization that LRRK2 mutations were more common in some populations than in
others. For example, whereas one to two percent of whites with European
ancestry carried LRRK2 mutations, these genetic changes were found in up to 20
percent of Ashkenazi Jews (people of Eastern European descent).
At about the same time, other research groups made a
link between Gaucher disease and Parkinson’s, shedding light on another gene:
GBA. People with Gaucher disease have mutations in both copies of a gene known
as GBA. Carriers of GBA (people with only one mutated copy of the gene) do not
show any symptoms of the disease, but have an increased risk of developing PD.
The Most Common PD Genes
Among the 30 genetic changes that have been linked to
Parkinson’s disease, changes in GBA and LRRK2 are the most common. Two researchers
at our Research Center at Columbia University Medical Center, Karen Marder,
M.D., Ph.D., and Roy N. Alcalay, M.D., M.Sc., have pushed the field forward in
understanding them.
It’s important to remember that not everyone with GBA
or LRRK2 mutations develops PD. So part of the research focuses on risk. “If
you have the mutations, what is your risk for Parkinson’s?” asks Dr. Alcalay.
“That’s a very important question for the family members of people with PD to
know — if I have mutation, what’s the risk that I will actually go onto develop
PD? It’s also important for research because if we develop a drug to reduce
genetic risk, we first need to understand a person’s baseline risk before we
start trying to reduce it.” For carriers of GBA mutations, Dr. Alcalay and
colleagues estimate the risk of PD to be 10 percent. Dr. Marder led the work on
LRRK2, finding a 30 percent risk of PD for carriers.
That was just the first step. While following the
progression of PD in hundreds of people with these mutations, Drs. Alcalay and
Marder observed distinct sets of symptoms associated with the two genes. For
example, as a group, people with GBA mutations had more rapidly progressing PD
compared to those with LRRK2 mutations, and experienced more nonmotor symptoms,
including cognitive difficulties. For the majority of people with PD, it is too
soon to use genetics to predict symptoms. These findings, however, represent a
step in that direction.
New knowledge about LRRK2 and GBA is guiding the
research of Dr. Alcalay and others into biomarkers — substances that could be
measured in blood or urine to diagnose Parkinson’s, monitor its progression and
possibly identify genetic mutations. Biomarkers would not only ease diagnosis,
they would also help clinical trials by tracking the effects of experimental
therapies.
For GBA carriers, those therapies may be near at hand.
“There is a lot of information about Gaucher disease, and there are treatments
for it,” explains Dr. Alcalay, noting that there are drugs that boost the activity
of the GBA enzyme called glucocerebrosidase. “The problem is that those
treatments cannot penetrate the brain. So the goals for scientists are very
clear — let’s try to enhance the activity of the GBA enzyme in the brain and
see what happens.” In fact, clinical trials for studies to do this already are
recruiting participants.
“Our hope is that the research we did five years ago
to identify PD genes will now lead us to studies of possible therapeutics,”
says Dr. Alcalay.
New Techniques
Early genetics research in PD had much success by
homing in on single genes, often associated with PD in families. But genetic
mutations that directly cause PD account for only ten percent of PD diagnoses.
In the remaining 90 percent of cases, small changes in many genes influence a
person’s risk of developing PD.
More recently, scientists have taken a more
big-picture approach, using a technique called genome-wide association studies
(GWAS), to study hundreds and thousands of genes at one time. With the GWAS
technique, scientists can scan the genomes of thousands of people with PD in
search of variations — essentially single-letter “spelling” differences —
associated with disease.
“The realization that all cases of PD have a genetic
component doesn’t mean that the disease will run in families,” says Andrew B.
Singleton, Ph.D., at the US National Institutes of Health. “Rather it shows us
that Parkinson’s occurs because of a very complex mixture of genetic changes,
which likely interact with the environment to increase risk for the disease.”
Dr. Singleton led a study published in 2014 that
analyzed data from earlier GWAS studies to compare the genetic make-up of
thousands of people with PD with the genetic make-up of healthy individuals.
The researchers identified six new gene regions associated with PD. Although
the PD risk associated with variations at each region was small, it was
cumulative — multiple changes added up to increased PD risk. The study points
to a different way to estimate Parkinson’s risk and to understand how genes
interact to cause the disease.
Spotlight on Populations
To date, most genetic studies on PD have been carried
out on populations of European or Asian ancestry. But gene variants differ
around the world. In 2009, we supported the work of Ignacio Fernandez Mata,
Ph.D., of the University of Washington and the VA Puget Sound Health Care
System, to create a research consortium for Parkinson’s genetics called the
Latin American Research Consortium on the Genetics of PD (LARGE-PD).
When Dr. Mata and team analyzed DNA collected from
nearly 3,000 participants, they found some surprises. For example, says Dr.
Mata, “In a European population the most common LRRK2 variant causes one to two
percent of PD cases. But in a lot of Latin American countries this variant is
rare, and the amount of LRRK2 carriers is tied to the amount of European
ancestry people have.”
When the team looked at another common PD gene, GBA,
in Latin American people with PD, they discovered a new variation in Colombia
(distinct from the mutations previously found) apparently traceable to the
African ancestry of the participants. This variation accounted for nearly half
of the GBA mutations found in this country. “This is one of the interesting
things about studying populations — we are finding new variants in known
genes,” says Dr. Mata.
The finding is important because, in the future, if
doctors want to screen Latinos for GBA variations, they will know to look for
this specific one. In addition, it’s possible that this variation contributes
to PD in European populations too, but has not yet been detected because of its
low frequency. With new funding from PDF, Dr. Mata is planning the first GWAS
study in Latinos with PD, with the ultimate goal of helping to determine how
gene variants affect the risk of someone of a certain ethnicity for developing
Parkinson’s.
Looking Ahead
Scientists have a wealth of genetic data to interpret,
and they are on the cusp of using it to develop new therapies. One way this is
shaping up is to allow for more focused and reliable clinical trials. It’s
possible that some Parkinson’s disease clinical trials in the past have failed
because they included a mix of participants, some of whom may be genetically
predisposed to respond to a therapy and others not. Using genetics, it may be
possible to develop therapies that target specific genetic variations and to
recruit participants who may be more likely to benefit. In other words, we can
use genetics to target the right treatments to the right people with PD.
A better understanding of genetic risks for PD will
also help researchers identify subtypes of PD in the future — clusters of
symptoms related to genetic variations. “Combining genetics with other factors,
such as imaging, biomarkers and clinical signs, will give us the best road to
predicting the course of disease, response to treatment and individualized
treatment,” says Dr. Singleton.
While personalized medicine is a goal for the future,
it will require the difficult and costly work of studying very large numbers of
people with PD. In addition, as we try to understand the mechanisms that
underlie Parkinson’s, studying in genetics in the lab will remain a critical
way to find answers. PDF is committed to the long-term support of this
research. It is only by continuing to move the field forward will we achieve
our goals of better ways to diagnose and treat PD, and ultimately to end it.
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