This document provides an overview of genetics and Parkinson's disease. It discusses how certain gene mutations can increase the risk of developing Parkinson's, including mutations in SNCA, Parkin, DJ-1, PINK1, GBA and LRRK2. These genes code for proteins involved in processes like recycling proteins and protecting neurons. Mutations may result in abnormal protein formation contributing to Parkinson's. The document also discusses family risk factors, genetic testing options, lifestyle factors that may influence risk like diet and exercise, and research being done to help predict and prevent Parkinson's disease.

1. P A C I F I C N E U R O . O R G
Genetics of Parkinson’s Disease
Melita Petrossian, MD
December 6, 2021
Medical Director, Pacific Movement Disorders Center

2. Genetics 101
• Gene = a package of information written with
DNA
– DNA is made up of nucleotides (A, C, G, T)
– Every 3 nucleotides codes for 1 amino acid
– Amino acids are the building blocks for
proteins
– Abnormalities in the DNA are called
mutations
– Often they don’t cause any trouble, but
some mutations may result in abnormal
protein formation which can contribute to
disease
• Allele = one copy of a gene
– One from your mother and one from your
father (other than genes on the Y
chromosome)

3. Genetics 101, continued
• Mutations can be autosomal dominant (AD)
– These are expressed even if the other copy is
normal
– E.g., Huntington’s disease, polycystic kidney
disease
– Having just one copy will cause the disease
– Having one parent with HD means each child
has 50% chance of getting the disorder
• Mutations can be autosomal recessive (AR)
– These are only expressed if both copies are
abnormal
– E.g., cystic fibrosis and sickle cell anemia
– Having just one copy makes the patient a
“carrier”
– Two carrier parents means each child has a 25%
chance of getting the disorder

4. Is Parkinson’s disease (PD) Genetic?
• Yes, but…
• 85% of patients who have PD do not have a family history of PD
– Family history can be limited by:
• Misdiagnosis
• Lack of knowledge of family
• Early death
• Small family
• Non-paternity
• De novo mutation (new)
• Many PD genes are RISK FACTOR genes

5. What are risk factor genes?
• Genes that increase the risk of developing a certain condition but
require either other genes or some environmental factors to create
the condition
• The likelihood that a given gene will cause a disease is called
penetrance
– The highest penetrance of these gene abnormalities is ~30%
– That means that 70% of people who carry these genes will NOT
get PD

6. Which Genes have been associated with PD?
• SNCA
• Parkin
• DJ-1
• PINK1
• GBA
• LRRK2
Schneider, et al. 2020

7. How do these genes abnormalities cause PD?
• SNCA makes alpha-synuclein
– Abnormal SNCA  abnormal alpha-
synuclein  Lewy bodies  brain cell
death  Parkinson’s symptoms
• PARK2 makes parkin
– Normally helps cells recycle proteins
• PARK7 makes DJ1
– Normally protects against stress in the
mitochondria
• PINK1 makes a protein kinase
– Normally protects mitochondria
• LRRK2 makes a protein kinase
• GBA makes glucocerebrosidase
– normally clears out worn out cell
components
Zell

8. How do mutations in GBA contribute to PD?
• Two abnormal copies of GBA causes Gaucher’s disease
– Lysosome storage disease causing build up of toxins
• Enlarged spleen and liver
• Eye movement disorder
• Anemia
• Low platelet count
• Seizures
• One abnormal copy of GBA is associated with risk of PD
– Mutated glucocerebrosidase
• Misfolds and can accumulate in brain cells
• Causes accumulation of alpha-synuclein
• Reduced function of lysosomes (important for cell function and recycling)

9. What are the ways GBA can manifest?
Riboldi, et al. 2019
• Penetrance of GBA for PD is 9-30%
(higher penetrance at higher ages)
• Proportion of people with GBA
mutations who develop PD
• GBA mutations are present in ~ 2-
30% of PD patients
• Proportion of people with PD
who have GBA mutations
• GBA-related PD
• Earlier age of onset
• Higher risk of dementia
• Higher risk of Hallucinations
• Higher risk of RBD
• More likely to have rigid
akinetic subtype rather than
tremor-predominant
• Higher risk of depression /
anxiety

10. What research is being done?
×
Ongoing clinical
trial for ambroxol,
results likely
coming soon

11. What research is being done?
© Prevail

12. Does ethnicity matter?
• Certain gene variants are more common in certain ethnicities
– LRRK2 p.G2019S is present in 26% of Ashkenazi Jewish patients
and 40% of N. African Berbers with PD but absent in Nigerian
PD patients
– GBA
• Prevalence and penetrance are highest in the Ashkenazi Jewish
population
– PINK1 is higher in Filipino populations
– However, genetic research unfortunately has mainly been in
Caucasian populations

13. Should I get tested?
• Personal decision
• Genetic underpinnings of PD may inform personalized medicine
• Some patients may want to participate in clinical trials, e.g., for
GBA or LRRK2 (BIIB094 and DNL151)
• Genetic testing may have increased implications if there is family
history of PD
• Genetic testing may have implications for offspring
• Most patients with PD will test negative

14. What is the risk of PD for my family?
• 2% of people with FH of PD in a 1st
generation relative (parent or sibling)
– Vs 1% in the general population
• Having a genetic link may confer a
higher risk
– SNCA is autosomal dominant, i.e., 50%
risk, but very rare
– LRRK2 is autosomal dominant, i.e., 50%
risk of carrying the gene mutation, but
only 30% penetrant (i.e., without
testing, risk for a 1st generation is 15%)
– Parkin mutations are autosomal
recessive, i.e., 25% risk
– Genetic risk factors such as GBA, MAPT,
PARK16 increase risk variably

15. Should my family get tested for PD-related genes?
• What will the family member do with the information?
• Some will be interested in research studies or clinical trials
• Some will be more motivated to improve lifestyle factors such as
diet and exercise (which they should be doing anyway)

16. How can we predict who will get PD?
• PREDIGT score
– PR (Parkinson’s Risk) = (E + D + I) x G x T
– E = Environmental factors
– D = DNA
– I = Initiation of tissue response
– G = Gender / Sex
– T = Time (Age)
• Environmental factors
– Pesticides
– Manganese (welding)
– Head trauma (concussive vs subconcussive)
– Chronic infection (e.g., H. pylori)
– Encephalitis
– Chronic constipation
– Reduced sense of smell
• Genetic factors
– SNCA, Parkin, DJ1, PINK1, GBA, LRRK2,
other risk loci
– FH of disease
• Initiation of tissue response
– Presence of anxiety / depression
– REM sleep behavior disorder
• Sex
– Male (very slightly increased risk)
• Protective factors are subtracted
– Regular exercise for >20 yrs
– 2 cups of coffee / day
– Smoking (but obviously please don’t
smoke!)
– Certain genetic risk factors are protective

17. What should my family do to prevent PD?
• At this time there is no specific treatment to prevent PD
• MIND diet / Mediterranean diet is associated with a lower risk of
developing PD or a later age of onset
• Higher frequency of vigorous physical exercise associated with a lower
risk of developing PD
• Probably would be a good idea to avoid unnecessary antibiotics (e.g., in
food) to maintain a healthy microbiome
• Air and water pollution appear to play a role
• Advocacy
– Give a Dime campaign (EndingPD.org)
– Ban paraquat, chlorpyrifos, trichloroethylene

18. How can I get tested?
• PDGENEration
– Observational study with genetic testing (8 genes including GBA and LRRK2)
– Virtual history and exam
– Genetic counseling
– Trying to establish connections between the genotype (the genetic information) and phenotype (the
individual symptoms of PD
– Parkinson.org/pdgeneration
• Invitae
– 26 genes including GBA (19 variants), LRKK2, PINK1, SNCA, PARK7, Parkin
– Invitae.com
– Sponsored testing and counseling
• Michael J. Fox Foundation
– Parkinson’s Progression Markers Initiative (PPMI)
– Michaeljfox.org/ppmi
• 23 and Me
– Only looks at one variant of GBA and one of LRRK2