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The Lubbe Lab endeavors to further understand the underlying genetics of neurodegenerative diseases, like Parkinson's disease, dystonia and other movement disorders, through family- and population-based approaches. We firmly believe that the best way to achieve this is through collaborative, open science and, as such, we are active members in several consortia. Without our many collaborators and the patients who donate their time and DNA, our research would not be possible. Learn more about our efforts below.


Parkinson’s Disease: Exploring the genetic architecture through large-scale omics analyses

Parkinson’s disease is a complex neurodegenerative disorder of which genetics is a known factor. Many genes have been shown to cause or significantly increase the risk of getting Parkinson’s disease (such as LRRK2, SNCA, PRKN, GBA); however, these genes only account for about 10 percent of all known cases. Many cases do not have an identified known cause, even when the disease appears to be familial.

Recent genome-wide association studies (GWAS) have found many common variants that increase risk in carriers, but these variants only account for about 30 percent of the total genetic heritability of Parkinson’s disease, suggesting that many new genetic variants are yet to be discovered. We lead several projects that utilize a wide array of large-scale genetics and other omics datasets in order to uncover novel genetic variants linked to Parkinson’s disease pathogenesis.

 Genome-wide assessment of common short-tandem repeats to Parkinson’s disease risk

DNA repetitive elements like short-tandem repeats account for more than 50 percent of the human genome, yet very little is known of their contribution to Parkinson’s disease risk. Selected short-tandem repeats within candidate genes have previously been studied in Parkinson’s disease, but their genome-wide contribution remains unexplored. We are undertaking the first genome-wide association study of common short-tandem repeats in Parkinson’s to assess their contribution to disease risk and to the genetic architecture of the disease. We aim to do this through a meta-analysis of 16 imputed case-control cohorts from the International Parkinson’s Disease Genomic Consortium, totaling 16,642 Parkinson’s disease cases and 22,445 controls.

Initial results have identified four novel independent (from known genome-wide association studies risk variants) short-tandem repeats near NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1. To try and understand how any candidate short-tandem repeat may contribute to disease pathology, we will incorporate brain gene expression data, DNA regulatory data, etc., as well as interrogate these variants in relation to disease-relevant tissues and pathways.

Read a preprint of this study here.

 Assessment of the contribution of different variant types to Parkinson’s disease risk

Many genetics studies are limited by statistical power or the power to detect an association given the size of the cohort and the number of variants assessed. Whole-exome sequencing data has revealed an unexpectedly large number of variants, thereby confounding efforts to identify novel variant associations. There are many types of variants, differing for example in their observed population frequency and their impact on protein/gene expression. Here we aim to characterize the contribution of the different types of variants in Parkinson’s disease to facilitate more informed approaches aimed at novel gene discovery. We will perform a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes by analyzing whole-exome sequencing data from several large-scale case-control cohorts. Preliminary data in 1,425 Parkinson’s disease cases and 596 controls demonstrated a significantly increased burden of ultra-rare (private variants absent from gnomAD) protein-altering variants in early-onset cases compared to late-onset cases where more common protein-altering variants (allele frequencies less than 0.001) showed the highest significance and effect. These results suggest that ultra-rare variants play a significant role in early-onset Parkinson’s disease and that distinct etiological bases may exist for early-onset disease and sporadic disease. We are in the process of replicating and validating our findings in two additional, independent large-scale cohorts totaling more than 350,000 individuals.

Read a preprint of this study here.

 Novel gene discovery through the assessment of genome-wide homozygosity

Early-onset Parkinson’s disease is known to be caused by recessive or biallelic mutations in genes such as PRKN, DJ1 and PINK1. While these genes account for the disease in some cases, the vast majority of early-onset cases still do not have an identified genetic cause. Hypothesizing that recessive genes remain to be found, we aim to use genome-wide homozygosity mapping to identify potential, novel early-onset Parkinson’s disease genes. Preliminary results generated from data on 3,381 Parkinson’s disease patients and 2,463 controls prioritized MIEF1 as a potential early-onset candidate gene. Additionally, functional data generated indicated that the candidate variants preferentially disrupted protein oligomerization. We are again in the process of replicating and validating these results in large-scale, case-control cohorts.

Read a preprint of this study here.

 Genome-wide analysis of genetic epistasis in Parkinson’s disease

Genome-wide association studies have identified 90 common variants associated with increased Parkinson’s disease risk. However, these studies fail to take into account that some variants may interact with each other to modulate disease risk. Epistasis occurs when independent variants work together to, for example, increase risk when individually they may not confer increased risk themselves. For this project, we will assess genome-wide epistasis in several large-scale European and Latino/Hispanic genome-wide association case-control cohorts. Working with collaborators, we aim to develop a tool for other researchers to help prioritize variants and to perform in-depth epistatic association testing.

 Rare noncoding variation in Parkinson’s disease

The contribution of noncoding variation to Parkinson’s disease pathology is well-established and is mostly focused on the role of common genome-wide association study identified variants. The majority of genetic studies also focus on the protein-coding regions of the genome, which account for less than 5 percent of the whole genome. We hypothesize that rarer variants (with an observed population frequency less than 1 percent) also contribute to Parkinson’s disease. Using several, large case-control whole-genome sequencing datasets, we aim to assess the role of rare noncoding variants in Parkinson’s disease etiology across different observed allele frequencies and ages of onset.

 Finding the causes of familial Parkinson’s disease through detailed genetics analyses

Many people with Parkinson’s report a positive family history of the disease. While several genes known to cause familial Parkinson’s disease have been found, these identified genes only explain about 10 percent of familial disease cases. This indicates that most of these families' cases are unsolved, and that there are many new genes to uncover. Working with the Parkinson’s Disease and Movement Disorders Center Biorepository, we are collecting DNA samples from people with Parkinson’s disease and their family members (both those who are also affected and those who don’t have the disease) to uncover whether genetic mutations are the reason for the disease in their family. We are super excited by the success we are achieving with this initiative and are hopeful that our findings will help us find better treatment for this devastating disease.


Parkinson’s disease and cutaneous malignant melanoma: Examining their unlikely link

Malignant melanoma is the cancer of melanocytes that produce melanin needed for skin pigmentation. Parkinson’s disease results from the uncontrolled death of neurons that make neuromelanin in the brain. Studies have long suggested that these two diseases share an unlikely genetic background. A few of our projects in the Lubbe Lab, some in collaboration with others, aim to untangle this link at the genetic and functional levels.

 Investigating the shared genetic background between Parkinson’s disease and cutaneous malignant melanoma

Epidemiological studies have long suggested that people with Parkinson’s disease are at an increased risk for malignant melanoma and, likewise, that individuals with melanoma have a higher chance of getting Parkinson’s disease. By generating whole-exome sequencing data on as many individuals with both Parkinson’s disease and malignant melanoma, we strive to identify rare variants in genes that predispose people to both diseases and to assess this increased risk in separate Parkinson’s and melanoma case-control cohorts. Integrating other omics datasets, we plan to help understand how the candidate variants modulate risk at a cellular level. Studies have also suggested that Parkinson’s disease and malignant melanoma are more common in fairer pigmented individuals (blond, fair skin) compared to people with darker pigmentation (black and brown hair). We are therefore intending to assess genes involved in skin, hair and eye pigmentation to learn if they are involved in influencing risk for Parkinson’s disease.

 Neuromelanin – friend or foe?

Neuromelanin-containing dopaminergic neurons in the substantia nigra are the most vulnerable neurons in Parkinson’s disease. The role of neuromelanin in the brain is interesting, as it can be both protective (by binding to cellular debris) and toxic (by stimulating inflammatory response). Neuromelanin (pheo- and eu-melanin) production, dopamine production and cellular toxicity appear to be linked within substantia nigra neurons. By combining large-scale genetics with detailed functional assessment in cellular models, we and our collaborators plan to determine whether neuromelanin plays a role in Parkinson’s disease.


Dystonia: Solving familial dystonia through collaborative genetics

Dystonia is a rare complex movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive, movements and/or postures. Several familial or monogenic forms of dystonia exist, and many genes linked to causing dystonia have been identified.

Through large collaborative studies, the Lubbe Lab has been instrumental in identifying and replicating several novel dystonia genes (MED27, AOPEP, EIF2AK2, VPS16, VPS41, KMT2B, YY1) by studying rare variants that track with dystonia in families. With access to one of the largest dystonia whole-exome sequencing cohorts (thanks to the Parkinson’s Disease and Movement Disorders Center Biorepository and our Italian collaborators), we will strive to identify the genetic causes of dystonia in each patient.