ARTICLE IN BRIEF
In a new analysis of data, investigators reported that penetrance of LRRK2 G2019S mutation associated with Parkinson's disease was lower than previously reported for Ashkenazi Jews.
A decade ago, scientists discovered several pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2) in patients with late-onset Parkinson's disease (PD). The G2019S LRRK2 mutation is found in higher rates in different ethnic groups, specifically among those of North African Arab-Berbers descent and Ashkenazi Jews. Another LRRK2 mutation is also found in Basque populations.
Since LRRK2 mutations have been identified, scientists have been trying to determine the penetrance of the genetic mutation — how often someone with the mutation will develop the disease. Studies have estimated anywhere from 24 percent to 100 percent, but many factors can influence study results.
With this in mind, scientists at Columbia University, Beth Israel Medical Center, and Tel Aviv's Sourasky Medical Center banded together to determine penetrance among Ashkenazi Jews. The data used in the study are part of the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium.
They reported at the AAN Annual Meeting in Philadelphia in April that the penetrance for the mutation was lower than previously reported. The study was funded by the Michael J. Fox Foundation and the Parkinson's Disease Foundation.
In the study, Columbia's Karen S. Marder, MD, MPH, FAAN; Beth Israel's Susan Bressman, MD, FAAN; and Tel Aviv Medical Center's Nir Giladi, MD, used the kin-cohort method to predict penetrance in 1,874 relatives of 131 Parkinson's patients who carry the LRRK2 G2019S mutations and 341 PD patients who did not have this genetic mutation. Family history interviews were completed with each patient, at which time information on age of diagnosis, current age, or age at death was recorded for each first-degree relative with PD. The kin-cohort method uses the LRRK2 G2019S mutation status in PD cases to infer unobserved genotypes in their relatives and combines this with the age at onset data to estimate penetrance.
A subset of relatives also underwent a detailed neurological examination. From the genetic data on each patient and the relationship of each relative to that patient, they made inferences about their relatives' LRRK2 genotypes and combined this with diagnostic information on PD in each relative to arrive at an estimated penetrance among relatives predicted to carry G2019S mutation and those who did not. In other words, without knowing for sure whether or not the relatives had the gene mutation, they could do the analytic work to figure out penetrance.
The 563 relatives were predicted to carry the G2019S mutation and 1,311 predicted not to have the G2019S mutation. The 126 relatives met diagnostic criteria for PD based on family history interview and exam. Of the 126 relatives, it was predicted that 56 had the G2019S mutation.
The method led them to a lifetime penetrance to age 80 of 26.3 percent in G2019S positive relatives (CI= 95%CI 15.8-35.9). That would mean that one in four with the genetic mutation would be diagnosed with PD by the time they celebrated their 80th birthday.
“This is a much lower penetrance than others have reported,” said Dr. Marder, the Sally Kerlin professor of neurology in the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at the Columbia University Medical Center. “There are several reasons why penetrance may be lower, including the specific ethnic group, age and gender of participants, whether the sample was ascertained at a medical center or the community, and whether familial cases were more highly represented.”
“Because we have reported through the consortium that almost 20 percent of Ashkenazi PD patients carry the G2019S mutation, and approximately 2 percent of the Ashkenazi Jewish population carry this mutation,” she continued, “many family members would like to understand what their own risk of developing PD is. We would like to provide this information to genetic counselors to help individuals make informed decisions about genetic testing. “
Dr. Marder and her colleagues plan to expand their family history interviews and exams across eight centers with diverse ethnic populations. They want to incorporate genotype data from relatives and collect more demographic characteristics from patients and their relatives.
“We specifically want to test whether the penetrance in LRRK2 Ashkenazi Jewish family members is lower than in non-Ashkenazi Jewish families using the same methodology and adjusting for the demographic and clinical factors that can modify penetrance. If penetrance is lower in the Ashkenazi, it suggests that there are genetic or environmental factors that delay the onset of PD in Ashkenazi LRRK2 carriers.”
Tatiana Foroud, PhD, the P. Michael Conneally professor of medical and molecular genetics and director of the Hereditary Genomics Division at Indiana University School of Medicine, said that families with LRRK2 mutations will need counseling to understand the risk but the finding “that penetrance is much lower than others have found is relatively good news for families.”
The hope, she added, is that scientists can develop biomarkers to identify people prior to clinical onset of Parkinson's. Such studies could be conducted in families with LRRK2 mutations, given that some will develop Parkinson's but most will not. “We will be able to follow these people longitudinally and identify factors that protect them or increase their risk for disease,” added Dr. Foroud.
Caroline M. Tanner, MD, PhD, FAAN, director of the Parkinson's Disease Research Education and Clinical Center at the San Francisco Veterans Affairs Medical Center and professor of neurology at University of California, San Francisco, agrees that genetic counseling is important for people with gene mutations that put them at risk for disease. She said the high penetrance rates from other studies could have been due to selection bias. Many genetic centers end up with more familial cases.
“This new penetrance rate is valuable information for genetic counseling,” she added. She is now working with the New York researchers on the next leg of their project: to understand what environmental factors might affect penetrance. They will be asking these questions about health behaviors, habits, chemical exposures, and drug use in a dozen languages in countries around the world.
This study was selected by members of the Neurology Today editorial advisory board as one of the noteworthy papers from the AAN Annual Meeting.
EXPERTS RESPOND TO FINDINGS ON LRRK2 PENETRANCE