Major Genetic Risk Factor Is Discovered for Parkinson's

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase confer the single strongest risk for developing Parkinson's disease of any gene that has been discovered, according to a multicenter analysis of patients from around the world.

A single mutant copy of the gene, GBA, was found in 15% of Ashkenazi Jewish patients with Parkinson's disease and in 3% of Parkinson's patients of other ethnicities, compared with 3% of control patients with Ashkenazi ethnicity and less than 1% with non-Ashkenazi background.

“The high frequency of mutations among ethnically diverse, heterogeneous cohorts of patients with Parkinson's disease makes the mutations in this gene the most common genetic risk factor for Parkinson's disease that has been identified to date,” Dr. Ellen Sidransky of the National Human Genome Research Institute and her associates wrote in the the New England Journal of Medicine.

Although previous smaller studies have indicated a potential association between heterozygous carriers of a single defective copy of GBA and the risk of Parkinson's disease, this is the first time that it has been conclusively shown that even a single copy of the mutated gene can contribute to disease.

Holders of two defective GBA alleles develop Gaucher's disease, which is characterized by an accumulation of glucocerebroside, an essential component of cell membranes. This can lead to a broad spectrum of disease manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, bone disease, and neurologic impairment.

Dr. Mark Hallett, chief of the medical neurology branch of the National Institute of Neurological Disorders and Stroke, said in an interview that the discovery of the contribution of GBA mutations to Parkinson's disease risk is “far from the whole answer, but it's a piece of the puzzle that I think is becoming clearer now. It seems very clear that there's going to be a number of risk genes that all add up together that will lead to Parkinson's disease.”

Dr. Hallett, who was not involved in the study, likened the GBA finding to the discovery of the apolipoprotein E gene's contribution to the increased risk for developing Alzheimer's disease, in combination with other susceptibility alleles and various environmental factors.

In the study, Dr. Sidransky and her colleagues pooled data from 16 centers that had genotyped 5,691 patients with Parkinson's disease and 4,898 control patients for mutations in GBA. The centers were located in North America (4), South America (1), Asia (3), Israel (2), and Europe (6). The analysis included 980 Ashkenazi Jewish patients with Parkinson's disease and 387 Ashkenazi Jewish control patients (N. Engl. J. Med. 2009;361:1651–61).

At least 6 out of 100 people of Ashkenazi descent carry a defective GBA allele, compared with fewer than 1 out of 100 people in the general population.

Among all patients, carriers of any GBA mutation had more than five times greater odds of developing Parkinson's disease than did noncarriers. Two mutations in particular–N370S and L444P–accounted for most of the GBA mutations and were most prevalent in Ashkenazi patients.

Individuals with the N370S or L444P mutation were nearly four times or nearly seven times more likely, respectively, to develop Parkinson's disease than were noncarriers.

The investigators found that incomplete sequencing of GBA, such as only screening for the N370S or L444P mutations, could miss many mutant alleles in non-Ashkenazi ethnic groups. For example, complete sequencing of GBA in non-Ashkenazi Jewish patients indicated that up to 45% of mutant alleles could be missed if only N370S and L444P were targeted.

Patients with GBA mutations developed Parkinson's disease at a significantly earlier mean age than did noncarriers (54.9 years vs. 58.8 years). A significantly higher proportion of patients with a GBA mutation also reported having a first- or second-degree relative with Parkinson's disease, compared with noncarriers (24% vs. 18%).

Some disease features showed up significantly more often among those with GBA mutations than in those without mutations, such as asymmetric onset, bradykinesia, resting tremor, rigidity, and cognitive changes.

The study was funded impart by large number of international grants. Dr. Sidransky had no disclosures to report, but many other investigators reported potential conflicts of interest.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase confer the single strongest risk for developing Parkinson's disease of any gene that has been discovered, according to a multicenter analysis of patients from around the world.

A single mutant copy of the gene, GBA, was found in 15% of Ashkenazi Jewish patients with Parkinson's disease and in 3% of Parkinson's patients of other ethnicities, compared with 3% of control patients with Ashkenazi ethnicity and less than 1% with non-Ashkenazi background.

“The high frequency of mutations among ethnically diverse, heterogeneous cohorts of patients with Parkinson's disease makes the mutations in this gene the most common genetic risk factor for Parkinson's disease that has been identified to date,” Dr. Ellen Sidransky of the National Human Genome Research Institute and her associates wrote in the the New England Journal of Medicine.

Although previous smaller studies have indicated a potential association between heterozygous carriers of a single defective copy of GBA and the risk of Parkinson's disease, this is the first time that it has been conclusively shown that even a single copy of the mutated gene can contribute to disease.

Holders of two defective GBA alleles develop Gaucher's disease, which is characterized by an accumulation of glucocerebroside, an essential component of cell membranes. This can lead to a broad spectrum of disease manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, bone disease, and neurologic impairment.

Dr. Mark Hallett, chief of the medical neurology branch of the National Institute of Neurological Disorders and Stroke, said in an interview that the discovery of the contribution of GBA mutations to Parkinson's disease risk is “far from the whole answer, but it's a piece of the puzzle that I think is becoming clearer now. It seems very clear that there's going to be a number of risk genes that all add up together that will lead to Parkinson's disease.”

Dr. Hallett, who was not involved in the study, likened the GBA finding to the discovery of the apolipoprotein E gene's contribution to the increased risk for developing Alzheimer's disease, in combination with other susceptibility alleles and various environmental factors.

In the study, Dr. Sidransky and her colleagues pooled data from 16 centers that had genotyped 5,691 patients with Parkinson's disease and 4,898 control patients for mutations in GBA. The centers were located in North America (4), South America (1), Asia (3), Israel (2), and Europe (6). The analysis included 980 Ashkenazi Jewish patients with Parkinson's disease and 387 Ashkenazi Jewish control patients (N. Engl. J. Med. 2009;361:1651–61).

At least 6 out of 100 people of Ashkenazi descent carry a defective GBA allele, compared with fewer than 1 out of 100 people in the general population.

Among all patients, carriers of any GBA mutation had more than five times greater odds of developing Parkinson's disease than did noncarriers. Two mutations in particular–N370S and L444P–accounted for most of the GBA mutations and were most prevalent in Ashkenazi patients.

Individuals with the N370S or L444P mutation were nearly four times or nearly seven times more likely, respectively, to develop Parkinson's disease than were noncarriers.

The investigators found that incomplete sequencing of GBA, such as only screening for the N370S or L444P mutations, could miss many mutant alleles in non-Ashkenazi ethnic groups. For example, complete sequencing of GBA in non-Ashkenazi Jewish patients indicated that up to 45% of mutant alleles could be missed if only N370S and L444P were targeted.

Patients with GBA mutations developed Parkinson's disease at a significantly earlier mean age than did noncarriers (54.9 years vs. 58.8 years). A significantly higher proportion of patients with a GBA mutation also reported having a first- or second-degree relative with Parkinson's disease, compared with noncarriers (24% vs. 18%).

Some disease features showed up significantly more often among those with GBA mutations than in those without mutations, such as asymmetric onset, bradykinesia, resting tremor, rigidity, and cognitive changes.

The study was funded impart by large number of international grants. Dr. Sidransky had no disclosures to report, but many other investigators reported potential conflicts of interest.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase confer the single strongest risk for developing Parkinson's disease of any gene that has been discovered, according to a multicenter analysis of patients from around the world.

A single mutant copy of the gene, GBA, was found in 15% of Ashkenazi Jewish patients with Parkinson's disease and in 3% of Parkinson's patients of other ethnicities, compared with 3% of control patients with Ashkenazi ethnicity and less than 1% with non-Ashkenazi background.

“The high frequency of mutations among ethnically diverse, heterogeneous cohorts of patients with Parkinson's disease makes the mutations in this gene the most common genetic risk factor for Parkinson's disease that has been identified to date,” Dr. Ellen Sidransky of the National Human Genome Research Institute and her associates wrote in the the New England Journal of Medicine.

Although previous smaller studies have indicated a potential association between heterozygous carriers of a single defective copy of GBA and the risk of Parkinson's disease, this is the first time that it has been conclusively shown that even a single copy of the mutated gene can contribute to disease.

Holders of two defective GBA alleles develop Gaucher's disease, which is characterized by an accumulation of glucocerebroside, an essential component of cell membranes. This can lead to a broad spectrum of disease manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, bone disease, and neurologic impairment.

Dr. Mark Hallett, chief of the medical neurology branch of the National Institute of Neurological Disorders and Stroke, said in an interview that the discovery of the contribution of GBA mutations to Parkinson's disease risk is “far from the whole answer, but it's a piece of the puzzle that I think is becoming clearer now. It seems very clear that there's going to be a number of risk genes that all add up together that will lead to Parkinson's disease.”

Dr. Hallett, who was not involved in the study, likened the GBA finding to the discovery of the apolipoprotein E gene's contribution to the increased risk for developing Alzheimer's disease, in combination with other susceptibility alleles and various environmental factors.

In the study, Dr. Sidransky and her colleagues pooled data from 16 centers that had genotyped 5,691 patients with Parkinson's disease and 4,898 control patients for mutations in GBA. The centers were located in North America (4), South America (1), Asia (3), Israel (2), and Europe (6). The analysis included 980 Ashkenazi Jewish patients with Parkinson's disease and 387 Ashkenazi Jewish control patients (N. Engl. J. Med. 2009;361:1651–61).

At least 6 out of 100 people of Ashkenazi descent carry a defective GBA allele, compared with fewer than 1 out of 100 people in the general population.

Among all patients, carriers of any GBA mutation had more than five times greater odds of developing Parkinson's disease than did noncarriers. Two mutations in particular–N370S and L444P–accounted for most of the GBA mutations and were most prevalent in Ashkenazi patients.

Individuals with the N370S or L444P mutation were nearly four times or nearly seven times more likely, respectively, to develop Parkinson's disease than were noncarriers.

The investigators found that incomplete sequencing of GBA, such as only screening for the N370S or L444P mutations, could miss many mutant alleles in non-Ashkenazi ethnic groups. For example, complete sequencing of GBA in non-Ashkenazi Jewish patients indicated that up to 45% of mutant alleles could be missed if only N370S and L444P were targeted.

Patients with GBA mutations developed Parkinson's disease at a significantly earlier mean age than did noncarriers (54.9 years vs. 58.8 years). A significantly higher proportion of patients with a GBA mutation also reported having a first- or second-degree relative with Parkinson's disease, compared with noncarriers (24% vs. 18%).

Some disease features showed up significantly more often among those with GBA mutations than in those without mutations, such as asymmetric onset, bradykinesia, resting tremor, rigidity, and cognitive changes.

The study was funded impart by large number of international grants. Dr. Sidransky had no disclosures to report, but many other investigators reported potential conflicts of interest.