Predictors of Parkin Mutations in Early Onset Parkinson disease: the CORE-PD Study
1Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
2Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA
3Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
4Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
5Department of Neurology/Movement Disorder Section, Rush University, Chicago, IL, USA
6Parkinson’s Disease and Movement Disorders Center, Pennsylvania Hospital, Philadelphia, Pennsylvania, USA
7The Institute for Neurodegenerative Disorders, New Haven, Connecticut 06510-2716, USA
8Struthers Parkinson’s Center, Park Nicollet Clinic, Golden Valley, MN, USA
9The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
10Department of Neurology, Albert Einstein College of Medicine
11Dr. John T Macdonald Foundation, Department of Human Genetics, Miami Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
12Parkinson’s Institute, Sunnyvale, California, USA
13Marshfield Clinic, Department of Neurology, Marshfield, WI 54449, USA
14New York State Psychiatric Institute, Data Coordinating Center, New York, NY, USA
15Department of Neurology, at NorthShore University Health System, Evanston, Illinois, USA
16Department of Neurology, at Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
17Parkinson’s Disease and Movement Disorders Center of NeuroHealth, Warwick, Rhode Island
18Department of Clinical Neurosciences, The Warren Alpert School of Medicine of Brown University, Providence, Rhode Island. USA
19Department of Neurology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
20Morris K. Udall Parkinson’s Disease Research Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
21Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
22Department of Neurology and Neurological Sciences Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
23Medical College of Wisconsin, Milwaukee, Wisconsin USA
24Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
25Epidemiology Division, New York State Psychiatric Institute, New York, NY, USA
26Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
27Center for Human Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Demographic and clinical characteristics of the cases are shown in . Sixty-four PD cases (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygotes, 2.2% compound heterozgyotes). The prevalence of mutations declined with AAO from 57% (8/14) in cases with AAO <20, 30% (13/43) in cases with AAO 20–29, 9% (23/254) in cases with AAO 30–39 and 3% (20/644) in those with AAO 40–50 (test for linear trend p<0.001). None of 12 Black non-Hispanics carried a parkin mutation, while 5.7% (48/838) White non-Hispanic, 15.6% (12/77) of Hispanics and 14.8 (4/27) of cases in “other” ethnic groups combined did (p<0.002). No Blacks, but nine Whites endorsed Hispanic ethnicity (Mexican) and were classified in the Hispanic category. One carried a heterozygous exon 6 deletion. Among those who reported a family history of PD in a first degree relative, 11.8% carried mutations compared to 5.7% of those who did not have a family history of PD (p=0.007). CNV was present in 52.3% of carriers (31.6% heterozygotes, 83.3% homozygotes, 81.0% compound heterozygotes). There was no reported consanguinity.
All mutation carriers were similar in age but compound heterozygotes and heterozgyotes were significantly younger than parkin non-carriers. Each mutation carrier group had significantly younger AAO than the non-carrier group Compound heterozygotes and homozygotes each had a significantly younger AAO than heterozygotes. The mean age of White non-Hispanics was 41.7(sd 6.7) years, Black non-HIspanics 36.6 (sd 6.9) years, Hispanics 39.7 (sd 8.1) years and “other” 40.4 (sd 8.3) years. White Non-Hispanics were significantly older than Black non-Hispanics (p <0.05).
Dystonia, as a presenting sign did not differ between carriers (0%) and non-carriers (1.7%) of parkin mutations (p=0.4) Similarly there was no difference in reported response to levodopa; 93.4% of carriers compared to 90.5% of non-carriers reported a response to anti-parkinson medications when tried in an adequate does.(p=0.60).
Logistic models examining the association of demographic risk factors with the presence of any parkin mutation or the presence of heterozygous mutations compared to non-carriers are shown in and . AAO was inversely related to the presence of any parkin mutation, after adjustment for ethnicity and family history of PD in a first-degree relative. Education and gender were not associated with mutation status in this model. Compared to White non-Hispanic, Hispanic ethnicity was associated with the presence of a parkin mutation in both the model examining the presence of any mutation (OR 2.7 95% CI 1.3–5.7, p<0.009) () and the model examining heterozygotes compared to non-carriers OR 2.8 95%CI 1.1–7.2, p<0.03 (). When cases with mutations in both alleles (compound heterozygote and homozygotes) were compared to non-carriers, AAO (OR 18.6 95%C I5.5–63.8 p<0.001) and family history of PD 3.5 95% CI 1.4–9.2 p <0.01 were significant but Hispanic ethnicity was no longer significant (data not shown). When those with two mutations were compared to those with a single mutation (heterozygotes), AAO was inversely associated with carrying two mutations (OR 6.6 95%CI 1.6–27.1 p<0.008) but neither ethnicity nor family history was associated with carrying two mutations.
The Odds of carrying any mutation in the parkin gene (heterozygous, homozygous, compound heterozygous) compared to probands who are non-carriers of parkin mutations
The Odds of carrying a single heterozygous mutation in the parkin gene compared to probands who are non-carriers of parkin mutations
All analyses were repeated excluding 35 LRRK2 G2019S mutation carriers, 45 Glucocerebrosidase N370S carriers and 23 Glucocerebrosidase L444P carriers. . One heterozygous parkin carrier (deletion) also carried a G2019S mutation and 3 heterozygous parkin carriers had GBA mutations (2 L444P and 1 N370S). The inverse relationship between AAO and carrying any parkin mutation (n=57) or a single mutation and the relationship between family history of PD and carrying either 1 or 2 mutations remained. Adjusting for AAO and family history of PD, the association between Hispanic ethnicity and carrying any parkin mutation (OR 2.6 95%CI 1.1–5.9 p<0.03) or a heterozygous mutation (OR 3.7 95%CI 1.3–10.08.3p<0.01) persisted.
The specific parkin mutations detected in heterozygotes, homozygotes and compound heterozygotes are listed in . The seven variants of uncertain significance detected among nine cases included Asp18Asn, Ala82Glu (n=2), Pro437Leu (n=2), Pro153Arg, ATG-23C>T and ATG-43T>C and Met192Leu. Findings were not significantly different when these variants were excluded from all analyses.
Mutations by ethnic group and zygosity
The nationalities of the 77 Hispanic cases included 21 from the Dominican Republic, 20 from Puerto Rico, 15 from Mexico, eight from Ecuador and fewer than five cases each from Cuba, Peru, Columbia, Chile and Ecuador. The 12 Hispanic carriers included seven Puerto Ricans, two Mexicans, one Cuban, one Dominican, and one Peruvian. Six cases (5 Puerto Rican and one Mexican carried deletions of exon 3–4. Both exon 3–4 homozygotes were of Puerto Rican descent. Family history of PD was reported by one homozygote, but was not available for the other. None of the other carriers of exon 3–4 deletions reported a family history of PD. The second most common mutation in Hispanics was 255delA, present in three Puerto Ricans in association with the exon 3–4 deletion and one Mexican heterozygote.