Abstract
Article abstract— A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine β-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.
Genetic studies in PD have been largely limited to gene identification in families with rare familial forms of the disease1 or candidate gene studies that focus on known genes with a putative role in the disease.2 To date, neither approach has identified a gene that contributes to susceptibility for common idiopathic PD. We formed an international multi-institutional consortium, termed the GenePD Project, to identify and recruit a large sample of sibships and families with multiple PD-affected members for genetic linkage studies. We report the first published findings for a genome-wide scan for PD in a set of 113 affected sibling pairs.
Methods.
Subjects.
Sibling pairs affected with PD were ascertained through index cases at 13 clinical sites. Neurologists from the participating sites examined and confirmed the PD diagnosis for each of the index cases and affected siblings, with the exception of seven individuals for whom confirmation of diagnosis is ongoing. Diagnostic criteria for PD were based on the UK Parkinson’s Disease Society Brain Bank Criteria,3 but removing “more than one affected relative” and “repeated head injury” as exclusionary criteria. In their original form, these criteria have a positive predictive value of 82%.4 The modifications are unlikely to degrade the positive predictive value. All neurologists participated in inter-rater reliability training to ensure diagnostic consistency. All participants signed a consent form approved by the human subjects committee of each participating institution.
Included in this study are 102 index cases and 107 affected siblings, yielding a total of 113 affected sibling pairs. Additionally, DNA samples were available on two parents (one affected) and eight unaffected siblings. DNA samples were collected, and family history and ancillary risk factor interviews were performed. Clinical information is presented in table 1.
Clinical characteristics of probands and affected siblings
Genotyping.
Genomic DNA was extracted from lymphocytes using a Nucleon II DNA extraction kit (Amersham Pharmacia Biotech, Piscataway, NJ). The scan consisted of 339 markers with an average distance of 11 cM from the Weber set 8 obtained from Research Genetics. The sib_kin program in the Aspex package (ftp://lahmed.stanford.edu/pub/aspex/index.html) was used to verify sibling relationships. Individuals not found to be full siblings were deleted from subsequent analyses. Mendelian inconsistencies were also identified using Aspex. Genotypes for the entire nuclear family were deleted for the particular marker that yielded errors.
Linkage analysis.
Two statistics were used to evaluate linkage to PD: the maximum likelihood score (MLS)5 and the nonparametric linkage score (NPL).6 The MLS compares the estimated proportion of alleles shared identical by descent (IBD) by siblings with the Mendelian expectation of alleles shared IBD given no linkage. The MLS is a lod score with a minimum value of 0; values above 3 are traditionally considered significant evidence of genetic linkage. The NPL score also evaluates the proportion of marker alleles shared IBD among affected relatives. The computed score, Zall, follows a normal distribution with a mean of 0 and a variance of 1 under the null hypothesis of no linkage. Zall scores are combined across pedigrees by taking a weighted average of scores in individual families, yielding the NPL score with its corresponding p value. Both statistics were computed using the program Genehunter.6
Results.
The index cases and their siblings were similar in onset age of PD, gender distribution, and clinical characteristics (table 1).
Linkage analysis revealed a maximum lod score of 1.30 on chromosome 9. The corresponding p value for the NPL statistic was 0.018. Three other regions on chromosomes 1, 10, and 16 yielded p values of <0.05 (table 2). The lod score curves for the four regions with greatest evidence of linkage are shown in the figure. There was no evidence of linkage (maxMLS = 0.04) to five regions containing genes implicated in familial forms of the disease1: 2p13 (PARK3),7 4p15 (ubiquitin carboxyl-terminal esterase L1, PARK4),8 4q21 (α-synuclein, PARK1), 6q25.2-q27 (PARK2), and 17q21 (Tau).
Chromosomal locations of lod scores of >1 or p values of <0.05
Figure. PD linkage on chromosome with suggestive evidence of linkage in 113 affected sibling pairs.
Discussion.
We have presented the results of a genome-wide scan for PD in a sample of 113 affected sibling pairs. Four areas of suggestive linkage to PD are identified on chromosomes 1, 9, 10, and 16. Because of the low frequency of PD-affected sibling pairs, substantial effort, across 13 centers specializing in PD, was required to assemble this sample. Although it is evident that this sample does not permit the identification of unequivocal evidence for linkage to any single locus, we and others are collecting additional families and sibships to further explore linkage for PD. The value of reporting these preliminary findings is to permit others performing similar work to compare their results with ours and to assess whether consistent evidence of linkage may be found across studies.
The four chromosomal locations that show suggestive evidence of linkage warrant further follow-up with additional markers and subjects. The region on chromosome 9q33-9q34.1 is of particular interest as the dopamine β-hydroxylase gene9 (134 to 138 cM, in NCBI, www.ncbi.nlm.nih.gov) co-localizes with the peak we observed, as does the torsion dystonia gene10 (132 to 134 cM). We are now exploring the role of these loci in this sample and a second similarly sized set of PD-affected sibling pairs recently collected.
Acknowledgments
Supported by PHS RO-1 NS36711-04, Genetic Linkage Study in Parkinson’s Disease.
- Received February 16, 2001.
- Accepted May 15, 2001.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
