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Parkinson disease loci in the mid-western Amish

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Abstract

Previous evidence has shown that Parkinson disease (PD) has a heritable component, but only a small proportion of the total genetic contribution to PD has been identified. Genetic heterogeneity complicates the verification of proposed PD genes and the identification of new PD susceptibility genes. Our approach to overcome the problem of heterogeneity is to study a population isolate, the mid-western Amish communities of Indiana and Ohio. We performed genome-wide association and linkage analyses on 798 individuals (31 with PD), who are part of a 4,998 member pedigree. Through these analyses, we identified a region on chromosome 5q31.3 that shows evidence of association (p value < 1 × 10−4) and linkage (multipoint HLOD = 3.77). We also found further evidence of linkage on chromosomes 6 and 10 (multipoint HLOD 4.02 and 4.35 respectively). These data suggest that locus heterogeneity, even within the Amish, may be more extensive than previously appreciated.

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Acknowledgments

We would like to thank the participants of this study who have so graciously allowed us to visit with them and have participated in studies with us for over 10 years. We would like to acknowledge additional work for this study that was performed using the Vanderbilt Center for Human Genetics Research Core facilities: the Genetic Studies Ascertainment Core, the DNA Resources Core, and the Computation Genomics Core. This study was supported by the National Institutes of Health grants AG019085 (to JLH and MAP-V) and AG019726 (to WKS), and a grant from the Michael J. Fox Foundation (to JLH). Some of the samples used in this study were collected while WKS, JRG, and MAP-V were faculty members at Duke University. The authors would like to thank L. L. McFarland, C. Knebusch, and the late C. E. Jackson for their contributions to the overall Amish projects.

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Authors and Affiliations

  1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA

    M. F. Davis, A. C. Cummings, L. N. D’Aoust, L. Jiang, D. R. Velez Edwards, R. Laux, D. Fuzzell & J. L. Haines

  2. Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA

    D. R. Velez Edwards

  3. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA

    L. Reinhart-Mercer, W. K. Scott & M. A. Pericak-Vance

  4. Dartmouth College, Hanover, NH, USA

    S. L. Lee

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  1. M. F. Davis
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  2. A. C. Cummings
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  3. L. N. D’Aoust
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  4. L. Jiang
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Correspondence to J. L. Haines.

Electronic supplementary material

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Supplementary Figure 1 LOD scores by sub-pedigree for regions with multipoint HLOD > 3.0 (TIFF 329 kb)

439_2013_1316_MOESM2_ESM.jpg

Supplementary Figure 2 Possible haplotypes and co-inheritance pattern on chromosome 5.Sub-pedigree 4 is shown with possible haplotype combinations for the peak region of co-inheritance on chromosome 5. The six SNPs in this haplotype are at the location of the maximum HLOD score. Genders have been randomized to protect privacy (TIFF 24 kb)

439_2013_1316_MOESM3_ESM.jpg

Supplementary Figure 3 Possible haplotypes and co-inheritance pattern on chromosome 6. Sub-pedigree 9 is shown with possible haplotype combinations for the peak region of co-inheritance on chromosome 6. The four SNPs in this haplotype are at the location of the maximum HLOD score. Genders have been randomized to protect privacy (TIFF 20 kb)

Supplementary Table 1 (DOCX 19 kb)

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Davis, M.F., Cummings, A.C., D’Aoust, L.N. et al. Parkinson disease loci in the mid-western Amish. Hum Genet 132, 1213–1221 (2013). https://doi.org/10.1007/s00439-013-1316-1

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