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A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

ABSTRACT: Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States. We performed tests for linkage and for association using a marker set of nearly 6000 single-nucleotide polymorphisms. Parametric multipoint linkage analysis generated a logarithm of the odds of linkage (LOD) score of 2.44 on chromosome 6 in the SYNE1 gene, approximately 8 Mbp from the PARK2 gene. In a different region on chromosome 6 (?67 Mbp from PARK2) an association was found for rs4302647 (p < 4.0 × 10(-6) ), which is not within 300 kb of any gene. While the association exceeds Bonferroni correction, it may yet represent a false positive due to the small sample size and the low minor allele frequency. The minor allele frequency in affecteds is 0.07 compared to 0.01 in unaffecteds. Taken together, these results support involvement of loci on chromosome 6 in the genetic etiology of PD.

SUBMITTER: Cummings AC

PROVIDER: S-EPMC3077806 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

Cummings Anna C AC Lee Stephen L SL McCauley Jacob L JL Jiang Lan L Crunk Amy A McFarland Lynne L LL Gallins Paul J PJ Fuzzell Denise D Knebusch Clare C Jackson Charles E CE Scott William K WK Pericak-Vance Margaret A MA Haines Jonathan L JL

Annals of human genetics 20110501 3

Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States. We performed tests for linkage and for association using a marker set of nea ...[more]

PMID: 21488853

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Project description:ImportanceRecent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.ObjectivesTo test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.Design, setting, and participantsUsing the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.Main outcomes and measuresThe primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.ResultsGenome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.Conclusions and relevanceThe study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

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A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

Publications

A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

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