Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease.
We previously reported a linkage region on chromosome 1p (LOD = 3.41) for genes controlling age at onset (AAO) in Parkinson disease (PD). This region overlaps with the previously reported PARK10 locus. To identify the gene(s) associated with AAO and risk of PD in this region, we first applied a genomic convergence approach that combined gene expression and linkage data. No significant results were found. Second, we performed association mapping across a 19.2-Mb region centered under the AAO linkage peak. An iterative association mapping approach was done by initially genotyping single-nucleotide polymorphisms at an average distance of 100 kb apart and then by increasing the density of markers as needed. Using the overall data set of 267 multiplex families, we identified six associated genes in the region, but further screening of a subset of 83 families linked to the chromosome 1 locus identified only two genes significantly associated with AAO in PD: the gamma subunit of the translation initiation factor EIF2B gene (EIF2B3), which was more significant in the linked subset and the ubiquitin-specific protease 24 gene (USP24). Unexpectedly, the human immunodeficiency virus enhancer-binding protein 3 gene (HIVEP3) was found to be associated with risk for susceptibility to PD. We used several criteria to define significant results in the presence of multiple testing, including criteria derived from a novel cluster approach. The known or putative functions of these genes fit well with the current suspected pathogenic mechanisms of PD and thus show great potential as candidates for the PARK10 locus.
Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Sofia A
SA
Oliveira
Yi-Ju
YJ
Li
Maher A
MA
Noureddine
Stephan
S
Zuchner
Xuejun
X
Qin
Margaret A
MA
Pericak-Vance
Jeffery M
JM
Vance
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D004268:DNA-Binding Proteins / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases
D004268:DNA-Binding Proteins; D020717:Eukaryotic Initiation Factor-2B; C425103:HIVEP3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D025801:Ubiquitin; D017346:Protein Serine-Threonine Kinases; C122169:TESK2 protein, human; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases