Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.
Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671-677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239-2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P<0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO.
Noureddine
Maher A
MA
Center for Human Genetics, Duke University, Durham, North Carolina 27710-2903, USA.
Li
Yi-Ju
YJ
van der Walt
Joelle M
JM
Walters
Robert
R
Jewett
Rita M
RM
Xu
Hong
H
Wang
Tianyuan
T
Walter
Jeffrey W
JW
Scott
Burton L
BL
Hulette
Christine
C
Schmechel
Don
D
Stenger
Judith E
JE
Dietrich
Fred
F
Vance
Jeffery M
JM
Hauser
Michael A
MA
D000368:Aged; D000369:Aged, 80 and over; D004272:DNA, Mitochondrial / Q000235:genetics; D020224:Expressed Sequence Tags / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015723:Gene Library; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D040901:Proteomics / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*
D004272:DNA, Mitochondrial; D012333:RNA, Messenger