Genetic control of human brain transcript expression in Alzheimer disease.
We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.
Webster
Jennifer A
JA
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Gibbs
J Raphael
JR
Clarke
Jennifer
J
Ray
Monika
M
Zhang
Weixiong
W
Holmans
Peter
P
Rohrer
Kristen
K
Zhao
Alice
A
Marlowe
Lauren
L
Kaleem
Mona
M
McCorquodale
Donald S
DS
Cuello
Cindy
C
Leung
Doris
D
Bryden
Leslie
L
Nath
Priti
P
Zismann
Victoria L
VL
Joshipura
Keta
K
Huentelman
Matthew J
MJ
Hu-Lince
Diane
D
Coon
Keith D
KD
Craig
David W
DW
Pearson
John V
JV
Heward
Christopher B
CB
Reiman
Eric M
EM
Stephan
Dietrich
D
Hardy
John
J
Myers
Amanda J
AJ
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D024363:Transcription Initiation Site; D014158:Transcription, Genetic