Genetic Control of Human Brain Transcript Expression in Alzheimer Disease

• Published in: American journal of human genetics Vol. 84; no. 4; pp. 445 - 458
• Main Authors: Webster, Jennifer A., Gibbs, J. Raphael, Clarke, Jennifer, Ray, Monika, Zhang, Weixiong, Holmans, Peter, Rohrer, Kristen, Zhao, Alice, Marlowe, Lauren, Kaleem, Mona, McCorquodale, Donald S., Cuello, Cindy, Leung, Doris, Bryden, Leslie, Nath, Priti, Zismann, Victoria L., Joshipura, Keta, Huentelman, Matthew J., Hu-Lince, Diane, Coon, Keith D., Craig, David W., Pearson, John V., Heward, Christopher B., Reiman, Eric M., Stephan, Dietrich, Hardy, John, Myers, Amanda J.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01.04.2009; Cell Press; American Society of Human Genetics
• Subjects: Age of Onset; Aged; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Biological and medical sciences; Brain; Brain - metabolism; Case-Control Studies; Correlation analysis; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene Regulatory Networks; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomics; Genotype & phenotype; Humans; Male; Medical genetics; Medical sciences; Mental disorders; Molecular and cellular biology; Neurology; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Psychopathology; Quantitative Trait Loci; Studies; Transcription Initiation Site; Transcription, Genetic; Human; Nervous system diseases; Messenger RNA; Alzheimer disease; Central nervous system disease; Genetics; Degenerative disease; Gene expression; Cerebral disorder
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2009.03.011

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.