Integrated whole transcriptome and DNA methylation analysis identifies gene networks specific to late-onset Alzheimer's disease.
Previous transcriptome studies observed disrupted cellular processes in late-onset Alzheimer's disease (LOAD), yet it is unclear whether these changes are specific to LOAD, or are common to general neurodegeneration. In this study, we address this question by examining transcription in LOAD and comparing it to cognitively normal controls and a cohort of "disease controls." Differential transcription was examined using RNA-seq, which allows for the examination of protein coding genes, non-coding RNAs, and splicing. Significant transcription differences specific to LOAD were observed in five genes: C10orf105, DIO2, a lincRNA, RARRES3, and WIF1. These findings were replicated in two independent publicly available microarray data sets. Network analyses, performed on 2,504 genes with moderate transcription differences in LOAD, reveal that these genes aggregate into seven networks. Two networks involved in myelination and innate immune response specifically correlated to LOAD. FRMD4B and ST18, hub genes within the myelination network, were previously implicated in LOAD. Of the five significant genes, WIF1 and RARRES3 are directly implicated in the myelination process; the other three genes are located within the network. LOAD specific changes in DNA methylation were located throughout the genome and substantial changes in methylation were identified within the myelination network. Splicing differences specific to LOAD were observed across the genome and were decreased in all seven networks. DNA methylation had reduced influence on transcription within LOAD in the myelination network when compared to both controls. These results hint at the molecular underpinnings of LOAD and indicate several key processes, genes, and networks specific to the disease.
University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA.
Crystal E
CE
Humphries
University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA.
Martin A
MA
Kohli
University of Miami, Miller School of Medicine, Department of Medicine, Miami, FL, USA Nova Southeastern University, Ft. Lauderdale, FL, USA.
Lubov
L
Nathanson
University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA.
Patrice
P
Whitehead
University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA.
Gary
G
Beecham
University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA.
Eden
E
Martin
University of Miami, Miller School of Medicine, Miami Brain Bank Endowment, FL, USA.
Deborah C
DC
Mash
University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA.
Margaret A
MA
Pericak-Vance
University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA.
John
J
Gilbert
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015723:Gene Library; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D008297:Male; D059467:Transcriptome
Alzheimer's disease; DNA methylation; Illumina Human Methylation 450K; RNA-seq; dementia with Lewy bodies; expression; human brain; late-onset transcriptome; myelination; networks; splicing