Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease
Abstract Background Alzheimer’s disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidat...
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doaj-cc1326de139a4ed99b3067c6cdc456ec2021-05-09T11:10:25ZengBMCGenome Medicine1756-994X2021-05-0113111510.1186/s13073-021-00890-2Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s diseaseJake Gockley0Kelsey S. Montgomery1William L. Poehlman2Jesse C. Wiley3Yue Liu4Ekaterina Gerasimov5Anna K. Greenwood6Solveig K. Sieberts7Aliza P. Wingo8Thomas S. Wingo9Lara M. Mangravite10Benjamin A. Logsdon11Sage BionetworksSage BionetworksSage BionetworksSage BionetworksDepartment of Neurology, Emory University School of MedicineDepartment of Neurology, Emory University School of MedicineSage BionetworksSage BionetworksDivision of Mental Health, Atlanta VA Medical CenterDepartment of Neurology, Emory University School of MedicineSage BionetworksCajal NeuroscienceAbstract Background Alzheimer’s disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions. Methods A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues. Results Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1. Conclusions We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.https://doi.org/10.1186/s13073-021-00890-2Alzheimer’s diseaseTWASFUSIONGWASDementiaNeurodegeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jake Gockley Kelsey S. Montgomery William L. Poehlman Jesse C. Wiley Yue Liu Ekaterina Gerasimov Anna K. Greenwood Solveig K. Sieberts Aliza P. Wingo Thomas S. Wingo Lara M. Mangravite Benjamin A. Logsdon |
spellingShingle |
Jake Gockley Kelsey S. Montgomery William L. Poehlman Jesse C. Wiley Yue Liu Ekaterina Gerasimov Anna K. Greenwood Solveig K. Sieberts Aliza P. Wingo Thomas S. Wingo Lara M. Mangravite Benjamin A. Logsdon Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease Genome Medicine Alzheimer’s disease TWAS FUSION GWAS Dementia Neurodegeneration |
author_facet |
Jake Gockley Kelsey S. Montgomery William L. Poehlman Jesse C. Wiley Yue Liu Ekaterina Gerasimov Anna K. Greenwood Solveig K. Sieberts Aliza P. Wingo Thomas S. Wingo Lara M. Mangravite Benjamin A. Logsdon |
author_sort |
Jake Gockley |
title |
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease |
title_short |
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease |
title_full |
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease |
title_fullStr |
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease |
title_full_unstemmed |
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease |
title_sort |
multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in alzheimer’s disease |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2021-05-01 |
description |
Abstract Background Alzheimer’s disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions. Methods A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues. Results Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1. Conclusions We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes. |
topic |
Alzheimer’s disease TWAS FUSION GWAS Dementia Neurodegeneration |
url |
https://doi.org/10.1186/s13073-021-00890-2 |
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