A transcriptome-wide association study of Alzheimer's disease using prediction models of relevant tissues identifies novel candidate susceptibility genes

Yanfa Sun; Jingjing Zhu; Dan Zhou; Saranya Canchi; Chong Wu; Nancy J Cox; Robert A Rissman; Eric R Gamazon; Lang Wu

doi:10.1186/s13073-021-00959-y

A transcriptome-wide association study of Alzheimer's disease using prediction models of relevant tissues identifies novel candidate susceptibility genes

Genome Med. 2021 Sep 1;13(1):141. doi: 10.1186/s13073-021-00959-y.

Authors

Yanfa Sun^#^{1

2

3

4}, Jingjing Zhu^#², Dan Zhou^#⁵, Saranya Canchi^{6

7}, Chong Wu⁸, Nancy J Cox⁵, Robert A Rissman^{6

7}, Eric R Gamazon^#^{5

9

10}, Lang Wu^#¹¹

Affiliations

¹ College of Life Science, Longyan University, Longyan, Fujian, 364012, People's Republic of China.
² Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, USA.
³ Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, Fujian, 364012, People's Republic of China.
⁴ Fujian Provincial Universities Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Longyan, Fujian, 364012, People's Republic of China.
⁵ Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁶ Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
⁷ Veterans Affairs San Diego Healthcare System, San Diego, CA, 92093, USA.
⁸ Department of Statistics, Florida State University, Tallahassee, FL, 32306, USA.
⁹ Clare Hall, University of Cambridge, Cambridge, CB3 9AL, UK.
¹⁰ MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SL, UK.
¹¹ Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, USA. lwu@cc.hawaii.edu.

^# Contributed equally.

Abstract

Background: Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer's disease (AD), but the genes responsible for these associations remain largely unknown.

Methods: We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry.

Results: We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10^-6). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal.

Conclusions: Our study provides new insights into the etiology and underlying genetic architecture of AD.

Keywords: Alzheimer’s disease; Etiology; Susceptibility genes; Transcriptome-wide association study.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles*
Alzheimer Disease / genetics*
Alzheimer Disease / metabolism
Chromosome Mapping
Computational Biology / methods
Databases, Genetic
Gene Expression Profiling
Gene Expression Regulation
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Models, Biological
Organ Specificity / genetics
Polymorphism, Single Nucleotide
Prognosis
Resorcinols
Signal Transduction
Transcriptome*

Substances

Resorcinols
sohirnone A

Abstract

Publication types

MeSH terms

Substances

Grants and funding