Genome‐wide association study of Alzheimer's disease endophenotypes at prediagnosis stages

Chung, Jaeyoon; Wang, Xulong; Maruyama, Toru; Ma, Yiyi; Zhang, Xiaoling; Mez, Jesse; Sherva, Richard; Takeyama, Haruko; Lunetta, Kathryn L.; Farrer, Lindsay A.; Jun, Gyungah

doi:10.1016/j.jalz.2017.11.006

Cited by 60 publications

(53 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6 ). According to NHGRI-EBI GWAS catalog 59 , the 90 TWAS-significant genes replicated four previous findings on brain structures, including JPH3 60 for hippocampal volume in mild cognitive impairment, CNNM2 61 for white matter lesion progression, FOXF1 62 for hippocampal volume in Alzheimer’s disease progression, and C1QL1 63 for white matter hyperintensity burden. The other 86 genes had not been linked to brain structure previously and thus can be regarded as novel genes for these 211 neuroimaging traits.…”

Section: Resultssupporting

confidence: 67%

Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits

Zhao

Shan

Yang

et al. 2019

Preprint

View full text Add to dashboard Cite

Structural and microstructural variations of human brain are heritable and highly polygenic traits, with hundreds of associated genes founded in recent genome-wide association studies (GWAS). Using gene expression data, transcriptome-wide association studies (TWAS) can prioritize these GWAS findings and also identify novel gene-trait associations. Here we performed TWAS analysis of 211 structural neuroimaging phenotypes in a discovery-validation analysis of six datasets. Using a cross-tissue approach, TWAS discovered 204 associated genes (86 new) exceeding Bonferroni significance threshold of 1.37*10−8 (adjusted for testing multiple phenotypes) in the UK Biobank (UKB) cohort, and validated 18 TWAS or previous GWAS-detected genes. The TWAS-significant genes of brain structures had been linked to a wide range of complex traits in different domains. Additional TWAS analysis of 11 cognitive and mental health traits detected 69 overlapping significant genes with brain structures, further characterizing the genetic overlaps among these brain-related traits. Through TWAS gene-based polygenic risk scores (PRS) prediction, we found that TWAS PRS gained substantial power in association analysis compared to conventional variant-based PRS, and up to 6.97% of phenotypic variance (p-value=7.56*10−31) in testing datasets can be explained by UKB TWAS-derived PRS. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.

show abstract

Section: Resultssupporting

confidence: 67%

Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits

Zhao

Shan

Yang

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to AQP1, we identified another 11 upregulated genes shared between AD, VaD, and FTD that have been associated with neurodegeneration. For instance, MTUS1 expression correlated with Braak staging in AD patients and it may be associated to changes in hippocampal volume prior to onset of cognitive impairment [28]. Similarly, QK1, a gene exclusively expressed in glial cells, was upregulated in human postmortem brain samples from AD patients compared to healthy controls [29].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Santiago¹,

Bottero

Potashkin

2020

IJMS

View full text Add to dashboard Cite

Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

show abstract

“…However, in a few reported cases, this approach led to the identification of several loci associated with endophenotypes. (Ramanan et al, 2015 ; Deming et al, 2017 ; Chibnik et al, 2018 ; Chung et al, 2018 ). These results generally provide additional candidate loci but do not clarify the effects of the GWAS hits for Alzheimer's dementia.…”

Section: Introductionmentioning

confidence: 99%

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia

et al. 2018

View full text Add to dashboard Cite

Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia.

show abstract

Genome‐wide association study of Alzheimer's disease endophenotypes at prediagnosis stages

Abstract: Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.

Cited by 60 publications

References 47 publications

Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits

Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia

Contact Info

Product

Resources

About