Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases

Allen, Mariet; Carrasquillo, Minerva M.; Funk, Cory C.; Heavner, Benjamin D.; Zou, Fanggeng; Younkin, Curtis S.; Burgess, Jeremy D.; Chai, High Seng; Crook, Julia E.; Eddy, James A.; Li, Hongdong; Logsdon, Ben; Peters, Mette A.; Dang, Kristen K.; Wang, Xue; Serie, Daniel J.; Wang, Chen; Nguyen, Thuy; Lincoln, Sarah; Malphrus, Kimberly G.; Bisceglio, Gina; Ma, Li; Golde, Todd E.; Mangravite, Lara M.; Asmann, Yan W.; Price, Nathan D.; Petersen, Ronald C.; Graff‐Radford, Neill R.; Dickson, Dennis W.; Younkin, Steven G.; Ertekin-Taner, Nilüfer

doi:10.1038/sdata.2016.89

Cited by 417 publications

(614 citation statements)

References 45 publications

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“…We accessed the Mayo Clinic Brain Bank (Mayo) RNAseq study from the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) portal (syn3163039; accessed April 2017). We examined gene expression in the temporal cortex of brains with neuropathologic diagnosis of AD dementia ( N = 82) and elderly control brains that lacked a diagnosis of neurodegenerative disease ( N = 80) [1]. Multi-variable linear regression analyses were conducted using CQN normalized gene expression measures and including age at death, gender, RNA integrity number (RIN), brain tissue source, and flow cell as biological and technical covariates.…”

Section: Methodsmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

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Section: Methodsmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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“…Differential gene expression was analyzed from the following data sets: the temporal cortices from patients with PSP and control brains (Synapse ID No. syn6090802) 28 and the frontal, hippocampus, and cerebellum from patients with FTD and controls (GEO accession number E13162). 29 Each data set of control and disease tissue was obtained from individuals of European descent.…”

Section: Methodsmentioning

confidence: 99%

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

et al. 2018

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IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.OBJECTIVES To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. DESIGN, SETTING, AND PARTICIPANTSIn this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. MAIN OUTCOMES AND MEASURESThe primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. RESULTS Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002

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“…The samples with obvious deviation were treated as outliers and removed for further analysis. The independent expression data, including ROSMAP study using microarray [9], ROSMAP study using RNA-seq [10], HBTRC study [9], Mayo's RNAseq study for cerebellum (CBE) and temporal cortex (TCX) [52]. All of them can be retrieved from AMP-AD projects.…”

Section: Data Collection and Processingmentioning

confidence: 99%

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

Meng

Yuan

et al. 2019

Preprint

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Alzheimer's disease (AD) is extremely complex for both causal mechanism and clinical manifestation, requiring efforts to uncover its diversity and the corresponding mechanisms. Here, we applied a modelling analysis to investigate the regulation divergence among a large-scale cohort of AD patients. We found that transcription regulation tended to get degenerated in AD patients, which contributed to disease development and the detrimental clinical outcomes, mainly by disrupting protein degradation, neuroinflammation, mitochondrial and synaptic functions. To measure the accumulated effects, we came up with a new concept, regulation loss burden, which better correlated with AD related clinical manifestations and the ageing process. The epigenetic studies to multiple active regulation marks also supported a tendency of regulation loss in AD patients. Our finding can lead to a unified model as AD causal mechanism, where AD and its diversity are contributed by accumulated degeneration of transcriptional regulation.The significance of this study is that: (1) it is the first system biology investigation to transcription regulation divergence among AD patients; (2) we observed an accumulated degeneration of transcription regulation, which well correlates with detrimental clinical outcomes; (3) transcriptional degeneration also contributes to the ageing process, where its correlation with ages is up to 0.78. IntroductionAlzheimer's disease (AD) is a complex chronic neurodegenerative disease that has been intensively studied for decades. However, its causal mechanismd remain elusive [1]. More attentions have been focused on the visible neuropathological features, especially the amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed of depositions of insoluble and densely packed amyloid beta (A ) protein whereas neurofibrillary tangles are composed of aggregations of hyperphosphorylated tau protein [2]. Early-onset AD studies in rare families led to the discovery of three genes, amyloid precursor protein, presenilin 1, and presenilin 2 that demonstrated the causal effects of A in the AD progression [3]. However, this is challenged 1 by the observation that some patients with substantial accumulations of plaques have no cognitive impairment [4] and that drugs targeting A all failed in clinical studies [5]. Although neurofibrillary tangles have a stronger correlation with the decline of cognitive ability and have drawn more attentions recently [6,7], strong or direct evidence linking neurofibrillary tangles to AD is still lacking [8].Integrated systematic approaches, especially coexpression regulatory network analysis, have advanced our understanding of AD in different ways [9,10,11]. In such studies, biological networks are constructed using gene-expression data to identify the gene modules related to AD genesis and development by integrating quantitative evaluation into both AD neuropathology and cognitive ability decline. In our previous work, we studied transcriptional dysregulation between AD patients an...

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Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases

Cited by 417 publications

References 45 publications

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

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