scholarly journals Integrative analysis of proteome-wide association and transcriptome-wide association study identifies candidate brain proteins associated with insomnia

2021 ◽  
Author(s):  
Peilin Meng ◽  
Bolun Cheng ◽  
Chun’e Li ◽  
Huijie Zhang ◽  
Shiqiang Cheng ◽  
...  
Keyword(s):  
Human Brain ◽  
Association Study ◽  
Brain Imaging ◽  
Expression Profiles ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Rna Seq ◽  
Brain Proteins ◽  
Brain Proteome ◽  
Associated Proteins

Abstract Great progress has been made in identifying risk loci for insomnia by genome-wide association studies (GWAS) analysis, but its association with human brain proteome is unclear. Two insomnia GWAS summary datasets were derived from deCODE (n = 113,006) and 23andMe (n = 1,331,010). Two human brain proteomic datasets were obtained from ROS/MAP and Banner, and two reference datasets were obtained from brain RNA-seq (CBR) and RNA-seq splicing (CBRS). Proteome-wide association study (PWAS) was first used to detect brain proteins associated with insomnia at the translation level. Transcriptome-wide association study (TWAS) was then used to verify the results at the DNA level. Finally, brain imaging GWAS was used to explore the brain functional areas related to the identified brain proteins and genes in insomnia. PWAS identified 4 and 1 common proteins shared by two human brain proteomic datasets in insomnia GWAS dataset 1 and 2, such as ME1 (PDataset1−Banner−full=1.08×10−2, PDataset1−ROS/MAP−full=8.21×10−3). Further TWAS identified 5 and 1 candidate genes shared by the two reference expression profiles in dataset 1 and 2, like ICA1L (PDataset2−CBR=3.01×10−2, PDataset2−CBRS=3.24×10−2). CAMLG was observed to associate with insomnia in both PWAS (PDataset2−ROS/MAP=2.94×10−2) and TWAS (PDataset2−CBR=1.11×10−2). Comparing the results of PWAS and TWAS, there are 9 common proteins and genes shared by both two datasets, such as INPP4A. Brain imaging analysis found that insomnia associated proteins and genes were functionally related to cortex. Our results may reinforce the understanding of the etiology and pathophysiology of insomnia and provide promising brain protein targets for further therapeutic and mechanistic studies.

A Proteome-Wide Association Study Identified Candidate Human Brain Proteins Associated with Coffee Consumption

2021 ◽  
Author(s):  
Chun'e Li ◽  
Xiao Liang ◽  
Yumeng Jia ◽  
Yan Wen ◽  
Huijie Zhang ◽  
...  
Keyword(s):  
Human Brain ◽  
Association Study ◽  
Plasma Proteins ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Coffee Consumption ◽  
Genetic Associations ◽  
Brain Proteins ◽  
Genome Wide ◽  
Brain Proteome

Abstract Background Increasing evidence suggests the association between caffeine and the brain and nervous system. However, there is limited research on the genetic associations between coffee consumption subtypes and brain proteome, plasma proteomes, and peripheral metabolites. Methods First, proteome-wide association study (PWAS) of coffee consumption subtypes was performed by integrating two independent genome-wide association study (GWAS) datasets (91,462–502,650 subjects) with two reference human brain proteomes (ROS/MAP and Banner), by using the FUSION pipeline. Second, transcriptome-wide association study (TWAS) analysis of coffee consumption subtypes was conducted by integrating the two gene expression weight references (RNAseq and splicing) of brain RNA-seq and the two GWAS datasets (91,462–502,650 subjects) of coffee consumption subtypes. Finally, we used the LD Score Regression (LDSC) analysis to evaluate the genetic correlations of coffee consumption subtypes with plasma proteomes and peripheral metabolites. Results For the traits related to coffee consumption, we identified 3 common PWAS proteins, such as MADD (P PWAS−Banner−dis=0.0114, P PWAS−ROS/MAP−rep =0.0489). In addition, 11 common TWAS genes were found in two cohorts, such as ARPC2 (P TWAS−splicing−dis =2063×10− 12, P TWAS−splicing−dis =1.25×10− 10, P TWAS−splicing−dis =1.24e-08, P TWAS−splicing−rep =3.25×10− 9 and P TWAS−splicing−rep =3.42×10− 13). Importantly, we have identified 8 common genes between PWAS and TWAS, such as ALDH2 (P PWAS−banner−rep =1.22×10− 22, PTWAS− splicing−dis = 4.54×10− 92). For the LDSC analysis of human plasma proteome, we identified 11 plasma proteins, such as CHL1 (P dis = 0.0151, P rep =0.0438). For the LDSC analysis of blood metabolites, 5 metabolites have been found, such as myo-inositol (P dis = 0.0073, P dis = 0.0152, P dis =0.0414, P rep =0.0216). Conclusions We identified several brain proteins and genes associated with coffee consumption subtypes. In addition, we also detected several candidate plasma proteins and metabolites related to these subtypes.

scholarly journals Transcriptome-wide association study in UK Biobank Europeans identifies associations with blood cell traits.

2021 ◽  
Author(s):  
Bryce Rowland ◽  
Sanan Venkatesh ◽  
Manuel Tardaguila ◽  
Jia Wen ◽  
Jonathan D Rosen ◽  
...  
Keyword(s):  
Association Study ◽  
Target Genes ◽  
Prediction Models ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Rna Seq ◽  
Genome Wide ◽  
Increased Sensitivity

Previous genome-wide association studies (GWAS) of hematological traits have identified over 10,000 distinct trait-specific risk loci, but the underlying causal mechanisms at these loci remain incompletely characterized. We performed a transcriptome-wide association study (TWAS) of 29 hematological traits in 399,835 UK Biobank (UKB) participants of European ancestry using gene expression prediction models trained from whole blood RNA-seq data in 922 individuals. We discovered 557 TWAS signals associated with hematological traits distinct from previously discovered GWAS variants, including 10 completely novel gene-trait pairs corresponding to 9 unique genes. Among the 557 associations, 301 were available for replication in a cohort of 141,286 participants of European ancestry from the Million Veteran Program (MVP). Of these 301 associations, 199 replicated at a nominal threshold (α = 0.05) and 108 replicated at a strict Bonferroni adjusted threshold (α = 0.05/301). Using our TWAS results, we systematically assigned 4,261 out of 16,900 previously identified hematological trait GWAS variants to putative target genes. Compared to coloc, our TWAS results show reduced specificity and increased sensitivity to assign variants to target genes.

scholarly journals Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 615
Author(s):  
Achala Fernando ◽  
Chamikara Liyanage ◽  
Afshin Moradi ◽  
Panchadsaram Janaththani ◽  
Jyotsna Batra
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Expression Profiles ◽  
Association Studies ◽  
Protein Isoforms ◽  
The Cancer Genome Atlas ◽  
Mass Spectrometry Analysis ◽  
Functional Domains ◽  
Homeodomain Protein ◽  
Genome Wide Association Studies

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.

Abstract 35: Transcriptome-wide Association Study of Circulating Lipid Levels

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Brian H Chen ◽  
Claudia Schurmann ◽  
Marjolein J Peters ◽  
Liliane Pfeiffer ◽  
Katharina Schramm ◽  
...  
Keyword(s):  
Association Study ◽  
Whole Blood ◽  
Association Studies ◽  
Hdl Cholesterol ◽  
Lipid Lowering ◽  
Genome Wide Association Studies ◽  
Lipid Levels ◽  
Expression Levels ◽  
Cell Counts ◽  
Pathway Gene

Genome-wide association studies have identified scores of DNA variants that are associated with circulating lipid levels. We conducted a transcriptome-wide association study (TWAS) of triglycerides (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and total cholesterol (TC) using whole blood derived RNA from 1,838 Framingham Heart Study participants using the Affymetrix GeneChip Human Exon 1.0 ST array. External replication was conducted in four separate population-based cohorts (SHIP-TREND, KORA F4, Rotterdam Study, InChianti) totaling 3,244 individuals assayed using the Illumina HumanHT-12 Expression BeadChip array. Individuals taking lipid-lowering medications were excluded from analysis. Models were adjusted for age, sex, blood cell counts, and technical covariates (e.g., batch). Using a stringent transcriptome-wide FDR of 0.05 in both discovery and replication results, there were 119 significant transcript associations for TG; 57 for HDL-C; 1 for LDL-C; and 3 for TC. Expression levels of HDC and CPA3 genes were the two strongest associations with all 4 lipid traits in both discovery and replication cohorts. Known lipid pathway gene MYLIP was inversely associated with triglycerides (replication P=6.4x10-45) and directly associated with HDL-C levels (replication P =3.5x10-26). ABCA1 was also directly associated with triglyceride levels (replication P =9.4x10-50). In summary, through TWAS we identified many known and novel genes whose expression levels in whole blood were associated with circulating lipid levels. We believe that TWAS may serve as a useful method for identifying novel therapeutic targets. However, further studies are needed to elucidate the role that these genes may play in regulating circulating lipid levels or mediating the effect of lipids on atherosclerotic cardiovascular diseases.

scholarly journals Identification and characterization of SEC24D as a susceptibility gene for hepatitis B virus infection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xianzhong Jiang ◽  
Bin Zhang ◽  
Junsheng Zhao ◽  
Yi Xu ◽  
Haijun Han ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Time Course ◽  
Expression Profiles ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Hbv Infection ◽  
Genome Wide Association Studies ◽  
B Virus

Abstract Single nucleotide polymorphisms (SNPs) and genes associated with susceptibility to hepatitis B virus (HBV) infection that have been identified by genome-wide association studies explain only a limited portion of the known heritability, indicating more genetic variants remain to be discovered. In this study, we adopted a new research strategy to identify more susceptibility genes and variants for HBV infection. We first performed genetic association analysis of 300 sib-pairs and 3,087 case-control samples, which revealed that 36 SNPs located in 31 genes showed nominal associations with HBV infection in both samples. Of these genes, we selected SEC24D for further molecular analysis according to the following two main lines of evidence. First, a time course analysis of the expression profiles from HBV-infected primary human hepatocytes (PHH) demonstrated that SEC24D expression increased markedly as time passed after HBV infection (P = 4.0 × 10−4). Second, SNP rs76459466 in SEC24D was adversely associated with HBV risk (ORmeta = 0.82; Pmeta = 0.002), which again indicated that SEC24D represents a novel susceptibility gene for HBV infection. Moreover, SEC24D appeared to be protective against HBV infection in vitro. Consistently, we found that SEC24D expression was significantly enhanced in non-infected liver tissues (P = 0.002). We conclude that SEC24D is a novel candidate gene linked to susceptibility to HBV infection.

Human Brain Proteome-Wide Association Study of Depression Identified 24 Proteins as Tractable Targets for Further Mechanistic Studies

2020 ◽  
Vol 87 (9) ◽  
pp. S183
Author(s):  
Thomas S. Wingo ◽  
Yue Liu ◽  
Adriana Lori ◽  
Ekaterina S. Gerasimov ◽  
Duc M. Duong ◽  
...  
Keyword(s):  
Human Brain ◽  
Association Study ◽  
Mechanistic Studies ◽  
Brain Proteome

F94. Human Brain Proteome-Wide Association Study of Longitudinally Assessed Late-Life Depression

2019 ◽  
Vol 85 (10) ◽  
pp. S249
Author(s):  
Aliza Wingo ◽  
Wen Fan ◽  
Nicholas Seyfried ◽  
Duc Duong ◽  
Eric Dammer ◽  
...  
Keyword(s):  
Human Brain ◽  
Association Study ◽  
Late Life ◽  
Late Life Depression ◽  
Brain Proteome

The HaemAtlas: Characterising Gene Expression in Differentiated Human Blood Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2453-2453
Author(s):  
Nicholas A. Watkins ◽  
Marloes R. Tijssen ◽  
Arief Gusnanto ◽  
Bernard de Bono ◽  
Subhajyoti De ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factors ◽  
Cell Function ◽  
Expression Profiles ◽  
Association Studies ◽  
Cytotoxic T Cells ◽  
Expression Patterns ◽  
Immunoglobulin Superfamily ◽  
Genome Wide Association Studies

Abstract Haematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell surface receptors. In order to further understand haematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B-cells, cytotoxic and helper T-cells, Natural Killer cells, granulocytes and monocytes using whole genome microarrays. A bioinformatics analysis of this data was performed focusing on transcription factors, immunoglobulin superfamily members and lineage specific transcripts. We observed that the numbers of lineage specific genes varies by two orders of magnitude, ranging from five for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel co-expression patterns for key transcription factors involved in haematopoiesis (eg. GATA3–GFI1 and GATA2–KLF1). This study represents the most comprehensive analysis of gene expression in haematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which is freely accessible, will be invaluable for future studies on haematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.

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