Fumihiko Takeuchi

Baker Heart and Diabetes Institute

Background: This study aims to develop a model for simultaneously assessing genetic and epigenetic contributions to plasma lipid levels. Methods: The predictive model was developed using two cardiovascular risk groups, i.e., individuals with high low-density lipoprotein cholesterol (LDL-C) levels (≥160 mg/dl, N = 296) and coronary artery disease (C...

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% n...

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed whil...

Background The stroke-prone spontaneously hypertensive rat (SHRSP) is a genetic model for cerebral stroke. Although a recent study on a congenic SHRSP suggested that a nonsense mutation in stromal interaction molecule 1 ( Stim1 ) encoding a major component of store-operated Ca ²⁺ entry was a causal variant for stroke in SHRSP, this was not conclusi...

Objectives Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. However, identifying the causal genes, pathways, and tissues/cell types responsible for these associations remains a challenge, and standardized analysis workflows are lacking. Additionally, due to limited treatment options for obe...

We investigated the progression of nonalcoholic fatty liver disease from fatty liver to steatohepatitis using single-nucleus and bulk ATAC-seq on the livers of rats fed a high-fat diet (HFD). Rats fed HFD for 4 wk developed fatty liver, and those fed HFD for 8 wk further progressed to steatohepatitis. We observed an increase in the proportion of in...

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,2...

Background Non-alcoholic fatty liver disease (NAFLD) develops from fatty liver to steatohepatitis during which multiple cell types may play different roles. Aiming to understand tissue composition of cell types, their gene expression and global gene regulation in the development of NAFLD, we performed single-nucleus and bulk ATAC-seq on the liver o...

Background Non-alcoholic fatty liver disease (NAFLD) develops from fatty liver to steatohepatitis during which multiple cell types may play different roles. Aiming to understand tissue composition of cell types, their gene expression and global gene regulation in the development of NAFLD, we performed single-nucleus and bulk ATAC-seq on the liver o...

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci atta...

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10−8 to 5.2 × 10...

Aims: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Methods and results: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising...

Background: Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide; still, the success rate of smoking cessation is low in general. From the viewpoint of public health and clinical care, an objective biomarker of long-term smoking behavior is sought.Methods and Results:This study assessed DNA methylation as a biomarker...

Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amel...

Left ventricular noncompaction cardiomyopathy (LVNC) is a heart muscle disorder morphologically characterized by reticulated trabeculations and intertrabecular recesses in the left ventricular (LV) cavity. LVNC is a genetically and phenotypically heterogeneous condition, which has been increasingly recognized with the accumulation of evidence provi...

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College”...

Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phe...

Venous thromboembolism (VTE) is a multifactorial disease. Because low-frequency variants and rare mutations have been found to predispose carriers toward VTE, there is a need for variant discovery in clinical settings. Therefore, we used a whole-exome approach for a young VTE patient with a positive family history. We identified in the proband and...

Importance Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. Objective To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. Design,...

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 dis...

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418...

Background and Purpose- oxLDL (oxidized low-density lipoprotein) has been known for its potential to induce endothelial dysfunction and used as a major serological marker of oxidative stress. Recently, LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a lectin-like receptor for oxLDL, has attracted attention in studies of neuronal ap...

Cholesteryl ester transfer protein (CETP) mediates a step in reverse cholesterol transport, which channels cholesterol from peripheral tissues back to the liver. Mice and rats are CETP-deficient species, which assumedly contribute to rodent atherosclerosis resistance. Both pro- and anti-atherogenic effects have been shown in studies of CETP-transge...

Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identif...

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. C...

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individua...

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small s...

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP var...

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understand...

Summary of biological description for novel BP loci. Information summary of the nearest genes for blood pressure novel loci. (DOCX)

Study design of SNV x alcohol interactions for BP. Schematic study design of the joint model of SNV main effect and SNV-alcohol consumption interaction; Blood pressure (BP) traits: systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP); Alcohol consumption was defined by two categories: (I) as current drinking...

Description of participating studies. Study descriptions of discovery cohorts (Stage 1) and replication cohorts (Stage 2). (DOCX)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for SBP in current drinkers (A) and in light/heavy drinkers (B) in European ancestry. Novel loci are highlighted in blue. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for SBP in current drinkers (A) and in light/heavy drinkers (B) in African ancestry. Novel loci are highlighted in blue. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for DBP in current drinkers (A) and in light/heavy drinkers (B) in African ancestry. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for SBP (A) and DBP (B) in current drinkers in Asian ancestry. (TIF)

Protein-protein interactions network. In the figure, ellipses in black represent all novel genes; ellipses in red represent novel from EA; squares in blue represent potential novel findings from African ancestry; and triangles in black from correlated-meta. Labeled with A and B free-hand circles are proteins that have two connections, while labeled...

Protein-protein interactions between tankyrase and beta-catenin. Tankyrase (from TNKS gene) and β-catenin (from CTNNB1 gene). (TIF)

Wnt signaling KEGG pathway. TNKS interacts with CTNNB1. (TIF)

Descriptive analyses for discovery data (Stage 1) in current drinkers. Characteristics of blood pressure (BP) in current drinkers (yes or no), within sub-sample of individuals with or without anti-hypertensive (BP Lowering) medications, and in combined samples; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial pressure; PP, pulse pressure; N,...

Descriptive analyses for blood pressure (BP) stratified by alcohol consumption for discovery data (Stage 1). Characteristics of systolic BP and diastolic BP, after correcting for BP lowering medication and winsorizing observations. (XLSX)

Descriptive analyses for replication data (Stage 2) in current drinkers. Characteristics of blood pressure (BP) within current drinkers (CURD: yes or no), and in alcohol combined samples; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial pressure; PP, pulse pressure; N, number of individuals; mean, mean levels; SD, standard deviation of mean;...

Demographic statistics for replication data (Stage 2). N, Number of subjects; % Hypertensive, defined whether participants presented: (i) SBP ≥ 140 mm Hg, (ii) DBP ≥ 90 mm Hg, and/or (iii) taking anti-hypertensive medication; Mean, age mean; SD, standard deviation of mean; Min, minimum age; Max, maximum age. (XLSX)

SNVs/genes associated with BP traits in European ancestry. Variants previously reported for blood pressure (BP) in genome-wide association studies. The most significant associated SNVs are shown per gene for each Blood Pressure (BP) trait and alcohol status. Abbreviations: Nb, order number based on genes; SNV, single nucleotide variant; Chr, chromo...

SNVs/genes associated with BP traits in multi-ancestry meta-analysis in combined Stage 1 and Stage 2. Variants previously reported for blood pressure (BP) in genome-wide association studies. The most significant associated SNVs are shown per gene for each Blood Pressure (BP) trait and alcohol status. Abbreviations: Nb, order number based on genes;...

Novel SNVs/genes associated with BP traits for eSNV/eQTL using GTEx. Target genes (Tissues and P-Values). Association findings from European Ancestry (novel) and correlated meta-analysis (novel variants). The annotation of variants was sourced from NCBI dbSNP build 138 (hg19) during the analyses and updated to dbSNP build 150 (hg38) for reporting r...

Data analysis tools and databases. (DOCX)

QQ plots for BP traits for light/heavy drinkers. Meta-analysis distributions of–log10 P-values of observed versus–log10 P-values expected (QQ plots) for light/heavy drinkers (1–7 drinks/week or ≥8 drinks/week) in European ancestry (A) and in African ancestry (B). (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for DBP in current drinkers (A) and in light/heavy drinkers (B) in European ancestry. Novel loci are highlighted in blue. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for PP in current drinkers (A) and in light/heavy drinkers (B) in European ancestry. Novel loci are highlighted in blue. (TIF)

Descriptive analyses for replication data (Stage 2) in light/heavy drinkers. Characteristics of blood pressure (BP) within light/heavy drinkers (LHD: 1–7 drinks/week or ≥8 drinks/week), and in alcohol combined samples; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial pressure; PP, pulse pressure; N, number of individuals; mean, mean levels;...

Characteristics of each study and their genotype data for replication data (Stage 2). Study design, population-based or cohort-unrelated; Principal components used; Other covariates entered in the model; Genotyping platforms; Genotyping calling algorithm; Imputation reference panel; NCBI dbSNP build; Analysis software; Robust or model-based statist...

Novel SNVs/ genes associated with BP traits in multi-ancestry and specific-ancestry meta-combined results. Top significant associated SNVs are shown per gene for each trait and alcohol exposure. (XLSX)

SNVs/genes associated with BP traits in African ancestry. Variants previously reported for blood pressure (BP) in genome-wide association studies. The most significant associated SNVs are shown per gene for each Blood Pressure (BP) trait and alcohol status. Abbreviations: Nb, order number based on genes; SNV, single nucleotide variant; Chr, chromos...

Regional association plots on 16q12. SNV x current drinker interaction for SBP (A), DBP (B), MAP (C) and PP (D) in European Ancestry. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for MAP in current drinkers (A) and in light/heavy drinkers (B) in European ancestry. Novel loci are highlighted in blue. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for PP in current drinkers (A) and in light/heavy drinkers (B) in African ancestry. Novel loci are highlighted in blue. (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for MAP (A) and PP (B) in current drinkers in Asian ancestry. (TIF)

Descriptive analyses for discovery data (Stage 1) in light/heavy drinkers. Characteristics of blood pressure (BP) in light/heavy drinkers (1–7 drinks/week or ≥8 drinks/week), within sub-sample of individuals with or without anti-hypertensive (BP Lowering) medications, and in combined samples; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial...

SNVs/genes associated with BP traits for regulatory features using HaploReg and RegulomeDB. Association findings from European Ancestry (novel), African Ancestry (potential) and correlated meta-analysis (novel variants). The annotation of variants was sourced from NCBI dbSNP build 138 (hg19) during the analyses and updated to dbSNP build 150 (hg38)...

QQ plots for BP traits for current drinkers. Meta-analysis distributions of–log10 P-values of observed versus–log10 P-values expected (QQ plots) for current drinkers (yes/no) European ancestry (A) and in African ancestry (B). (TIF)

Regional association plots on 8p23. SNV x current drinker interaction for SBP (A), DBP (B), MAP (C) and PP (D) in European Ancestry; four linkage disequilibrium (LD) blocks (see also Fig 1). (TIF)

Manhattan plots of combined Stage 1 and Stage 2 meta-analysis for MAP in current drinkers (A) and in light/heavy drinkers (B) in African ancestry. (TIF)

Characteristics of each study and their genotype data for discovery data (Stage 1). Study design, population-based or cohort-unrelated; Principal components used; Other covariates entered in the model; Genotyping platforms; Genotyping calling algorithm; Quality Control Filters; Imputation reference panel; Number of SNVs (single nucleotide variants)...

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and dias...

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and dias...