ORCID Profile
0000-0001-8748-5597
Current Organisation
University of Tokyo
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Publisher: Springer Science and Business Media LLC
Date: 26-10-2018
DOI: 10.1038/S41467-018-06356-1
Abstract: Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 in iduals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2019
DOI: 10.1038/S41398-019-0532-4
Abstract: Over 3000 candidate gene association studies have been performed to elucidate the genetic underpinnings of schizophrenia. However, a comprehensive evaluation of these studies’ findings has not been undertaken since the decommissioning of the schizophrenia gene (SzGene) database in 2011. As such, we systematically identified and carried out random-effects meta-analyses for all polymorphisms with four or more independent studies in schizophrenia along with a series of expanded meta-analyses incorporating published and unpublished genome-wide association (GWA) study data. Based on 550 meta-analyses, 11 SNPs in eight linkage disequilibrium (LD) independent loci showed Bonferroni-significant associations with schizophrenia. Expanded meta-analyses identified an additional 10 SNPs, for a total of 21 Bonferroni-significant SNPs in 14 LD-independent loci. Three of these loci ( MTHFR , DAOA , ARVCF ) had never been implicated by a schizophrenia GWA study. In sum, the present study has provided a comprehensive summary of the current schizophrenia genetics knowledgebase and has made available all the collected data as a resource for the research community.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2019
Publisher: Springer Science and Business Media LLC
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 11-12-2017
DOI: 10.1038/S41398-017-0019-0
Abstract: Bipolar disorder (BPD) and major depressive disorder (MDD) are primary major mood disorders. Recent studies suggest that they share certain psychopathological features and common risk genes, but unraveling the full genetic architecture underlying the risk of major mood disorders remains an important scientific task. The public genome-wide association study (GWAS) data sets offer the opportunity to examine this topic by utilizing large amounts of combined genetic data, which should ultimately allow a better understanding of the onset and development of these illnesses. Genome-wide meta-analysis was performed by combining two GWAS data sets on BPD and MDD (19,637 cases and 18,083 controls), followed by replication analyses for the loci of interest in independent 12,364 cases and 76,633 controls from additional s les that were not included in the two GWAS data sets. The single-nucleotide polymorphism (SNP) rs10791889 at 11q13.2 was significant in both discovery and replication s les. When combining all s les, this SNP and multiple other SNPs at 2q11.2 (rs717454), 8q21.3 (rs10103191), and 11q13.2 (rs2167457) exhibited genome-wide significant association with major mood disorders. The SNPs in 2q11.2 and 8q21.3 were novel risk SNPs that were not previously reported, and SNPs at 11q13.2 were in high LD with potential BPD risk SNPs implicated in a previous GWAS. The genome-wide significant loci at 2q11.2 and 11q13.2 exhibited strong effects on the mRNA expression of certain nearby genes in cerebellum. In conclusion, we have identified several novel loci associated with major mood disorders, adding further support for shared genetic risk between BPD and MDD. Our study highlights the necessity and importance of mining public data sets to explore risk genes for complex diseases such as mood disorders.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2019
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2020
DOI: 10.1101/2020.02.02.20020065
Abstract: Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Publisher: Springer Science and Business Media LLC
Date: 10-2019
Publisher: Oxford University Press (OUP)
Date: 23-02-2022
DOI: 10.1093/EURHEARTJ/EHAC093
Abstract: 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. Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 in iduals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. In iduals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43–3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk in iduals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk in iduals with intermediate (20–80%) PRS. The PRS could stratify in iduals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk in iduals for targeted intervention in clinical utility.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
Publisher: Springer Science and Business Media LLC
Date: 03-01-2019
DOI: 10.1038/S41467-018-07867-7
Abstract: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 in iduals of erse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2019
DOI: 10.1038/S41598-019-53654-9
Abstract: Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P 5.0 × 10 −8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 ( ALCAM ) and rs75286142 on 21q22.12 ( CLIC6-RUNX1 ). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that in iduals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to in iduals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2023
Publisher: Springer Science and Business Media LLC
Date: 08-12-2020
DOI: 10.1038/S41467-020-19111-2
Abstract: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older in iduals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk in iduals and for genetically-informed prioritization of drug targets for prevention trials.
No related grants have been discovered for Yoichiro Kamatani.