Characterization of non-coding variants associated with transcription-factor binding through ATAC-seq-defined footprint QTLs in liver

The American Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Diabetes mellitus polygenic risk scores: heterogeneity and clinical translation

Nature Reviews Endocrinology, Год журнала: 2025, Номер unknown

Опубликована: Июнь 4, 2025

Язык: Английский

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Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study

The American Journal of Human Genetics, Год журнала: 2023, Номер 110(10), С. 1704 - 1717

Опубликована: Окт. 1, 2023

Язык: Английский

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Blood cell traits’ GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants

Cell Genomics, Год журнала: 2023, Номер 3(7), С. 100327 - 100327

Опубликована: Май 17, 2023

Genome-wide association studies (GWASs) have uncovered numerous trait-associated loci across the human genome, most of which are located in noncoding regions, making interpretation difficult. Moreover, causal variants hard to statistically fine-map at many because widespread linkage disequilibrium. To address this challenge, we present a strategy utilizing transcription factor (TF) binding quantitative trait (bQTLs) for colocalization analysis identify associations likely mediated by TF occupancy variation and pinpoint using motif scores. We applied approach PU.1 bQTLs lymphoblastoid cell lines blood GWAS data. Colocalization revealed 69 putatively driven variation. nominate motif-altering as shared 51 loci. Such integration bQTL data with other may reveal transcriptional regulatory mechanisms underlying additional complex traits.

Язык: Английский

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Genome-wide association studies and fine-mapping identify genomic loci for n-3 and n-6 polyunsaturated fatty acids in Hispanic American and African American cohorts

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Авг. 16, 2023

Abstract Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 n-6 PUFAs European Americans from the CHARGE Consortium have documented strong genetic signals in/near FADS locus on chromosome 11. We performed a GWAS four Hispanic American ( n = 1454) African 2278) participants three cohorts. Applying significance threshold P < 5 × 10 −8 , we confirmed signal found evidence two additional (in DAGLA BEST1 ) within 200 kb originally reported signal. Outside region, identified novel for arachidonic acid (AA) located genes including TMX2 SLC29A2 ANKRD13D POLD4 spanning > 9 Mb region 11 (57.5 ~ 67.1 Mb). Among these signals, associations unique to Americans, rs28364240, missense variant AA that is common but absent other race/ancestry groups. Our study sheds light genetics value investigating complex trait across diverse ancestry populations.

Язык: Английский

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The breadth and impact of the Global Lipids Genetics Consortium

Current Opinion in Lipidology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 27, 2024

Purpose of review This highlights contributions the Global Lipids Genetics Consortium (GLGC) in advancing understanding genetic etiology blood lipid traits, including total cholesterol, LDL HDL triglycerides, and non-HDL cholesterol. We emphasize consortium's collaborative efforts, discoveries related to lipoprotein biology, methodological advancements, utilization areas extending beyond research. Recent findings The GLGC has identified over 923 genomic loci associated with traits through genome-wide association studies (GWASs), involving more than 1.65 million individuals from globally diverse populations. Many have been functionally validated by inside outside community. show increased population diversity enhances variant discovery, fine-mapping causal loci, polygenic score prediction for levels. Moreover, publicly available GWAS summary statistics facilitated exploration lipid-related influences on cardiovascular noncardiovascular diseases, implications therapeutic development drug repurposing. Summary significantly advanced basis levels serves as leading resource these traits. Continued collaboration will be critical further understand biology large-scale assessments

Язык: Английский

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Association of exposure factors and their causal relationship with oral cancer: A Mendelian randomization study

Clinical Oral Investigations, Год журнала: 2024, Номер 28(4)

Опубликована: Март 23, 2024

Язык: Английский

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Multi‐tissue transcriptome‐wide association study reveals susceptibility genes and drug targets for insulin resistance‐relevant phenotypes

Diabetes Obesity and Metabolism, Год журнала: 2023, Номер 26(1), С. 135 - 147

Опубликована: Окт. 1, 2023

Abstract Aim Genome‐wide association studies ( GWAS ) have identified multiple susceptibility loci associated with insulin resistance IR )‐relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify ‐relevant phenotypes via a transcriptome‐wide study. Materials and Methods conducted large‐scale multi‐tissue study (Insulin Sensitivity Index, homeostasis model assessment‐IR, fasting insulin) lipid‐relevant traits (high‐density lipoprotein cholesterol, triglycerides, low‐density cholesterol total cholesterol) using largest summary statistics precomputed gene expression weights of 49 human tissues. Conditional joint analyses were implemented significantly independent genes. Furthermore, we estimated causal effects by Mendelian randomization inference analysis. Results 1190 causally IR‐relevant phenotypes, including 58 that not implicated in original GWAS. Among them, 11 further supported differential or knockout mice database, such as KRIT1 showed both IR‐related phenotypic mice. Meanwhile, seven proteins encoded targeted clinically approved drugs, three H6PD , CACNB2 DRD2 been served drug targets diseases/traits. Moreover, repurposing analysis four compounds profiles opposing risk. Conclusions Our provided new insights into aetiology avenues therapeutic development.

Язык: Английский

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Systematic elucidation of genetic mechanisms underlying cholesterol uptake

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Янв. 10, 2023

Genetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combining analysis of rare coding variants from the UK Biobank genome-scale CRISPR-Cas9 knockout activation screening, we have substantially improved identification genes whose disruption alters serum LDL-C levels. We identify 21 in which significantly alter at least partially through altered uptake. use co-essentiality-based gene module show that dysfunction RAB10 vesicle transport pathway leads hypercholesterolemia humans mice by impairing surface receptor Further, demonstrate loss function

Язык: Английский

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The diabetic myocardial transcriptome reveals Erbb3 as a novel biomarker of incident heart failure

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 7, 2024

Abstract Aims Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but the molecular basis of diabetic disease is poorly defined in humans. We aimed to define myocardial transcriptome validate hits their circulating protein form mechanisms biomarkers. Methods Results RNA-sequencing data from Genotype-Tissue Expression (GTEx) project was used differentially expressed genes (DEGs) right atrial (RA) left ventricular (LV) myocardium people with versus without DM (type 1 or 2). DEGs were validated UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins characterized participants, irrespective diabetes status, using cardiac magnetic resonance imaging, incident cardiovascular mortality. found 32 associated RA LV, respectively, no overlap between these. Plasma proteomic available 6 hits, only ERBB3 (LV hit) exhibiting directional concordance, being lower blood DM. Irrespective impaired contractility higher LV mass. Participants lowest quartile had increased death vs. participants all other quartiles. Similar associations noted ERBB2 ERBB4. Conclusions by expression concentration. This dysfunction,

Язык: Английский

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