Publications by authors named "Adrienne M Stilp"

Article Synopsis
  • Coronary artery calcification (CAC) is linked to heart disease and assessed through a genome-wide association study (GWAS) involving 22,400 participants from various backgrounds.
  • The study confirmed connections with four known genetic loci and discovered two new loci related to CAC, with supportive replication findings for both.
  • Functional tests suggest that ARSE promotes calcification in vascular smooth muscle cells and its variants may influence CAC levels, identifying ARSE as a key target for potential treatments in vascular calcific diseases.
View Article and Find Full Text PDF

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood.

View Article and Find Full Text PDF

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program.

View Article and Find Full Text PDF
Article Synopsis
  • Type 2 diabetes (T2D) is a complex disease influenced by various genetic factors and molecular mechanisms that vary by cell type and ancestry.
  • In a large study involving over 2.5 million individuals, researchers identified 1,289 significant genetic associations linked to T2D, including 145 new loci not previously reported.
  • The study categorized T2D signals into eight distinct clusters based on their connections to cardiometabolic traits and showed that these genetic profiles are linked to vascular complications, emphasizing the role of obesity-related processes across different ancestry groups.
View Article and Find Full Text PDF

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF
Article Synopsis
  • Genome-wide association studies have found thousands of genetic variations affecting blood traits, but the impact of structural variants on these traits was previously unclear.
  • A study using whole genome sequencing from a diverse group of nearly 50,700 participants identified 21 significant structural variants linked to red and white blood cell traits, with most findings confirmed in other datasets.
  • Experimental evidence showed that a specific deletion linked to lower monocyte counts disrupts an enhancer for the S1PR3 gene, leading to reduced S1PR3 expression.
View Article and Find Full Text PDF
Article Synopsis
  • - Individuals with cystic fibrosis (CF) can develop complications like cystic fibrosis-related diabetes (CFRD) and meconium ileus (MI), which are influenced by genetic factors beyond the CFTR gene.
  • - A study using whole-genome sequencing identified 11 genetic variants linked to MI and 12 to CFRD, with some variants (like those in SLC26A9, CEBPB, and PRSS1) affecting both conditions.
  • - While some genetic loci increase the risk for both CFRD and MI, others specifically impact one condition, suggesting both differences and shared genetic mechanisms between these complications.
View Article and Find Full Text PDF

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting.

View Article and Find Full Text PDF

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

View Article and Find Full Text PDF

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project.

View Article and Find Full Text PDF

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538).

View Article and Find Full Text PDF
Article Synopsis
  • - Human genetic studies show that shorter leukocyte telomere length (LTL) is linked to a higher risk of coronary artery disease (CAD), while the relationship between LTL and various cancers is less clear.
  • - Clonal hematopoiesis of indeterminate potential (CHIP), which involves the growth of blood cells with certain mutations, increases the risk for both blood cancers and CAD, with telomerase reverse transcriptase being a key genetic factor in CHIP.
  • - Research from the TOPMed program and UK Biobank reveals that longer genetically predicted LTL increases the likelihood of developing CHIP, which then leads to a decrease in measured LTL, providing insights into how these factors might contribute to CAD prevention.
View Article and Find Full Text PDF

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples.

View Article and Find Full Text PDF
Article Synopsis
  • Whole-genome sequencing (WGS) was used to analyze genetic variants associated with seven red blood cell (RBC) traits in a diverse group of 62,653 participants, revealing 14 novel variant-RBC trait associations.
  • Many of these associations, particularly those linked to genes like RPN1 and PIEZO1, were found to be rare and more common in non-European ancestry populations.
  • The study underscores the potential of WGS and gene editing techniques to enhance understanding of genetic factors influencing RBC traits and hereditary disorders.
View Article and Find Full Text PDF
Article Synopsis
  • Genotype-phenotype association studies improve statistical power by combining phenotype data from multiple research efforts, but data harmonization poses challenges due to varying definitions and methods.
  • A centralized harmonization system was developed for the National Heart, Lung, and Blood Institute's TOPMed program, successfully standardizing 63 phenotypes from studies conducted between 1948 and 2012.
  • The harmonized data, along with documentation and software for future harmonization, have been shared with NIH data repositories, promoting collaboration and reproducibility in scientific research.
View Article and Find Full Text PDF
Article Synopsis
  • A study involving over 65,000 participants analyzed genetic variations on the X chromosome and their impact on blood lipids, revealing significant associations with lower cholesterol levels.
  • The research identified Xq23 region alleles that not only lower cholesterol and triglycerides but are also linked to reduced risk of coronary heart disease and type 2 diabetes.
  • Additionally, while there was a relation to higher body mass index (BMI), adjustments showed that certain fat distributions are healthier, suggesting a complex relationship between fat, gene expression, and blood lipids.
View Article and Find Full Text PDF
Article Synopsis
  • The Trans-Omics for Precision Medicine (TOPMed) programme aims to understand the genetic factors behind heart, lung, blood, and sleep disorders to enhance their diagnosis, treatment, and prevention.
  • TOPMed uses whole-genome sequencing from diverse individuals, revealing over 400 million genetic variants, many of which are rare and offer insights into human evolution and disease mechanisms.
  • The programme provides tools like a variant browser and access to genomic data, improving the capability of genome-wide association studies to include rare variants that could have significant health implications.
View Article and Find Full Text PDF

Background: Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants.

Methods: This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in the Women's Health Initiative and the UK Biobank when variants were available.

View Article and Find Full Text PDF

Five sequence variants in SLC16A11 (rs117767867, rs13342692, rs13342232, rs75418188, and rs75493593), which occur in two non-reference haplotypes, were recently shown to be associated with diabetes in Mexicans from the SIGMA consortium. We aimed to determine whether these previous findings would replicate in the HCHS/SOL Mexican origin group and whether genotypic effects were similar in other HCHS/SOL groups. We analyzed these five variants in 2492 diabetes cases and 5236 controls from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes U.

View Article and Find Full Text PDF