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Donna K Arnett

Publications and source records attributed to Donna K Arnett.

6 recordsLinked to original sources
PubMed2025

Influence of Ancestral and Geographic Factors on Intracerebral Hemorrhage Risks Among Africans and Americans.

BACKGROUND: We investigated whether risk factors for intracerebral hemorrhage (ICH) among indigenous Africans (IA) would vary in prevalence and effect compared with self-reported African, Hispanic, and White Americans by comparing data from 2 independent population-based case-control studies conducted in West Africa and the United States. METHODS: We compared ICH risk factors common to the SIREN (Stroke Investigative Research and Educational Network: 1100 case-control pairs) and the ERICH (Ethnic/Racial Variation of Intracerebral Hemorrhage: 999 case-control pairs African American participants, 998 case-control pairs, Hispanic Americans, 1000 case-control pairs, White Americans) studies. Ethnicity/Race was self-reported. The effect measure of interest is the odds ratio (OR). To test for differences in the effects of the risk factors between the SIREN IA study population and each of the ERICH study populations, a test for heterogeneity was computed using the R program, metagen (version 4.9-6). RESULTS: ICH occurred at a younger age among IA (54.3±13.4 years), African Americans (58.0±12.7), and Hispanic Americans (58.9±14.3), compared with White Americans (69.1±13.9). The largest distinction was for hypertension, where IA exhibited a much larger risk of ICH than the American study population (OR, 67.02 [95% CI, 33.30-134.85]), African American (OR, 3.71 [95% CI, 2.53-5.44]); Hispanic (OR, 3.55 [95% CI, 2.54-4.92]), and White population (OR, 2.69 [95% CI, 1.95-3.69]). Current alcohol use exhibited increased risk in IA (OR, 2.24 [95% CI, 1.36-3.67]), but not in African Americans (OR, 0.63 [95% CI, 0.46-0.86]), Hispanic (OR, 0.87 [95% CI, 0.65-1.17]), and White Americans (OR, 0.51 [95% CI, 0.38-0.69]). CONCLUSIONS: Identical or comparable risk factors do not consistently result in the same disease risk across different cultures and regions. Therefore, to improve our understanding of the genetic determinants and biological pathways driving ICH risk, it is crucial to study multiple populations, including IA, while accounting for the influence of environmental and social factors.

Adult↗
PubMed2025

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Humans↗
PubMed2025

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls. To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of BD association with single-variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD GWAS loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.

Journal Article↗
PubMed2024

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Humans↗
PubMed2024

Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height.

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N&#x2009;=&#x2009;200,003), TOPMed (N&#x2009;=&#x2009;87,652) and All of Us (N&#x2009;=&#x2009;45,445). We performed rare (&#x2009;<&#x2009;0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P&#x2009;<&#x2009;after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7&#x2009;cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5&#x2009;cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

Humans↗
PubMed2024

A methylation risk score for chronic kidney disease: a HyperGEN study.

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

Humans↗