Publications by authors named "Nora Franceschini"

246 Publications

Multiethnic Genome-wide Association Study of Subclinical Atherosclerosis in Individuals with Type 2 Diabetes.

Circ Genom Precis Med 2021 Jul 9. Epub 2021 Jul 9.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC.

- Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease (CVD). Type 2 diabetes (T2D) is an independent CVD risk factor that accelerates atherosclerosis. - We performed meta-analyses of genome-wide association studies (GWAS) in up to 2,500 T2D individuals of European ancestry (EA) and 1,590 T2D individuals of African ancestry (AA) with or without exclusion of prevalent CVD, for CAC measured by cardiac computed tomography, and 3,608 EA and 838 AA with T2D for cIMT measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. - We replicated two loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and AA. The expression QTL analysis with nearby expressed genes derived from arterial wall and metabolic tissues from GTEx pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for three previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT). - Our results provide potential biological mechanisms that could link CAC and cIMT to increased CVD risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
July 2021

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.

Clin Epigenetics 2021 Jun 2;13(1):121. Epub 2021 Jun 2.

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria.

Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.
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http://dx.doi.org/10.1186/s13148-021-01082-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170969PMC
June 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 Apr 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.

Hum Mol Genet 2021 Mar 30. Epub 2021 Mar 30.

MRC/UVRI and LSHTM, Entebbe, Uganda.

Background: Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD).

Method: We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (p < 5x10-8) were followed up with Bayesian fine-mapping to localise potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead SNPs was evaluated in the Uganda GPC.

Findings: We identified and validated two eGFR loci. At the GATM locus, the association signal (lead SNP rs2433603, p = 1.0x10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the HBB locus, the association signal (lead SNP rs141845179, p = 3.0x10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population.

Interpretation: In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.
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http://dx.doi.org/10.1093/hmg/ddab088DOI Listing
March 2021

Genetic variation and urine cadmium levels: ABCC1 effects in the Strong Heart Family Study.

Environ Pollut 2021 May 11;276:116717. Epub 2021 Feb 11.

Area of Cardiometabolic and Renal Risk, Institute for Biomedical Research Hospital Clinic of Valencia (INCLIVA), Valencia, Valencia, Spain; Department of Preventive Medicine and Public Health and Microbiology, Universidad Autonoma de Madrid, Madrid, Madrid, Spain; Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Madrid, Spain; Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD, USA.

Genetic effects are suspected to influence cadmium internal dose. Our objective was to assess genetic determinants of urine cadmium in American Indian adults participating in the Strong Heart Family Study (SHFS). Urine cadmium levels and genotyped short tandem repeat (STR) markers were available on 1936 SHFS participants. We investigated heritability, including gene-by-sex and smoking interactions, and STR-based quantitative trait locus (QTL) linkage, using a variance-component decomposition approach, which incorporates the genetic information contained in the pedigrees. We also used available single nucleotide polymorphisms (SNPs) from Illumina's Metabochip and custom panel to assess whether promising QTLs associated regions could be attributed to SNPs annotated to specific genes. Median urine cadmium levels were 0.44 μg/g creatinine. The heritability of urine cadmium concentrations was 28%, with no evidence of gene-by-sex or -smoking interaction. We found strong statistical evidence for a genetic locus at chromosome 16 determining urine cadmium concentrations (Logarithm of odds score [LOD] = 3.8). Among the top 20 associated SNPs in this locus, 17 were annotated to ABCC1 (p-values from 0.0002 to 0.02), and attenuated the maximum linkage peak by a ∼40%. Suggestive QTL signals (LOD>1.9) in chromosomes 2, 6, 11, 14, and 19, showed associated SNPs in the genes NDUFA10, PDE10A, PLEKHA7, BAZ1A and CHAF1A, respectively. Our findings support that urinary cadmium levels are heritable and influenced by a QTL on chromosome 16, which was explained by genetic variation in ABCC1. Studies with extended sets of genome-wide markers are needed to confirm these findings and to identify additional metabolism and toxicity pathways for cadmium.
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http://dx.doi.org/10.1016/j.envpol.2021.116717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026674PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study.

Neurology 2021 03 25;96(13):e1732-e1742. Epub 2021 Jan 25.

From the Institute for Stroke and Dementia Research (M.K.G., R.M., M.D.), Department of Neurology (M.K.G), University Hospital, and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Stroke Research Group, Department of Clinical Neurosciences (E.L.H., H.S.M.), and MRC Epidemiology Unit (C.L., N.J.W.), University of Cambridge, UK; Department of Epidemiology (N.F.), UNC Gillings Global School of Public Health, Chapel Hill, NC; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Objective: We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.

Methods: We selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and β-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).

Results: Genetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume.

Conclusions: This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms.

Classification Of Evidence: This study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000011555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055310PMC
March 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

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

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA Netw Open 2021 01 4;4(1):e2030435. Epub 2021 Jan 4.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

Design, Setting, And Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes And Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions And Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786247PMC
January 2021

Effect of Sickle Cell Trait and Genotype on the Association of Soluble uPAR with Kidney Function Measures in Black Americans.

Clin J Am Soc Nephrol 2021 02 2;16(2):287-289. Epub 2020 Dec 2.

Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont.

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http://dx.doi.org/10.2215/CJN.12100720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863645PMC
February 2021

When the At-Risk Do Not Develop Heart Failure: Understanding Positive Deviance Among Postmenopausal African American and Hispanic Women.

J Card Fail 2021 Feb 22;27(2):217-223. Epub 2020 Nov 22.

Division of General Medicine and Clinical Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: African American and Hispanic postmenopausal women have the highest risk for heart failure compared with other races, but heart failure prevalence is lower than expected in some national cohorts. It is unknown whether psychosocial factors are associated with lower risk of incident heart failure hospitalization among high-risk postmenopausal minority women.

Methods And Results: Using the Women's Health Initiative Study, African American and US Hispanic women were classified as high-risk for incident heart failure hospitalization with 1 or more traditional heart failure risk factors and the highest tertile heart failure genetic risk scores. Positive psychosocial factors (optimism, social support, religion) and negative psychosocial factors (living alone, social strain, depressive symptoms) were measured using validated survey instruments at baseline. Adjusted subdistribution hazard ratios of developing heart failure hospitalization were determined with death as a competing risk. Positive deviance indicated not developing incident heart failure hospitalization with 1 or more risk factors and the highest tertile for genetic risk. Among 7986 African American women (mean follow-up of 16 years), 27.0% demonstrated positive deviance. Among high-risk African American women, optimism was associated with modestly reduced risk of heart failure hospitalization (subdistribution hazard ratio 0.94, 95% confidence interval 0.91-0.99), and social strain was associated with modestly increased risk of heart failure hospitalization (subdistribution hazard ratio 1.07, 95% confidence interval 1.02-1.12) in the initial models; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses. Among 3341 Hispanic women, 25.1% demonstrated positive deviance. Among high-risk Hispanic women, living alone was associated with increased risk of heart failure hospitalization (subdistribution hazard ratio 1.97, 95% confidence interval 1.06-3.63) in unadjusted analyses; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses.

Conclusions: Among postmenopausal African American and Hispanic women, a significant proportion remained free from heart failure hospitalization despite having the highest genetic risk profile and 1 or more traditional risk factors. No observed psychosocial factors were associated with incident heart failure hospitalization in high-risk African Americans and Hispanics. Additional investigation is needed to understand protective factors among high-risk African American and Hispanic women.
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http://dx.doi.org/10.1016/j.cardfail.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880886PMC
February 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Engulfment and cell motility 1 (ELMO1) and apolipoprotein A1 (APOA1) as candidate genes for sickle cell nephropathy.

Br J Haematol 2021 May 20;193(3):628-632. Epub 2020 Nov 20.

Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Sickle cell disease (SCD) and apolipoprotein L1 (APOL1) G1/G2 variants increase chronic kidney disease (CKD) risk in African Americans by poorly understood mechanisms. We applied bioinformatics to identify new candidate genes associated with SCD-related CKD. An interaction network demonstrated APOA1 connecting haemoglobin subunit β (HBB) and APOL1 with 36 other candidate genes. Gene expression revealed upregulation of engulfment and cell motility 1 (ELMO1) and downregulation of APOA1 in the kidney cortex of SCD versus non-SCD mice. Analysis of candidate genes identified ELMO1 rs10951509 to be associated with albuminuria and APOA1 rs11216132 with haemoglobinuria in patients with SCD. A bioinformatic approach highlights ELMO1 and APOA1 as potentially associated with SCD nephropathy.
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http://dx.doi.org/10.1111/bjh.17224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084902PMC
May 2021

Current Smoking Raises Risk of Incident Hypertension: Hispanic Community Health Study-Study of Latinos.

Am J Hypertens 2021 03;34(2):190-197

Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Hypertension has been implicated as a smoking-related risk factor for cardiovascular disease but the dose-response relationship is incompletely described. Hispanics, who often have relatively light smoking exposures, have been understudied in this regard.

Methods: We used data from a 6-year follow-up study of US Hispanic adults aged 18-76 to address the dose-response linking cigarette use with incident hypertension, which was defined by measured blood pressure above 140/90 mm Hg or initiation of antihypertensive medications. Adjustment was performed for potential confounders and mediators, including urinary albumin-to-creatinine ratio which worsened over time among smokers.

Results: Current smoking was associated with incident hypertension, with a threshold effect above 5 cumulative pack-years of smoking (vs. never smokers, hazard ratio for hypertension [95% confidence interval] of 0.95 [0.67, 1.35] for 0-5 pack-years, 1.47 [1.05, 2.06] for 5-10 pack-years, 1.40 [1.00, 1.96] for 10-20 pack-years, and 1.34 [1.09, 1.66] for ≥20 pack-years, P = 0.037). In contrast to current smokers, former smokers did not appear to have increased risk of hypertension, even at the highest cumulative pack-years of past exposure.

Conclusions: The results confirm that smoking constitutes a hypertension risk factor in Hispanic adults. A relatively modest cumulative dose of smoking, above 5 pack-years of exposure, raises risk of hypertension by over 30%. The increased hypertension risk was confined to current smokers, and did not increase further with higher pack-year levels. The lack of a smoking-hypertension association in former smokers underscores the value of smoking cessation.
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http://dx.doi.org/10.1093/ajh/hpaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951044PMC
March 2021

Prevalence, Awareness, and Treatment of Hypertension in Hispanics/Latinos With CKD in the Hispanic Community Health Study/Study of Latinos.

Kidney Med 2020 May-Jun;2(3):332-340. Epub 2020 Apr 21.

University of Illinois at Chicago, Chicago, IL.

Rationale & Objective: Lower rates of hypertension awareness, treatment, and control have been observed in Hispanics/Latinos compared with non-Hispanic whites. These factors have not been studied in Hispanics/Latinos with chronic kidney disease (CKD). We sought to describe the prevalence, awareness, treatment, and control of hypertension in Hispanic/Latino adults with CKD.

Study Design: Cross-sectional cohort.

Setting & Participants: US.Hispanics/Latinos aged 18 to 74 years enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) with CKD. Comparisons were made with the National Health and Nutrition Examination Survey (NHANES) 2007 to 2010.

Exposure: CKD was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m or urinry albumin-creatinine ratio ≥ 30 mg/g creatinine.

Outcomes: Hypertension was defined as systolic blood pressure (BP) ≥ 140 or diastolic BP ≥ 90 mm Hg or use of antihypertensives. For hypertension control, 2 thresholds were examined: <140/90 and <130/80 mm Hg.

Results: The prevalence of hypertension was 51.5%; among those with hypertension, hypertension awareness and treatment were present in 78.1% and 70.4%, respectively. A low prevalence of BP control was observed (32.6% with BP < 140/90 mm Hg; 17.9% with BP < 130/80 mm Hg). Health insurance coverage was associated with higher odds of BP < 140/90 mm Hg (OR, 1.98; 95% CI, 1.15-3.43). Compared with non-Hispanic whites with CKD in NHANES, HCHS/SOL participants with CKD had a lower prevalence of hypertension but a lower rate of BP control (32.6% vs 48.6% for BP < 140/90 mm Hg).

Limitations: Use of a single measurement of creatinine, cystatin C, and urinary albumin excretion to define CKD. Single-visit measurement of BP.

Conclusions: Hispanics/Latinos with CKD residing in the United States have very low rates of BP control. The association of health insurance coverage with hypertension control suggests that improved access to health care may improve outcomes for this growing population.
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http://dx.doi.org/10.1016/j.xkme.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380346PMC
April 2020

Genome-Wide Association of Kidney Traits in Hispanics/Latinos Using Dense Imputed Whole-Genome Sequencing Data: The Hispanic Community Health Study/Study of Latinos.

Circ Genom Precis Med 2020 08 29;13(4):e002891. Epub 2020 Jun 29.

Department of Epidemiology (N.F.), University of North Carolina, Chapel Hill.

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.

Results: Two low-frequency intronic variants were associated with estimated glomerular filtration rate (rs58720902 at , minor allele frequency=0.01, =1.6×10) or urine albumin-to-creatinine ratio (rs527493184 at , minor allele frequency=0.002, =1.1×10). An additional variant at (rs2422935, minor allele frequency=0.54, =2.89×10) was significantly associated with estimated glomerular filtration rate in meta-analysis with replication samples. We also identified 2 known loci for urine albumin-to-creatinine ratio ( rs116907128, =5.6×10 and rs344, =9.3×10) and validated 8 loci for urine albumin-to-creatinine ratio previously identified in the UK Biobank.

Conclusions: Our study shows gains in gene discovery when using dense imputation from multi-ethnic whole-genome sequencing data in admixed Hispanics/Latinos. It also highlights limitations in genetic research of kidney traits, including the lack of suitable replication samples for variants that are more common in non-European ancestry and those at low frequency in populations.
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http://dx.doi.org/10.1161/CIRCGEN.119.002891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442703PMC
August 2020

Genetics of kidney traits in worldwide populations: the Continental Origins and Genetic Epidemiology Network (COGENT) Kidney Consortium.

Kidney Int 2020 07;98(1):35-41

Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1016/j.kint.2020.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749437PMC
July 2020

Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.

Circ Genom Precis Med 2020 08 8;13(4):e002772. Epub 2020 Jun 8.

Department of Epidemiology, School of Public Health (L.F.B., J.A.S., W.Z., S.L.R.K.), University of Michigan, Ann Arbor, MI.

Background: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

Methods: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

Results: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

Conclusions: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
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http://dx.doi.org/10.1161/CIRCGEN.119.002772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442680PMC
August 2020

Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.

Circ Genom Precis Med 2020 06 12;13(3):e002872. Epub 2020 May 12.

Institute for Stroke and Dementia Research (ISD) (M.K.G., R.M., M.D.), University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany.

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http://dx.doi.org/10.1161/CIRCGEN.119.002872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299212PMC
June 2020

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

PLoS One 2020 7;15(5):e0230815. Epub 2020 May 7.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States of America.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205201PMC
August 2020

Incident Chronic Kidney Disease Risk among Hispanics/Latinos in the United States: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

J Am Soc Nephrol 2020 06 16;31(6):1315-1324. Epub 2020 Apr 16.

Department of Medicine, University of Illinois, Chicago, Illinois.

Background: Although Hispanics/Latinos in the United States are often considered a single ethnic group, they represent a heterogenous mixture of ancestries who can self-identify as any race defined by the U.S. Census. They have higher ESKD incidence compared with non-Hispanics, but little is known about the CKD incidence in this population.

Methods: We examined rates and risk factors of new-onset CKD using data from 8774 adults in the Hispanic Community Health Study/Study of Latinos. Incident CKD was defined as eGFR <60 ml/min per 1.73 m with eGFR decline ≥1 ml/min per 1.73 m per year, or urine albumin/creatinine ratio ≥30 mg/g. Rates and incidence rate ratios were estimated using Poisson regression with robust variance while accounting for the study's complex design.

Results: Mean age was 40.3 years at baseline and 51.6% were women. In 5.9 years of follow-up, 648 participants developed CKD (10.6 per 1000 person-years). The age- and sex-adjusted incidence rates ranged from 6.6 (other Hispanic/mixed background) to 15.0 (Puerto Ricans) per 1000 person-years. Compared with Mexican background, Puerto Rican background was associated with 79% increased risk for incident CKD (incidence rate ratios, 1.79; 95% confidence interval, 1.33 to 2.40), which was accounted for by differences in sociodemographics, acculturation, and clinical characteristics. In multivariable regression analysis, predictors of incident CKD included BP >140/90 mm Hg, higher glycated hemoglobin, lower baseline eGFR, and higher baseline urine albumin/creatinine ratio.

Conclusions: CKD incidence varies by Hispanic/Latino heritage and this disparity may be in part attributed to differences in sociodemographic characteristics. Culturally tailored public heath interventions focusing on the prevention and control of risk factors might ameliorate the CKD burden in this population.
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http://dx.doi.org/10.1681/ASN.2019101008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269353PMC
June 2020

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study.

Sci Rep 2019 11 29;9(1):17899. Epub 2019 Nov 29.

Department of Nutrition, and UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25-44%; P < 3 × 10) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.
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http://dx.doi.org/10.1038/s41598-019-52924-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884539PMC
November 2019

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Cell 2019 10;179(4):984-1002.e36

Wellcome Sanger Institute, Hinxton, Cambridge, UK.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.
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http://dx.doi.org/10.1016/j.cell.2019.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202134PMC
October 2019

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Nat Genet 2019 11 28;51(11):1580-1587. Epub 2019 Oct 28.

National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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http://dx.doi.org/10.1038/s41588-019-0514-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858575PMC
November 2019