Publications by authors named "Ayush Giri"

54 Publications

The Relationship of Aging and Smoking with Rotator Cuff Disease: A Systematic Review and Meta-Analysis.

Am J Phys Med Rehabil 2021 Jun 12. Epub 2021 Jun 12.

Vanderbilt University School of Medicine, Nashville, TN Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN University of Rochester School of Medicine, Rochester, NY Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN Departments of Physical Medicine and Rehabilitation, Orthopaedics, and Population & Data Sciences, University of Texas Southwestern.

Objective: Despite rotator cuff disease being one of the most common causes of shoulder pain, its pathogenesis and biology are poorly understood. In this study, we synthesized evidence from studies reporting associations for aging and smoking status in relation to rotator cuff disease.

Design: A systematic review was performed using multiple databases (PubMed, Embase, Cochrane, CINAHL, and Science Direct). Articles that met our eligibility criteria and presented data on the association between aging and/or smoking status and rotator cuff disease were included. We performed meta-analyses and report cumulative effects using odds ratios (OR) and corresponding 95% confidence intervals (CI).

Results: Of the 212 articles eligible for full-text review, seven studies reported on the relationship between aging and rotator cuff disease and ten studies reported on the relationship between smoking and rotator cuff disease. Aging was consistently associated with increased odds of having rotator cuff disease when assessed continuously (per 10-year increase: OR = 1.20, 95% CI: 1.18, 1.21) or categorically [<40 years old versus: (a) 40-44 years old (OR = 2.71, 95% CI: 1.78, 4.13), (b) 45-49 years old (OR = 4.33, 95% CI: 2.88, 6.55), and (c) 50 years of age or older (OR = 6.97, 95% CI: 4.85, 10.01)]. Assessing studies that reported smoking status as current smokers versus non-smokers, current smokers were more likely to have rotator cuff disease (OR = 1.94, 95% CI: 1.52, 2.48). However, a statistically significant association was not found when never smokers were compared to former smokers (OR = 1.08, 95% CI: 0.97, 1.20) and to current smokers (OR = 0.97, 95% CI: 0.87, 1.07).

Conclusion: In this systematic review and meta-analysis, increasing age was a strong risk factor for rotator cuff disease. The finding that current smokers are more likely to have rotator cuff disease as compared with non-smokers implies that cessation of smoking can potentially lead to mitigation of this risk factor.
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http://dx.doi.org/10.1097/PHM.0000000000001820DOI Listing
June 2021

Associations of biogeographic ancestry with hypertension traits.

J Hypertens 2021 04;39(4):633-642

Vanderbilt Genetics Institute, Vanderbilt University.

Objectives: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits.

Methods: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples.

Results: Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion).

Conclusion: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.
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http://dx.doi.org/10.1097/HJH.0000000000002701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362794PMC
April 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

Family history and pelvic organ prolapse: a systematic review and meta-analysis.

Int Urogynecol J 2021 Apr 21;32(4):759-774. Epub 2020 Oct 21.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Introduction And Hypothesis: Numerous analytic observational studies assess family history as a risk factor for POP and report a wide range of associations. This review aims to systematically evaluate the role of family history of POP in relation to POP risk and its recurrence.

Methods: A review was performed of the PubMed/MEDLINE database with search criteria specifying family history, risk factors, POP, and their synonyms as title/abstract keywords, as well as MESH terms, up to March 2020. We aggregated evidence across studies with fixed effects (FE) and random effects (RE) meta-analysis.

Results: Forty-three articles underwent full-text review. Eighteen independent studies evaluating the relationship between family history of POP and POP risk in 3639 POP cases and 10,912 controls were eligible for meta-analysis. Four studies evaluating family history and POP recurrence in 224 recurrent cases and 400 non-recurrent cases were eligible for inclusion into another meta-analyses. A positive family history of POP is on average associated with 2.3- to 2.7-fold increased risk for POP (RE OR = 2.64; 95% CI = 2.07, 3.35) as well as a 1.4-fold increased risk for POP recurrence (FE OR = 1.44; 95% CI = 1.00, 2.08). Meta-analysis estimates of POP risk varied by study design, definition of family history, and model adjustment status. We found evidence that publication bias and recall bias are a possibility.

Conclusions: Family history of POP is a risk factor for both POP presence and recurrence. However, reported magnitudes may be overestimates due to confounding, recall bias, and publication bias.
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http://dx.doi.org/10.1007/s00192-020-04559-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086380PMC
April 2021

The polygenic architecture of left ventricular mass mirrors the clinical epidemiology.

Sci Rep 2020 05 5;10(1):7561. Epub 2020 May 5.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.
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http://dx.doi.org/10.1038/s41598-020-64525-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200691PMC
May 2020

Development and Validation of an Electronic Medical Record Algorithm to Identify Phenotypes of Rotator Cuff Tear.

PM R 2020 11 29;12(11):1099-1105. Epub 2020 Apr 29.

Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: A lack of studies with large sample sizes of patients with rotator cuff tears is a barrier to performing clinical and genomic research.

Objective: To develop and validate an electronic medical record (EMR)-based algorithm to identify individuals with and without rotator cuff tear.

Design: We used a deidentified version of the EMR of more than 2 million subjects. A screening algorithm was applied to classify subjects into likely rotator cuff tear and likely normal rotator cuff groups. From these subjects, 500 likely rotator cuff tear and 500 likely normal rotator cuff were randomly chosen for algorithm development. Chart review of all 1000 subjects confirmed the true phenotype of rotator cuff tear or normal rotator cuff based on magnetic resonance imaging and operative report. An algorithm was then developed based on logistic regression and validation of the algorithm was performed.

Results: The variables significantly predicting rotator cuff tear included the number of times a Current Procedural Terminology code related to rotator cuff procedures was used (odds ratio [OR] = 3.3; 95% confidence interval [CI]: 1.6-6.8 for ≥3 vs 0), the number of times a term related to rotator cuff lesions occurred in radiology reports (OR = 2.2; 95% CI: 1.2-4.1 for ≥1 vs 0), and the number of times a term related to rotator cuff lesions occurred in physician notes (OR = 4.5; 95% CI: 2.2-9.1 for 1 or 2 times vs 0). This phenotyping algorithm had a specificity of 0.89 (95% CI: 0.79-0.95) for rotator cuff tear, area under the curve (AUC) of 0.842, and diagnostic likelihood ratios (DLRs), DLR+ and DLR- of 5.94 (95% CI: 3.07-11.48) and 0.363 (95% CI: 0.291-0.453).

Conclusion: Our informatics algorithm enables identification of cohorts of individuals with and without rotator cuff tear from an EMR-based data set with moderate accuracy.
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http://dx.doi.org/10.1002/pmrj.12367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593991PMC
November 2020

Jellyfish-Inspired Soft Robot Driven by Fluid Electrode Dielectric Organic Robotic Actuators.

Front Robot AI 2019 21;6:126. Epub 2019 Nov 21.

Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA, United States.

Robots for underwater exploration are typically comprised of rigid materials and driven by propellers or jet thrusters, which consume a significant amount of power. Large power consumption necessitates a sizeable battery, which limits the ability to design a small robot. Propellers and jet thrusters generate considerable noise and vibration, which is counterproductive when studying acoustic signals or studying timid species. Bioinspired soft robots provide an approach for underwater exploration in which the robots are comprised of compliant materials that can better adapt to uncertain environments and take advantage of design elements that have been optimized in nature. In previous work, we demonstrated that frameless DEAs could use fluid electrodes to apply a voltage to the film and that effective locomotion in an eel-inspired robot could be achieved without the need for a rigid frame. However, the robot required an off-board power supply and a non-trivial control signal to achieve propulsion. To develop an untethered soft swimming robot powered by DEAs, we drew inspiration from the jellyfish and attached a ring of frameless DEAs to an inextensible layer to generate a unimorph structure that curves toward the passive side to generate power stroke, and efficiently recovers the original configuration as the robot coasts. This swimming strategy simplified the control system and allowed us to develop a soft robot capable of untethered swimming at an average speed of 3.2 mm/s and a cost of transport of 35. This work demonstrates the feasibility of using DEAs with fluid electrodes for low power, silent operation in underwater environments.
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http://dx.doi.org/10.3389/frobt.2019.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806063PMC
November 2019

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.

Am J Hypertens 2019 11;32(12):1146-1153

Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.

Background: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

Methods: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

Results: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

Conclusion: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
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http://dx.doi.org/10.1093/ajh/hpz150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856621PMC
November 2019

Calcium: magnesium intake ratio and colorectal carcinogenesis, results from the prostate, lung, colorectal, and ovarian cancer screening trial.

Br J Cancer 2019 10 23;121(9):796-804. Epub 2019 Sep 23.

Division of Epidemiology, Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: We aimed to evaluate the associations between calcium and various stages of colorectal carcinogenesis and whether these associations are modified by the calcium to magnesium (Ca:Mg) ratio.

Methods: We tested our hypotheses in the prostate lung, colorectal and ovarian cancer screening trial.

Results: Calcium intake did not show a dose-response association with incident adenoma of any size/stage (P- = 0.17), but followed an inverse trend when restricted to synchronous/advanced adenoma cases (P- = 0.05). This inverse trend was mainly in participants with Ca:Mg ratios between 1.7 and 2.5 (P- = 0.05). No significant associations were observed for metachronous adenoma. Calcium intake was inversely associated with CRC (P- = 0.03); the association was primarily present for distal CRC (P- = 0.01). The inverse association between calcium and distal CRC was further modified by the Ca:Mg ratio (P- < 0.01); significant dose-response associations were found only in participants with a Ca:Mg ratio between 1.7 and 2.5 (P- = 0.04). No associations for calcium were found in the Ca:Mg ratio above 2.5 or below 1.7.

Conclusion: Higher calcium intake may be related to reduced risks of incident advanced and/or synchronous adenoma and incident distal CRC among subjects with Ca:Mg intake ratios between 1.7 and 2.5.
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http://dx.doi.org/10.1038/s41416-019-0579-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889387PMC
October 2019

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Nat Commun 2019 09 11;10(1):4130. Epub 2019 Sep 11.

Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.

Nat Commun 2019 08 26;10(1):3842. Epub 2019 Aug 26.

Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.
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http://dx.doi.org/10.1038/s41467-019-11704-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710266PMC
August 2019

Association of Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

Circulation 2019 09 24;140(12):1031-1040. Epub 2019 Jul 24.

Massachusetts General Hospital, Boston (A.G.B., D.K., P.N., S.K.).

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 () risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between risk alleles and cardiovascular disease (CVD) that is independent of the effects of on kidney disease. We sought to test the association of G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program.

Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association.

Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; =0.031). When both cardiovascular and renal outcomes were modeled, was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets.

Conclusions: risk variants display a modest association with CVD, and this association is likely mediated by the known association with chronic kidney disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754626PMC
September 2019

A -Ethnic Genome-Wide Association Study of Uterine Fibroids.

Front Genet 2019 12;10:511. Epub 2019 Jun 12.

Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, United States.

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS ( < 1 × 10) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; = 4.7 × 10), chromosome 16q12.1 (sentinel-SNP rs4785384; = 1.5 × 10) and chromosome 20q13.1 (sentinel-SNP rs6094982; = 2.6 × 10). Our statistically significant findings further support previously reported loci including SNPs near , and /. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the / locus ( = 1.76 × 10). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including in vagina ( = 4.6 × 10), in esophageal mucosa ( = 8.7 × 10), in multiple tissues including subcutaneous adipose tissue ( = 3.3 × 10), and in skeletal muscle tissue ( = 5.8 × 10) were associated with fibroids. The finding for was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.
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http://dx.doi.org/10.3389/fgene.2019.00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582231PMC
June 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Miniature Diamond-Based Fiber Optic Pressure Sensor with Dual Polymer-Ceramic Adhesives.

Sensors (Basel) 2019 May 13;19(9). Epub 2019 May 13.

Howard Nanoscale Science and Engineering Facility, Department of Electrical and Computer Science, NSF STC Center for Integrated Quantum Materials, Howard University, Washington, DC 20059, USA.

Diamond is a good candidate for harsh environment sensing due to its high melting temperature, Young's modulus, and thermal conductivity. A sensor made of diamond will be even more promising when combined with some advantages of optical sensing (i.e., EMI inertness, high temperature operation, and miniaturization). We present a miniature diamond-based fiber optic pressure sensor fabricated using dual polymer-ceramic adhesives. The UV curable polymer and the heat-curing ceramic adhesive are employed for easy and reliable optical fiber mounting. The usage of the two different adhesives considerably improves the manufacturability and linearity of the sensor, while significantly decreasing the error from the temperature cross-sensitivity. Experimental study shows that the sensor exhibits good linearity over a pressure range of 2.0-9.5 psi with a sensitivity of 18.5 nm/psi (R = 0.9979). Around 275 °C of working temperature was achieved by using polymer/ceramic dual adhesives. The sensor can benefit many fronts that require miniature, low-cost, and high-accuracy sensors including biomedical and industrial applications. With an added antioxidation layer on the diamond diaphragm, the sensor can also be applied for harsh environment applications due to the high melting temperature and Young's modulus of the material.
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http://dx.doi.org/10.3390/s19092202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539731PMC
May 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Nat Genet 2019 01 21;51(1):51-62. Epub 2018 Dec 21.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
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http://dx.doi.org/10.1038/s41588-018-0303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365102PMC
January 2019

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Nat Genet 2018 10 17;50(10):1412-1425. Epub 2018 Sep 17.

Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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http://dx.doi.org/10.1038/s41588-018-0205-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284793PMC
October 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018

Population Stratification in Genetic Association Studies.

Curr Protoc Hum Genet 2017 10 18;95:1.22.1-1.22.23. Epub 2017 Oct 18.

Vanderbilt Genetics Institute, Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Population stratification (PS) is a primary consideration in studies of genetic determinants of human traits. Failure to control for PS may lead to confounding, causing a study to fail for lack of significant results, or resources to be wasted following false-positive signals. Here, historical and current approaches for addressing PS when performing genetic association studies in human populations are reviewed. Methods for detecting the presence of PS, including global and local ancestry methods, are described. Also described are approaches for accounting for PS when calculating association statistics, such that measures of association are not confounded. Many traits are being examined for the first time in minority populations, which may inherently feature PS. © 2017 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cphg.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007879PMC
October 2017

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.

Circ Cardiovasc Genet 2017 Oct;10(5)

Background: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

Methods And Results: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (<5×10) for BP, of which 4 are new BP loci: rs9678851 (missense, ), rs7437940 (), rs13303 (missense, ), and rs1055144 (). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at ) was genome-wide significant.

Conclusions: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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http://dx.doi.org/10.1161/CIRCGENETICS.117.001778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776077PMC
October 2017

African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

PLoS Genet 2017 Jul 17;13(7):e1006871. Epub 2017 Jul 17.

Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.
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http://dx.doi.org/10.1371/journal.pgen.1006871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536439PMC
July 2017

Admixture mapping of pelvic organ prolapse in African Americans from the Women's Health Initiative Hormone Therapy trial.

PLoS One 2017 5;12(6):e0178839. Epub 2017 Jun 5.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Evidence suggests European American (EA) women have two- to five-fold increased odds of having pelvic organ prolapse (POP) when compared with African American (AA) women. However, the role of genetic ancestry in relation to POP risk is not clear. Here we evaluate the association between genetic ancestry and POP in AA women from the Women's Health Initiative Hormone Therapy trial. Women with grade 1 or higher classification, and grade 2 or higher classification for uterine prolapse, cystocele or rectocele at baseline or during follow-up were considered to have any POP (N = 805) and moderate/severe POP (N = 156), respectively. Women with at least two pelvic exams with no indication for POP served as controls (N = 344). We performed case-only, and case-control admixture-mapping analyses using multiple logistic regression while adjusting for age, BMI, parity and global ancestry. We evaluated the association between global ancestry and POP using multiple logistic regression. European ancestry at the individual level was not associated with POP risk. Case-only and case-control local ancestry analyses identified two ancestry-specific loci that may be associated with POP. One locus (Chromosome 15q26.2) achieved empirically-estimated statistical significance and was associated with decreased POP odds (considering grade ≥2 POP) with each unit increase in European ancestry (OR: 0.35; 95% CI: 0.30, 0.57; p-value = 1.48x10-5). This region includes RGMA, a potent regulator of the BMP family of genes. The second locus (Chromosome 1q42.1-q42.3) was associated with increased POP odds with each unit increase in European ancestry (Odds ratio [OR]: 1.69; 95% confidence interval [CI]: 1.28, 2.22; p-value = 1.93x10-4). Although this region did not reach statistical significance after considering multiple comparisons, it includes potentially relevant genes including TBCE, and ACTA1. Unique non-overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178839PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459562PMC
September 2017
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