Publications by authors named "Jennifer A Smith"

240 Publications

The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study.

Epigenetics 2021 Jul 6:1-23. Epub 2021 Jul 6.

Department of Epidemiology, School of Public Health, University of Michigan, USA.

Epigenetic clocks have been widely used to predict disease risk in multiple tissues or cells. Their success as a measure of biological ageing has prompted research on the connection between epigenetic pathways of ageing and the socioeconomic gradient in health and mortality. However, studies examining social correlates of epigenetic ageing have yielded inconsistent results. We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighbourhood environment, and childhood SES) and eight epigenetic clocks in two well-powered US ageing studies: The Multi-Ethnic Study of Atherosclerosis (MESA) (n = 1,211) and the Health and Retirement Study (HRS) (n = 4,018). In both studies, we found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm clocks (Bonferroni-corrected -value < 0.01). In the HRS, significant associations with the Levine and Yang clocks were also evident. These associations were only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviours alone cannot explain the SES gradient in epigenetic ageing in older adults. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic ageing, SES, and the Levine clock, indicating that genetic risk and social disadvantage may contribute additively to faster biological aging.
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http://dx.doi.org/10.1080/15592294.2021.1939479DOI Listing
July 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 Jun 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.

Nat Commun 2021 06 28;12(1):3987. Epub 2021 Jun 28.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance.

J Exp Med 2021 Aug 11;218(8). Epub 2021 Jun 11.

Diabetes Center, University of California, San Francisco, San Francisco, CA.

Naturally occurring cases of monogenic type 1 diabetes (T1D) help establish direct mechanisms driving this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator STAT3 was found to cause neonatal T1D. We engineered a novel knock-in mouse incorporating this highly diabetogenic human STAT3 mutation (K392R) and found that these mice recapitulated the human autoimmune diabetes phenotype. Paired single-cell TCR and RNA sequencing revealed that STAT3-GOF drives proliferation and clonal expansion of effector CD8+ cells that resist terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and have differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed a CD8+ cell reacting against known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ cells is sufficient to accelerate diabetes onset. Altogether, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis.
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http://dx.doi.org/10.1084/jem.20210759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203485PMC
August 2021

Accelerated DNA methylation age and medication use among African Americans.

Aging (Albany NY) 2021 06 3;13(11):14604-14629. Epub 2021 Jun 3.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.

DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.
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http://dx.doi.org/10.18632/aging.203115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221348PMC
June 2021

Live cell, image-based high-throughput screen to quantitate p53 stabilization and viability in human papillomavirus positive cancer cells.

Virology 2021 Aug 22;560:96-109. Epub 2021 May 22.

Department of Immunology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA. Electronic address:

Approximately 5% of cancers are caused by high-risk human papillomaviruses. Although very effective preventive vaccines will reduce this cancer burden significantly over the next several decades, they have no therapeutic effect for those already infected and remaining at risk for malignant progression of hrHPV lesions. HPV-associated cancers are dependent upon the expression of the viral E6 and E7 oncogenes. The oncogenic function of hrHPV E6 relies partially on its ability to induce p53 degradation. Since p53 is generally wildtype in hrHPV-associated cancers, p53 stabilization arrests proliferation, induces apoptosis and/or results in senescence. Here we describe a live cell, image-based high-throughput screen to identify compounds that stabilize p53 and/or affect viability in HPV-positive cancer HeLa cells. We validate the robustness and potential of this screening assay by assessing the activities of approximately 6,500 known bioactive compounds, illustrating its capability to function as a platform to identify novel therapeutics for hrHPV.
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http://dx.doi.org/10.1016/j.virol.2021.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206038PMC
August 2021

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree.

Elife 2021 May 19;10. Epub 2021 May 19.

Diabetes Center, University of California, San Francisco, San Francisco, United States.

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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http://dx.doi.org/10.7554/eLife.67776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184217PMC
May 2021

Genetic variants predictive of reproductive aging are associated with vasomotor symptoms in a multiracial/ethnic cohort.

Menopause 2021 Apr 26. Epub 2021 Apr 26.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI.

Objective: Vasomotor symptoms (VMS), hot flashes, and night sweats are cardinal symptoms of the menopausal transition. Little is known about genetic influences on VMS. This study evaluated whether previously identified genetic factors predictive of VMS, age at menarche, and age at menopause were associated with VMS in a multiracial/ethnic cohort.

Methods: For 702 White, 306 Black, 126 Chinese, and 129 Japanese women from the Study of Women's Health Across the Nation (SWAN) Genomic Substudy, we created polygenic risk scores (PRSs) from genome-wide association studies of VMS and ages at menarche and menopause. PRSs and single nucleotide polymorphisms (SNPs) from a previously identified VMS locus (tachykinin receptor 3 [TACR3]) were evaluated for associations with frequent VMS (VMS ≥6 days in the past 2 weeks at any visit) and with VMS trajectories (persistently low, early onset, final menstrual period onset, persistently high).

Results: The C-allele of rs74827081 in TACR3 was associated with reduced likelihood of frequent VMS in White women (odds ratio [OR] = 0.49 [95% CI, 0.29-0.83]). With higher menarche PRS (later menarche), Black women were less likely (OR = 0.55 [95% CI, 0.38-0.78]) to report frequent VMS. With higher PRS for age at menarche, Black women were also less likely to have a persistently high VMS trajectory (OR = 0.55 [95% CI, 0.34-0.91]), whereas White women (OR = 0.75 [95% CI, 0.58-0.98]) were less likely to have a final menstrual period onset trajectory (vs persistently low). Chinese women with higher menopause PRS were more likely to have frequent VMS (OR = 2.29 [95% CI, 1.39-3.78]). Associations were substantively similar after excluding rs74827081 C-allele carriers.

Conclusions: Genetic factors predictive of reproductive aging are also associated with VMS, suggesting that VMS have a polygenic architecture. Further study in this area may help to identify new targets for novel VMS therapies.

Video Summary:http://links.lww.com/MENO/A761.
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http://dx.doi.org/10.1097/GME.0000000000001785DOI Listing
April 2021

Associations between polygenic risk score for age at menarche and menopause, reproductive timing, and serum hormone levels in multiple race/ethnic groups.

Menopause 2021 04 19;28(7):819-828. Epub 2021 Apr 19.

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

Objective: We assessed associations of genetic loci that contribute to age at menarche and menopause with sentinel menopausal traits in multiple race/ethnic groups.

Methods: Genetic data from the Study of Women's Health Across the Nation include 738 White, 366 Black, 139 Chinese, and 145 Japanese women aged 42 to 52 at baseline. We constructed standardized polygenic risk scores (PRSs) using single nucleotide polymorphisms identified from large-scale genome-wide association studies meta-analyses of ages at menopause and menarche, evaluating associations with each trait within each race/ethnic group.

Results: Menopause PRS was significantly associated with age at menopause in White women after Bonferroni correction (P < 0.004) and nominally associated in Chinese and Japanese women (P < 0.05) (7.4-8.5 mo delay for one standard deviation [SD] increase in PRS). Menarche PRS was significantly associated with age at menarche in White (P < 0.004) and nominally associated in Black and Japanese women (P < 0.05) (2.6-4.8 mo delay for one SD increase). In White women, menarche and menopause PRSs were significantly associated (P < 0.004) with shorter and longer (5.9 and 9.6 mo for one SD increase) reproductive lifespans, respectively, and menopause PRS with a longer menopausal transition (7.1 mo for one SD increase). We observed a significant positive association (P < 0.004) between menopause PRS and E2 level 2 years before menopause and a nominal association (P < 0.05) 2 years after menopause in Japanese women.

Conclusions: In addition to menopausal timing, PRSs associated with onset and ending of reproductive life were associated with reproductive lifespan, length of the menopausal transition, and E2 levels in different race/ethnic groups.
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http://dx.doi.org/10.1097/GME.0000000000001775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225555PMC
April 2021

Racial disparities in treatment and outcomes of children with type 1 diabetes.

Pediatr Diabetes 2021 03 25;22(2):241-248. Epub 2020 Oct 25.

Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA.

Objective: The aim of this study was to assess racial disparities in treatments and outcomes between Non-Hispanic black (NHB), Hispanic and Non-Hispanic white (NHW) children with type 1 diabetes (T1D).

Methods: We reviewed electronic health records of children (<18 years) attending a large, pediatric tertiary care diabetes center in the United States between October 1, 2018, and December 31, 2019. Health care utilization (appointment attendance, ED visits, hospitalizations), technology use (insulin pumps, continuous glucose monitors [CGM]) and hemoglobin A1c (HbA1c) were examined for each race/ethnicity and stratified by insurance type (private/government) as a proxy for socioeconomic status (SES).

Results: Of 1331 children (47% female) with a median (IQR) age of 14.2 (11.5, 16.3) years and T1D duration of 5.8 (3.8, 9) years; 1026 (77%) were NHW, 198 (15%) NHB, and 107 (8%) Hispanic. Government insurance was used by 358 (27%) children, representing 60% of NHB and 53% of Hispanic, but only 18% of NHW children. NHB children had higher HbA1c, more ED visits and hospitalizations, and were less likely to be treated with insulin pumps or CGM than NHW children (P < .001 for all). There were no racial disparities with regard to the number of appointments attended.

Conclusions: Racial disparities in technology use and diabetes outcomes persist in children with T1D, regardless of insurance status. To ensure equitable care, pediatric healthcare providers should remain cognizant of racial disparities in diabetes treatment. The impact of provider and patient factors should be explored when studying the etiology of these health disparities.
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http://dx.doi.org/10.1111/pedi.13139DOI Listing
March 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

Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans.

Clin Epigenetics 2021 Mar 16;13(1):55. Epub 2021 Mar 16.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Background: Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention.

Results: Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22-2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040-0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006-0.064).

Conclusions: Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.
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http://dx.doi.org/10.1186/s13148-021-01035-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962278PMC
March 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Cumulative Genetic Risk and Are Independently Associated With Dementia Status in a Multiethnic, Population-Based Cohort.

Neurol Genet 2021 Apr 5;7(2):e576. Epub 2021 Mar 5.

Department of Epidemiology (K.M.B., S.L.R.K., J.A.S.), School of Public Health, University of Michigan; Survey Research Center (H.S.V., J.D.F., S.G.H., K.M.L., C.M.M., E.B.W.), Institute for Social Research, University of Michigan; VA Center for Clinical Management Research (K.M.L.), Ann Arbor, MI; Department of Neurology (J.J.M.), Columbia University, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain (J.J.M.), New York; and Department of Mental Health (K.S.B.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.

Objective: Alzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.

Methods: In the US population-based Health and Retirement Study (waves 1995-2014), we evaluated the role of cumulative genetic risk of AD, with and without the alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.

Results: In the European ancestry sample (n = 8,399), both AD polygenic score excluding the genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00-1.20) and the presence of any alleles (OR = 2.42; 95% CI: 1.99-2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any alleles was associated with 1.77 (95% CI: 1.20-2.61) times higher odds of dementia, whereas the AD polygenic score excluding the genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97-1.30).

Conclusions: Cumulative genetic risk of AD and are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.
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http://dx.doi.org/10.1212/NXG.0000000000000576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938646PMC
April 2021

Depression and interleukin-6 signaling: A Mendelian Randomization study.

Brain Behav Immun 2021 07 23;95:106-114. Epub 2021 Feb 23.

Department of Epidemiology, School of Public Health, University of Michigan, United States; Institute for Social Research, University of Michigan, United States.

Background: A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship.

Methods: This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms.

Results: Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism.

Discussion: These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation.
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http://dx.doi.org/10.1016/j.bbi.2021.02.019DOI Listing
July 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

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

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.

Blood Adv 2020 11;4(22):5825-5835

Ichan School of Medicine at Mount Sinai, New York, NY.

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.
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http://dx.doi.org/10.1182/bloodadvances.2020003314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686901PMC
November 2020

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

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Anti-Müllerian hormone (AMH) is expressed by antral stage ovarian follicles in women. Consequently, circulating AMH levels are detectable until menopause. Variation in age-specific AMH levels has been associated with breast cancer and polycystic ovary syndrome (PCOS), amongst other diseases. Identification of genetic variants underlying variation in AMH levels could provide clues about the physiological mechanisms that explain these AMH-disease associations. To date, only one variant in has been identified to be associated with circulating AMH levels in women. We aimed to identify additional variants for AMH through a GWAS meta-analysis including data from 7049 premenopausal women of European ancestry, which more than doubles the sample size of the largest previous GWAS. We identified four loci associated with AMH levels at p < 5×10 : the previously reported locus and three novel signals in or near , and . The strongest signal was a missense variant in the gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among SNPs for AMH levels and for age at menopause (r = 0.82, FDR=0.003). Exploratory Mendelian randomization analyses did not support a causal effect of AMH on breast cancer or PCOS risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. In conclusion, we identified a variant in the gene and three other loci that may affect circulating AMH levels in women.
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http://dx.doi.org/10.1101/2020.10.29.20221390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654897PMC
November 2020

Understanding the impact of interruptions to HIV services during the COVID-19 pandemic: A modelling study.

EClinicalMedicine 2020 Sep 31;26:100483. Epub 2020 Jul 31.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.

Background: There is concern that the COVID-19 pandemic could severely disrupt HIV services in sub-Saharan Africa. However, it is difficult to determine priorities for maintaining different elements of existing HIV services given widespread uncertainty.

Methods: We explore the impact of disruptions on HIV outcomes in South Africa, Malawi, Zimbabwe, and Uganda using a mathematical model, examine how impact is affected by model assumptions, and compare potential HIV deaths to those that may be caused by COVID-19 in the same settings.

Findings: The most important determinant of HIV-related mortality is an interruption to antiretroviral treatment (ART) supply. A three-month interruption for 40% of those on ART could cause a similar number of additional deaths as those that might be saved from COVID-19 through social distancing. An interruption for more than 6-90% of individuals on ART for nine months could cause the number of HIV deaths to exceed the number of COVID-19 deaths, depending on the COVID-19 projection. However, if ART supply is maintained, but new treatment, voluntary medical male circumcision, and pre-exposure prophylaxis initiations cease for 3 months and condom use is reduced, increases in HIV deaths would be limited to <2% over five years, although this could still be accompanied by a 7% increase in new HIV infections.

Interpretation: HIV deaths could increase substantially during the COVID-19 pandemic under reasonable worst-case assumptions about interruptions to HIV services. It is a priority in high-burden countries to ensure continuity of ART during the pandemic.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2020.100483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564522PMC
September 2020

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Responding to the ECHO trial results: modelling the potential impact of changing contraceptive method mix on HIV and reproductive health in South Africa.

J Int AIDS Soc 2020 10;23(10):e25620

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.

Introduction: Some observational data suggest that the progestogen injectable contraceptive depot medroxyprogesterone acetate (DMPA) may increase a woman's risk of HIV acquisition but a randomized clinical trial did not find a statistically significant increase in HIV risk for women using DMPA compared to two other methods. However, it could not rule out up to 30% increased HIV risk for DMPA users. We evaluate changes to contraceptive method mix in South Africa under different assumptions about the existence and strength of a possible undetected relationship between DMPA use and HIV risk.

Methods: A mathematical model was developed to simulate the ongoing HIV epidemic and contraceptive method mix in South Africa to estimate how changes in method mix could impact HIV- and reproductive health-related outcomes. We made different assumptions about the relationship between DMPA use and HIV risk, from no relationship to a 30% increase in HIV risk for women using DMPA. Scenario analyses were used to investigate the impact of switching away from DMPA predominance to new patterns of contraceptive use.

Results: In South Africa, the HIV-related benefits of reduced DMPA use could be as great as the harms of increased adverse reproductive health outcomes over 20 years, if DMPA did increase the risk of HIV acquisition by a relative hazard of infection of 1.1 or greater. A reduction in DMPA use among HIV-positive women would have no benefit in terms of HIV infections, but would incur additional negative reproductive health outcomes. The most important driver of adverse reproductive health outcomes is the proportion of women who switch away from DMPA to no contraceptive method.

Conclusions: If there is any real increased HIV risk for DMPA users that has not been detected by the recent randomized trial, a reduction in DMPA use could reduce the ongoing number of new HIV infections. However, such a change would place more women at risk of adverse reproductive health effects. It is imperative that these effects are minimized by focusing on expanding access to safe, effective and acceptable alternative contraceptive methods for all women.
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http://dx.doi.org/10.1002/jia2.25620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543057PMC
October 2020

Underlying features of epigenetic aging clocks in vivo and in vitro.

Aging Cell 2020 10 15;19(10):e13229. Epub 2020 Sep 15.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.

Epigenetic clocks, developed using DNA methylation data, have been widely used to quantify biological aging in multiple tissues/cells. However, many existing epigenetic clocks are weakly correlated with each other, suggesting they may capture different biological processes. We utilize multi-omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. Despite the striking lack of overlap in CpGs, multi-omics analysis suggested five clocks (Horvath1, Horvath2, Levine, Hannum, and Lin) share transcriptional associations conserved across purified CD14+ monocytes and dorsolateral prefrontal cortex. The pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. Results from in vitro experiments showed that two clocks (Levine and Lin) were accelerated in accordance with two hallmarks of aging-cellular senescence and mitochondrial dysfunction. Finally, using multi-tissue data to deconstruct the epigenetic clock signals, we developed a meta-clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.
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http://dx.doi.org/10.1111/acel.13229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576259PMC
October 2020
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