Publications by authors named "Dan E Arking"

189 Publications

Proteins Associated with Risk of Kidney Function Decline in the General Population.

J Am Soc Nephrol 2021 Sep;32(9):2291-2302

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD.

Methods: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR.

Results: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and -trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2).

Conclusions: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline.
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http://dx.doi.org/10.1681/ASN.2020111607DOI Listing
September 2021

Epigenome-wide association study of mitochondrial genome copy number.

Hum Mol Genet 2021 Aug 20. Epub 2021 Aug 20.

Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.
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http://dx.doi.org/10.1093/hmg/ddab240DOI Listing
August 2021

Development and optimization of an in vivo electrocardiogram recording method and analysis program for adult zebrafish.

Dis Model Mech 2021 08 11;14(8). Epub 2021 Aug 11.

McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Clinically pertinent electrocardiogram (ECG) data from model systems, such as zebrafish, are crucial for illuminating factors contributing to human cardiac electrophysiological abnormalities and disease. Current zebrafish ECG collection strategies have not adequately addressed the consistent acquisition of high-quality traces or sources of phenotypic variation that could obscure data interpretation. Thus, we developed a novel platform to ensure high-quality recording of in vivo subdermal adult zebrafish ECGs and zebrafish ECG reading GUI (zERG), a program to acquire measurements from traces that commercial software cannot examine owing to erroneous peak calling. We evaluate normal ECG trait variation, revealing highly reproducible intervals and wave amplitude variation largely driven by recording artifacts, and identify sex and body size as potential confounders to PR, QRS and QT intervals. With this framework, we characterize the effect of the class I anti-arrhythmic drug flecainide acetate on adults, provide support for the impact of a Long QT syndrome model, and establish power calculations for this and other studies. These results highlight our pipeline as a robust approach to evaluate zebrafish models of human cardiac electrophysiological phenotypes.
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http://dx.doi.org/10.1242/dmm.048827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380046PMC
August 2021

Use of oral contraceptives in women with congenital long QT syndrome.

Heart Rhythm 2021 Jul 30. Epub 2021 Jul 30.

Clinical Cardiovascular Research Center, Division of Cardiology, University of Rochester Medical Center, Rochester, New York.

Background: Use of oral contraceptives (OCs) may modulate the clinical course of women with congenital long QT syndrome (LQTS). The safety of OC use by sex hormone content has not been assessed in women with LQTS.

Objective: We aimed to evaluate the association of OCs with the risk of cardiac events (CEs) in women with LQTS.

Methods: Beginning in 2010, information on menarche onset, OC use, pregnancy, and menopause were obtained from women enrolled in the Rochester LQTS Registry. Type of OC was categorized as progestin-only, estrogen-only, or combined (estrogen/progestin). Andersen-Gill multivariate modeling was used to evaluate the association of time-dependent OC use with the burden of CE (total number of syncope, aborted cardiac arrest, and LQTS-related sudden cardiac death) from menarche onset through 40 years. Findings were adjusted for genotype, corrected QT duration, and time-dependent β-blocker therapy.

Results: A total of 1659 women with LQTS followed through March 2021, of whom 370 (22%) were treated with an OC. During a cumulative follow-up of 35,797 years, there were a total of 2027 CE. Multivariate analysis showed that progestin-only OC was associated with a pronounced 2.8-fold (P = .01) increased risk of CEs in women who did not receive β-blocker therapy, while β-blockers were highly protective during progestin-only OC treatment (hazard ratio 0.22; P = .01; P = .006 for β-blocker-by-OC interaction). The risk associated with OC use without concomitant β-blocker treatment was pronounced in women with LQTS type 2.

Conclusion: Our findings suggest that progestin-only OC should not be administered in women with LQTS without concomitant β-blocker therapy. OCs should be used with caution in women with LQTS type 2.
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http://dx.doi.org/10.1016/j.hrthm.2021.07.058DOI Listing
July 2021

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

Circ Genom Precis Med 2021 Aug 28;14(4):e003300. Epub 2021 Jul 28.

Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.).

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.

Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).

Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (, , and ), a controversial monogenic SCD gene (), and novel genes ( and ) involved in cardiac conduction. Loss-of-function and pathogenic variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (=8.4×10). Similar variants in and (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (=4×10), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.

Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.
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http://dx.doi.org/10.1161/CIRCGEN.120.003300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373440PMC
August 2021

Risk Prediction in Women With Congenital Long QT Syndrome.

J Am Heart Assoc 2021 Jul 9;10(14):e021088. Epub 2021 Jul 9.

Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY.

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life-threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and β-blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome-related sudden cardiac death), and was applied with the end point of life-threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow-up duration among the 767 enrolled women was 22 243 patient-years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype-phenotype data, we identified 3 risk groups with 10-year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10-year projected rates of life-threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65-0.71) and 0.71 (95% CI 0.66-0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60-0.70) and 0.77 (95% CI 0.70-0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life-threatening events in women with type 1 or type 2 long QT based on personalized genotype-phenotype data. The projected risk estimates can be used to guide female-specific management in long QT syndrome.
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http://dx.doi.org/10.1161/JAHA.121.021088DOI Listing
July 2021

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

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

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

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

Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension.

Kidney Int 2021 08 8;100(2):430-439. Epub 2021 Apr 8.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.
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http://dx.doi.org/10.1016/j.kint.2021.03.026DOI Listing
August 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

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.

Genome Res 2021 03 13;31(3):349-358. Epub 2021 Jan 13.

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and is associated with aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated relationships between mtDNA-CN measured in whole blood and gene expression from whole blood and 47 additional tissues in 419 individuals. mtDNA-CN was significantly associated with expression of 700 genes in whole blood, including nuclear genes required for mtDNA replication. Significant enrichment was observed for splicing and ubiquitin-mediated proteolysis pathways, as well as target genes for the mitochondrial transcription factor NRF1. In nonblood tissues, there were more significantly associated genes than expected in 30 tissues, suggesting that global gene expression in those tissues is correlated with blood-derived mtDNA-CN. Neurodegenerative disease pathways were significantly associated in multiple tissues, and in an independent data set, the UK Biobank, we observed that higher mtDNA-CN was significantly associated with lower rates of both prevalent (OR = 0.89, CI = 0.83; 0.96) and incident neurodegenerative disease (HR = 0.95, 95% CI = 0.91;0.98). The observation that mtDNA-CN measured in blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Identification of key pathways including splicing, RNA binding, and catalysis reinforces the importance of mitochondria in maintaining cellular homeostasis. Finally, validation of the role of mtDNA CN in neurodegenerative disease in a large independent cohort study solidifies the link between blood-derived mtDNA-CN, altered gene expression in multiple tissues, and aging-related disease.
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http://dx.doi.org/10.1101/gr.269381.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919448PMC
March 2021

Variants, N-Acetylated Amino Acids, and Progression of CKD.

Clin J Am Soc Nephrol 2020 12;16(1):37-47

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

Background And Objectives: Genetic variants in , a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two -associated metabolites, N--acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in , N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts.

Design, Setting, Participants, & Measurements: We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; =962), the Atherosclerosis Risk in Communities (ARIC) study (=1050), and Bio, an electronic health record-linked biorepository (=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (=1624).

Results: Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N--acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study.

Conclusions: We demonstrate significant associations between an gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.
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http://dx.doi.org/10.2215/CJN.08600520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792648PMC
December 2020

Outcome by Sex in Patients With Long QT Syndrome With an Implantable Cardioverter Defibrillator.

J Am Heart Assoc 2020 10 21;9(19):e016398. Epub 2020 Sep 21.

Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY.

Background Sex differences in outcome have been reported in patients with congenital long QT syndrome. We aimed to report on the incidence of time-dependent life-threatening events in male and female patients with long QT syndrome with an implantable cardioverter defibrillator (ICD). Methods and Results A total of 60 patients with long QT syndrome received an ICD for primary or secondary prevention indications. Life-threatening events were evaluated from the date of ICD implant and included ICD shocks for ventricular tachycardia, ventricular fibrillation, or death. ICDs were implanted in 219 women (mean age 38±13 years), 46 girls (12±5 years), 55 men (43±17 years), and 40 boys (11±4 years). Mean follow-up post-ICD implantation was 14±6 years for females and 12±6 years for males. At 15 years of follow-up, the cumulative probability of life-threatening events was 27% in females and 34% in males (log-rank =0.26 for the overall difference). In the multivariable Cox model, sex was not associated with significant differences in risk first appropriate ICD shock (hazard ratio, 0.83 female versus male; 95% CI, 0.52-1.34; =0.47). Results were similar when stratified by age and by genotype: long QT syndrome type 1 (LQT1), long QT syndrome type 2 (LQT2), and long QT syndrome type 3 (LQT3). Incidence of inappropriate ICD shocks was higher in males versus females (4.2 versus 2.7 episodes per 100 patient-years; =0.018), predominantly attributed to atrial fibrillation. The first shock did not terminate ventricular tachycardia/ventricular fibrillation in 48% of females and 62% of males (=0.25). Conclusions In patients with long QT syndrome with an ICD, the risk and rate of life-threatening events did not significantly differ between males and females regardless of ICD indications or genotype. In a substantial proportion of patients with long QT syndrome, first shock did not terminate ventricular tachycardia/ventricular fibrillation.
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http://dx.doi.org/10.1161/JAHA.120.016398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792399PMC
October 2020

Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.

Genome Med 2020 09 28;12(1):84. Epub 2020 Sep 28.

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

Methods: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

Results: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies.

Conclusions: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
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http://dx.doi.org/10.1186/s13073-020-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523322PMC
September 2020

Mitochondrial DNA copy number and incident atrial fibrillation.

BMC Med 2020 09 16;18(1):246. Epub 2020 Sep 16.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building, Room 459, Baltimore, MD, 21205, USA.

Background: Mechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown.

Methods: We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates.

Results: The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups.

Conclusions: Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk.
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http://dx.doi.org/10.1186/s12916-020-01715-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493408PMC
September 2020

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.

Circ Genom Precis Med 2020 10 21;13(5):387-395. Epub 2020 Aug 21.

DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (, , , , , , , ). The top variants at known sarcomere genes () were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, and ) were associated with longer PWD but lower AF risk.

Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
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http://dx.doi.org/10.1161/CIRCGEN.119.002874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578098PMC
October 2020

Mitochondrial DNA copy number and diabetes: the Atherosclerosis Risk in Communities (ARIC) study.

BMJ Open Diabetes Res Care 2020 08;8(1)

Epidemiology, JHSPH Welch Center for Prevention Epidemiology and Clinical Research, Baltimore, Maryland, USA.

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is a measure of mitochondrial dysfunction and is associated with diabetes in experimental models. To explore the temporality of mitochondrial dysfunction and diabetes, we estimated the prevalent and incident association of mtDNA-CN and diabetes.

Research Design And Methods: We assessed the associations of mtDNA-CN measured from buffy coat with prevalent and incident diabetes, stratified by race, in 8954 white and 2444 black participants in the Atherosclerosis Risk in Communities (ARIC) study, an observational cohort study. Follow-up for incident analyses was complete through visit 6, 2016.

Results: Mean age at mtDNA-CN measurement was 57 years and 59% were female. Prevalence of diabetes at time of mtDNA-CN measurement was higher in blacks (563/2444, 23%) than whites (855/8954, 10%). The fully adjusted odds of prevalent diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.05 (95% CI 0.74 to 1.49) among black and 1.49 (95% CI 1.20 to 1.85) among white participants. Over a median follow-up time of 19 years (Q1, Q3: 11, 24 years), we observed 617 incident diabetes cases among 1744 black and 2121 cases among 7713 white participants free of diabetes at baseline. The fully adjusted hazard of incident diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.07 (95% CI 0.84 to 1.38) among black and 0.97 (95% CI 0.86 to 1.10) among white participants.

Conclusions: Lower mtDNA-CN in buffy coat was associated with prevalent diabetes in white but not black ARIC participants. Lower mtDNA-CN was not associated with incident diabetes over 20 years of follow-up in whites or blacks.
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http://dx.doi.org/10.1136/bmjdrc-2020-001204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430458PMC
August 2020

Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.

Circ Genom Precis Med 2020 08 30;13(4):e002680. Epub 2020 Jun 30.

Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.

Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.

Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test.

Results: We identified 6 novels (, and ) and 87 known loci (adaptive sum of powered score test <5×10). Lead single-nucleotide polymorphism rs3211938 at was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci.

Conclusions: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
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http://dx.doi.org/10.1161/CIRCGEN.119.002680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520945PMC
August 2020

Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease.

Mitochondrion 2020 07 13;53:214-223. Epub 2020 Jun 13.

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address:

Mitochondrial DNA copy number (mtDNA-CN) is a biomarker of mitochondrial function and levels of mtDNA-CN have been reproducibly associated with overall mortality and a number of age-related diseases, including cardiovascular disease, chronic kidney disease, and cancer. Recent advancements in techniques for estimating mtDNA-CN, in particular the use of DNA microarrays and next-generation sequencing data, have led to the comprehensive assessment of mtDNA-CN across these and other diseases and traits. The importance of mtDNA-CN measures to disease and these advancing technologies suggest the potential for mtDNA-CN to be a useful biomarker in the clinic. While the exact mechanism(s) underlying the association of mtDNA-CN with disease remain to be elucidated, we review the existing literature which supports roles for inflammatory dynamics, immune function and alterations to cell signaling as consequences of variation in mtDNA-CN. We propose that future studies should focus on characterizing longitudinal, cell-type and cross-tissue profiles of mtDNA-CN as well as improving methods for measuring mtDNA-CN which will expand the potential for its use as a clinical biomarker.
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http://dx.doi.org/10.1016/j.mito.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375936PMC
July 2020

Mitochondrial DNA Copy Number and Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study.

Circulation 2020 06 1;141(22):1823-1825. Epub 2020 Jun 1.

Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Bloomberg School of Public Health (Y.S.H., D.Z., K.M., E.G.), Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295435PMC
June 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 Jun 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Consistent RNA sequencing contamination in GTEx and other data sets.

Nat Commun 2020 04 22;11(1):1933. Epub 2020 Apr 22.

Department of Pathology, Johns Hopkins University SOM, Baltimore, MD, 21205, USA.

A challenge of next generation sequencing is read contamination. We use Genotype-Tissue Expression (GTEx) datasets and technical metadata along with RNA-seq datasets from other studies to understand factors that contribute to contamination. Here we report, of 48 analyzed tissues in GTEx, 26 have variant co-expression clusters of four highly expressed and pancreas-enriched genes (PRSS1, PNLIP, CLPS, and/or CELA3A). Fourteen additional highly expressed genes from other tissues also indicate contamination. Sample contamination is strongly associated with a sample being sequenced on the same day as a tissue that natively expresses those genes. Discrepant SNPs across four contaminating genes validate the contamination. Low-level contamination affects ~40% of samples and leads to numerous eQTL assignments in inappropriate tissues among these 18 genes. This type of contamination occurs widely, impacting bulk and single cell (scRNA-seq) data set analysis. In conclusion, highly expressed, tissue-enriched genes basally contaminate GTEx and other datasets impacting analyses.
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http://dx.doi.org/10.1038/s41467-020-15821-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176728PMC
April 2020

High-Risk, High-Reward Genetics in ASD.

Neuron 2020 02;105(3):407-410

McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA. Electronic address:

In a recent issue of Cell, Satterstrom et al. leverage de novo high-impact variants to identify 102 genes associated with autism spectrum disorder (ASD). Most of these genes have roles in regulation of gene expression or neuronal communication, implicating both developmental and functional changes in ASD.
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http://dx.doi.org/10.1016/j.neuron.2020.01.007DOI Listing
February 2020

Evaluation of mitochondrial DNA copy number estimation techniques.

PLoS One 2020 31;15(1):e0228166. Epub 2020 Jan 31.

Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

Mitochondrial DNA copy number (mtDNA-CN), a measure of the number of mitochondrial genomes per cell, is a minimally invasive proxy measure for mitochondrial function and has been associated with several aging-related diseases. Although quantitative real-time PCR (qPCR) is the current gold standard method for measuring mtDNA-CN, mtDNA-CN can also be measured from genotyping microarray probe intensities and DNA sequencing read counts. To conduct a comprehensive examination on the performance of these methods, we use known mtDNA-CN correlates (age, sex, white blood cell count, Duffy locus genotype, incident cardiovascular disease) to evaluate mtDNA-CN calculated from qPCR, two microarray platforms, as well as whole genome (WGS) and whole exome sequence (WES) data across 1,085 participants from the Atherosclerosis Risk in Communities (ARIC) study and 3,489 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We observe mtDNA-CN derived from WGS data is significantly more associated with known correlates compared to all other methods (p < 0.001). Additionally, mtDNA-CN measured from WGS is on average more significantly associated with traits by 5.6 orders of magnitude and has effect size estimates 5.8 times more extreme than the current gold standard of qPCR. We further investigated the role of DNA extraction method on mtDNA-CN estimate reproducibility and found mtDNA-CN estimated from cell lysate is significantly less variable than traditional phenol-chloroform-isoamyl alcohol (p = 5.44x10-4) and silica-based column selection (p = 2.82x10-7). In conclusion, we recommend the field moves towards more accurate methods for mtDNA-CN, as well as re-analyze trait associations as more WGS data becomes available from larger initiatives such as TOPMed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994099PMC
April 2020

Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death.

J Am Heart Assoc 2019 12 21;8(23):e013751. Epub 2019 Nov 21.

Department of Genetic Medicine McKusick-Nathans Institute Johns Hopkins Baltimore MD.

Background Sudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex- and coronary artery disease-stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval-associated single-nucleotide polymorphism, rs12143842 (in the locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non-ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.
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http://dx.doi.org/10.1161/JAHA.119.013751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912973PMC
December 2019

Human cardiac myosin light chain 4 (MYL4) mosaic expression patterns vary by sex.

Sci Rep 2019 09 3;9(1):12681. Epub 2019 Sep 3.

Division of Cardiovascular Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Sex disparities modulate cardiac function, although the proteins and mechanisms remain to be elucidated. We recently demonstrated a mosaic pattern of protein expression in the heart for over 100 proteins. Here we investigate one of these proteins, myosin light chain 4 (MYL4), which is important for contractile functions by increasing force production. We assayed the expression pattern of MYL4 across 756 ventricular myocardial samples from 668 individuals utilizing a semi-automated Cell Profiler method on five tissue microarrays (TMAs) of cardiac tissues across a diverse set of diseases. The percentage of MYL4 positive cells was significantly higher in male subjects independently across all five TMAs, regardless of disease state (p = 8.66e-15). Higher MYL4 expression was also modestly associated with hypertrophic cardiomyopathy (p = 6.3e-04). MYL4 expression did not associate with sudden cardiac death or other cardiomyopathies. This study demonstrates a new mosaic pattern of protein expression that underlies sex disparities in the human heart.
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http://dx.doi.org/10.1038/s41598-019-49191-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722118PMC
September 2019

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Nat Commun 2019 08 14;10(1):3669. Epub 2019 Aug 14.

Department of Public Health, University of Southern Denmark, 5000, Odense C, Denmark.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
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http://dx.doi.org/10.1038/s41467-019-11558-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694136PMC
August 2019

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Am J Hum Genet 2019 08;105(2):334-350

Centre for Epidemiology, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M139PL, United Kingdom; School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699140PMC
August 2019
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