Publications by authors named "Seyedeh M Zekavat"

29 Publications

  • Page 1 of 1

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Nat Med 2021 06 7;27(6):1012-1024. Epub 2021 Jun 7.

Institute for Molecular Medicine Finland, Helsinki, Finland.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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http://dx.doi.org/10.1038/s41591-021-01371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245201PMC
June 2021

Cardiovascular and Kidney Outcomes Across the Glycemic Spectrum: Insights From the UK Biobank.

J Am Coll Cardiol 2021 Aug 17;78(5):453-464. Epub 2021 May 17.

Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts, USA. Electronic address: https://twitter.com/mvaduganathan.

Background: Treatment guidelines for prediabetes primarily focus on glycemic control and lifestyle management. Few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population.

Objectives: This study sought to characterize cardiovascular and kidney outcomes across the glycemic spectrum.

Methods: Among participants in the UK Biobank without prevalent type 1 diabetes, cardiovascular disease, or kidney disease, Cox models tested the association of glycemic exposures (type 2 diabetes [T2D], prediabetes, normoglycemia) with outcomes (atherosclerotic cardiovascular disease [ASCVD], chronic kidney disease [CKD], and heart failure), adjusting for demographic, lifestyle, and cardiometabolic risk factors.

Results: Among 336,709 individuals (mean age: 56.3 years, 55.4% female), 46,911 (13.9%) had prediabetes and 12,717 (3.8%) had T2D. Over median follow-up of 11.1 years, 6,476 (13.8%) individuals with prediabetes developed ≥1 incident outcome, of whom only 802 (12.4%) developed T2D prior to an incident diagnosis. Prediabetes and T2D were independently associated with ASCVD (prediabetes: adjusted HR [aHR]: 1.11; 95% CI: 1.08-1.15; P < 0.001; T2D: aHR: 1.44; 95% CI: 1.37-1.51; P < 0.001), CKD (prediabetes: aHR: 1.08; 95% CI: 1.02-1.14; P < 0.001; T2D: aHR: 1.57; 95% CI: 1.46-1.69; P < 0.001), and heart failure (prediabetes: aHR: 1.07; 95% CI: 1.01-1.14; P = 0.03; T2D: aHR: 1.25; 95% CI: 1.14-1.37; P < 0.001). Compared with hemoglobin A1c (HbA1c) <5.0%, covariate-adjusted risks increased significantly for ASCVD above HbA1c of 5.4%, CKD above HbA1c of 6.2%, and heart failure above HbA1c of 7.0%.

Conclusions: Prediabetes and T2D were associated with ASCVD, CKD, and heart failure, but a substantial gradient of risk was observed across HbA levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.
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http://dx.doi.org/10.1016/j.jacc.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324525PMC
August 2021

Elevated Blood Pressure Increases Pneumonia Risk: Epidemiological Association and Mendelian Randomization in the UK Biobank.

Med (N Y) 2021 Feb 30;2(2):137-148.e4. Epub 2020 Nov 30.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Background: Small studies have correlated hypertension with pneumonia risk; whether this is recapitulated in larger prospective studies, and represents a causal association, is unclear.

Methods: We estimated the risk for prevalent hypertension with incident respiratory diseases over mean follow-up of 8 years among 377,143 British participants in the UK Biobank. Mendelian randomization of blood pressure on pneumonia was implemented using 75 independent, genome-wide significant variants associated with systolic and diastolic blood pressures among 299,024 individuals not in the UK Biobank. Secondary analyses with pulmonary function tests were performed.

Findings: In total, 107,310 participants (30%) had hypertension at UK Biobank enrollment, and 9,969 (3%) developed pneumonia during follow-up. Prevalent hypertension was independently associated with increased risk for incident pneumonia (HR: 1.36; 95% CI: 1.29-1.43; p < 0.001), as well as other incident respiratory diseases. Genetic predisposition to a 5 mm Hg increase in blood pressure was associated with increased risk for incident pneumonia for systolic blood pressure (HR: 1.08; 95% CI: 1.04-1.13; p < 0.001) and diastolic blood pressure (HR: 1.11; 95% CI: 1.03-1.20; p = 0.005). Additionally, consistent with epidemiologic associations, increased blood pressure genetic risk was significantly associated with reduced performance on pulmonary function tests (p < 0.001).

Conclusions: These results suggest that elevated blood pressure increases risk for pneumonia. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia.

Funding: S.M.Z. (1F30HL149180-01), M.H. (T32HL094301-07), and P.N. (R01HL1427, R01HL148565, and R01HL148050) are supported by the National Institutes of Health. J.P. is supported by the John S. LaDue Memorial Fellowship.
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http://dx.doi.org/10.1016/j.medj.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703520PMC
February 2021

Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer.

medRxiv 2020 Nov 16. Epub 2020 Nov 16.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood . Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality . Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.
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http://dx.doi.org/10.1101/2020.11.12.20230821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685330PMC
November 2020

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Circulation 2021 Feb 9;143(5):410-423. Epub 2020 Nov 9.

Cardiology Division (M.C.H., J.P.P., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.

Methods: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.

Results: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; =0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; =0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; =0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; <0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; =0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; =0.005).

Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911856PMC
February 2021

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

Transcriptomic signatures across human tissues identify functional rare genetic variation.

Science 2020 09 10;369(6509). Epub 2020 Sep 10.

University of Mississippi Medical Center, Jackson, MS, USA.

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.
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http://dx.doi.org/10.1126/science.aaz5900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646251PMC
September 2020

Rare Genetic Variants Associated With Sudden Cardiac Death in Adults.

J Am Coll Cardiol 2019 11 11;74(21):2623-2634. Epub 2019 Nov 11.

Verve Therapeutics, Cambridge, Massachusetts.

Background: Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection.

Objectives: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population.

Methods: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death.

Results: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02).

Conclusions: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.
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http://dx.doi.org/10.1016/j.jacc.2019.08.1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067308PMC
November 2019

Genetic Link Between Arterial Stiffness and Atrial Fibrillation.

Circ Genom Precis Med 2019 06 18;12(6):e002453. Epub 2019 Jun 18.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (S.M.Z., C.R., G.H., S.A.L., P.T.E., P.N.).

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http://dx.doi.org/10.1161/CIRCGEN.118.002453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582989PMC
June 2019

Genetic Association of Finger Photoplethysmography-Derived Arterial Stiffness Index With Blood Pressure and Coronary Artery Disease.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1253-1261

From the Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (S.M.Z., K.A., C.E., A.V.K., D.K., P.N.).

Objective- Arterial stiffness index (ASI) is independently associated with blood pressure (BP) and coronary artery disease (CAD) epidemiologically. However, it is unknown whether these associations represent causal relationships. Here, we assess whether genetic predisposition to increased ASI is associated with elevated BP and CAD risk. Approach and Results- We first performed a large-scale epidemiological association of finger photoplethysmography-derived ASI in the UK Biobank, finding significant associations with systolic BP (β=0.55 mm Hg; [95% CI, 0.45-0.65]; P=5.77×10; N=137 858), diastolic BP (β=1.05 mm Hg; [95% CI, 0.99-1.11]; P=7.27×10; N=137 862), and incident CAD (hazard ratio, 1.08; [95% CI, 1.04-1.11]; P=1.5×10; N=3692 cases, 126 615 controls) in multivariable models. We then performed an ASI genome-wide association study analysis in 131 686 participants from the UK Biobank. Across participants not in the ASI genome-wide association study, a 6-variant ASI polygenic risk score was calculated. Each SD increase in genetic ASI was associated with systolic BP (β=4.63 mm Hg; [95% CI, 2.1-7.2]; P=3.37×10; N=208 897), and diastolic BP (β=2.61 mm Hg; [95% CI, 1.2-4.0]; P=2.85×10; N=208 897); however, no association was observed with incident CAD (hazard ratio, 1.12; [95% CI, 0.55-2.3]; P=0.75; N=223 061; 7534 cases). The lack of CAD association observed was replicated among 184 305 participants (60 810 cases) from the CARDIOGRAMplusC4D (Coronary Artery Disease Genetics Consortium; odds ratio, 0.56; [95% CI, 0.26-1.24]; P=0.15). Conclusions- Our data support the conclusion that finger photoplethysmography-derived ASI is an independent, genetically causal risk factor for BP, but do not support the notion that ASI is a suitable surrogate for CAD risk.
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http://dx.doi.org/10.1161/ATVBAHA.119.312626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531323PMC
June 2019

A statistical framework for cross-tissue transcriptome-wide association analysis.

Nat Genet 2019 03 25;51(3):568-576. Epub 2019 Feb 25.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.
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http://dx.doi.org/10.1038/s41588-019-0345-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788740PMC
March 2019

Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.

Circulation 2019 03;139(13):1593-1602

Center for Genomic Medicine (A.V.K., R.L.C., M.E.T., S.K.), Massachusetts General Hospital, Boston.

Background: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.

Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.

Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).

Conclusions: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433484PMC
March 2019

DNA Sequence Variation in Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes.

Diabetes 2019 01 2;68(1):226-234. Epub 2018 Nov 2.

Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, = 3.4 × 10), Ile195Thr (-0.15 SD, = 1.0 × 10), Ile482Val (-0.019 SD, = 1.6 × 10), and rs72927479 (-0.035 SD, = 2.6 × 10). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; = 5.6 × 10). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; = 0.006). These findings indicate that variants predicted to lead to loss of gene function influence body fat distribution and protect from type 2 diabetes.
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http://dx.doi.org/10.2337/db18-0857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302541PMC
January 2019

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun 2018 08 23;9(1):3493. Epub 2018 Aug 23.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41467-018-05975-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107495PMC
August 2018

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun 2018 07 4;9(1):2606. Epub 2018 Jul 4.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
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http://dx.doi.org/10.1038/s41467-018-04668-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031652PMC
July 2018

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

Am J Hum Genet 2018 06 31;102(6):1204-1211. Epub 2018 May 31.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden.

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
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http://dx.doi.org/10.1016/j.ajhg.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992130PMC
June 2018

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Nat Commun 2018 04 24;9(1):1613. Epub 2018 Apr 24.

Department of Biomedical & Saint Luke's Mid America Heart Institute and the Health Informatics, Division of Endocrinology and Metabolism, University of Missouri-Kansas City, Kansas City, MO, 64110, USA.

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.
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http://dx.doi.org/10.1038/s41467-018-03911-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915445PMC
April 2018

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

Circulation 2018 01 5;137(3):222-232. Epub 2017 Oct 5.

Center for Genomic Medicine (C.A.E., A.V.K., D.K., P.N., S.M.Z., A.N., M.H., K.A., A.P., N.G., S.G., S.K.)

Background: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy.

Methods: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [] and Guanylate Cyclase 1, Soluble, Alpha 3 []) with a range of human phenotypes. We selected 2 common variants (rs3918226 in and rs7692387 in ) known to associate with increased and expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in and were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815).

Results: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; =5.5*10], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; =0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; =0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the or genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; =5.6*10) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; =0.01).

Conclusions: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771958PMC
January 2018

A computational model of 1,5-AG dynamics during pregnancy.

Physiol Rep 2017 Aug;5(16)

California Institute of Technology, Pasadena, California

The importance of 1,5-anhydroglucitol (1,5-AG) as an intermediate biomarker for diabetic pregnancy is multi-fold: (1) it serves as a reliable indicator of moderate-level glycemic control, especially during early gestation; (2) it has been associated with increased risk of diabetes, independent of HbA1c and fasting glucose; and (3) it is an independent risk factor for the development of eclampsia during pregnancy. However, the clinical use of this biomarker during pregnancy has been underutilized due to physiological changes in glomerular filtration rate, plasma volume, and other hemodynamic parameters which have been hypothesized to bias gestational serum 1,5-AG concentrations. Here, we develop an model of gestational 1,5-AG by combining pre-existing physiological data in the literature with a two-compartment mathematical model, building off of a previous kinetic model described by Stickle and Turk (1997) Am. J. Physiol., 273, E821. Our model quantitatively characterizes how renal and hemodynamic factors impact measured 1,5-AG during normal pregnancy and during pregnancy with gestational diabetes and diabetes mellitus. During both normal and diabetic pregnancy, we find that a simple two-compartment model of 1,5-AG kinetics, with all parameters but reabsorption fraction adjusted for time in pregnancy, efficiently models 1,5-AG kinetics throughout the first two trimesters. Allowing reabsorption fraction to decrease after 25 weeks permits parameters closer to expected physiological values during the last trimester. Our quantitative model of 1,5-AG confirms the involvement of hypothesized renal and hemodynamic mechanisms during pregnancy, clarifying the expected trends in 1,5-AG to aid clinical interpretation. Further research and data may elucidate biological changes during the third trimester that account for the drop in 1,5-AG concentrations, and clarify physiological differences between diabetes subtypes during pregnancy.
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http://dx.doi.org/10.14814/phy2.13375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582262PMC
August 2017

A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression.

Cell 2017 Jul;170(3):522-533.e15

Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.
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http://dx.doi.org/10.1016/j.cell.2017.06.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785707PMC
July 2017

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

Circ Res 2017 Jun 15;121(1):81-88. Epub 2017 May 15.

Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the gene may provide insight into the efficacy of CETP inhibition.

Objective: To test whether protein-truncating variants (PTVs) at the gene were associated with plasma lipid levels and CHD.

Methods And Results: We sequenced the exons of the gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the gene. Compared with noncarriers, carriers of PTV at had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; <1.0×10), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; =0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; =0.043). PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; =5.1×10).

Conclusions: Compared with noncarriers, carriers of PTV at displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523940PMC
June 2017

ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.

J Am Coll Cardiol 2017 Apr 3;69(16):2054-2063. Epub 2017 Apr 3.

Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. Electronic address:

Background: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

Objectives: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

Methods: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

Results: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).

Conclusions: ANGPTL3 deficiency is associated with protection from CAD.
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http://dx.doi.org/10.1016/j.jacc.2017.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404817PMC
April 2017

Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease.

JAMA 2017 02;317(6):626-634

Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.

Importance: In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain.

Objective: To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes.

Design, Setting, And Participants: A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank.

Exposures: Genetic predisposition to increased WHR adjusted for BMI.

Main Outcomes And Measures: Type 2 diabetes and CHD.

Results: Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1-mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440).

Conclusions And Relevance: A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.
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http://dx.doi.org/10.1001/jama.2016.21042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571980PMC
February 2017

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

Proc Natl Acad Sci U S A 2017 01 28;114(3):E327-E336. Epub 2016 Dec 28.

Broad Institute of MIT and Harvard, Cambridge, MA 02142;

Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.
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http://dx.doi.org/10.1073/pnas.1619052114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5255587PMC
January 2017

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

J Am Coll Cardiol 2016 Dec;68(25):2761-2772

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Background: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation.

Objectives: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD.

Methods: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.

Results: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.

Conclusions: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.
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http://dx.doi.org/10.1016/j.jacc.2016.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328146PMC
December 2016

Ultra-rare disruptive and damaging mutations influence educational attainment in the general population.

Nat Neurosci 2016 12 3;19(12):1563-1565. Epub 2016 Oct 3.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.
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http://dx.doi.org/10.1038/nn.4404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127781PMC
December 2016

Mathematical framework for activity-based cancer biomarkers.

Proc Natl Acad Sci U S A 2015 Oct 28;112(41):12627-32. Epub 2015 Sep 28.

Institute for Medical Engineering and Science, Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Chevy Chase, MD 20815

Advances in nanomedicine are providing sophisticated functions to precisely control the behavior of nanoscale drugs and diagnostics. Strategies that coopt protease activity as molecular triggers are increasingly important in nanoparticle design, yet the pharmacokinetics of these systems are challenging to understand without a quantitative framework to reveal nonintuitive associations. We describe a multicompartment mathematical model to predict strategies for ultrasensitive detection of cancer using synthetic biomarkers, a class of activity-based probes that amplify cancer-derived signals into urine as a noninvasive diagnostic. Using a model formulation made of a PEG core conjugated with protease-cleavable peptides, we explore a vast design space and identify guidelines for increasing sensitivity that depend on critical parameters such as enzyme kinetics, dosage, and probe stability. According to this model, synthetic biomarkers that circulate in stealth but then activate at sites of disease have the theoretical capacity to discriminate tumors as small as 5 mm in diameter-a threshold sensitivity that is otherwise challenging for medical imaging and blood biomarkers to achieve. This model may be adapted to describe the behavior of additional activity-based approaches to allow cross-platform comparisons, and to predict allometric scaling across species.
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http://dx.doi.org/10.1073/pnas.1506925112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611621PMC
October 2015
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