Publications by authors named "Samantha Laber"

14 Publications

  • Page 1 of 1

Linking the obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo.

Sci Adv 2021 Jul 21;7(30). Epub 2021 Jul 21.

Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire OX11 0RD, UK.

Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates and gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.
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http://dx.doi.org/10.1126/sciadv.abg0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294759PMC
July 2021

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

Cell Metab 2021 03 28;33(3):615-628.e13. Epub 2021 Jan 28.

Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cell Circuits and Epigenomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA; University of Hohenheim, Institute of Nutritional Science, Stuttgart 70599, Germany. Electronic address:

Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.
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http://dx.doi.org/10.1016/j.cmet.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928941PMC
March 2021

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

A lead candidate functional single nucleotide polymorphism within the WARS2 gene associated with waist-hip-ratio does not alter RNA stability.

Biochim Biophys Acta Gene Regul Mech 2020 11 30;1863(11):194640. Epub 2020 Sep 30.

MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK. Electronic address:

We have prioritised a single nucleotide polymorphism (SNP) rs2645294 as one candidate functional SNP in the TBX15-WARS2 waist-hip-ratio locus using posterior probability analysis. This SNP is located in the 3' untranslated region of the WARS2 (tryptophanyl tRNA synthetase 2, mitochondrial) gene with which it has an expression quantitative trait in subcutaneous white adipose tissue. We show that transcripts of the WARS2 gene in a human white adipose cell line, heterozygous for the rs2645294 SNP, showed allelic imbalance. We tested whether the rs2645294 SNP altered WARS2 RNA stability using three different methods: actinomycin-D inhibition and RNA decay, mature and nascent RNA analysis and luciferase reporter assays. We found no evidence of a difference in RNA stability between the rs2645294 alleles indicating that the allelic expression imbalance was likely due to transcriptional regulation.
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http://dx.doi.org/10.1016/j.bbagrm.2020.194640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695619PMC
November 2020

Machine Learning based histology phenotyping to investigate the epidemiologic and genetic basis of adipocyte morphology and cardiometabolic traits.

PLoS Comput Biol 2020 08 14;16(8):e1008044. Epub 2020 Aug 14.

Big Data Institute, University of Oxford, Oxford, United Kingdom.

Genetic studies have recently highlighted the importance of fat distribution, as well as overall adiposity, in the pathogenesis of obesity-associated diseases. Using a large study (n = 1,288) from 4 independent cohorts, we aimed to investigate the relationship between mean adipocyte area and obesity-related traits, and identify genetic factors associated with adipocyte cell size. To perform the first large-scale study of automatic adipocyte phenotyping using both histological and genetic data, we developed a deep learning-based method, the Adipocyte U-Net, to rapidly derive mean adipocyte area estimates from histology images. We validate our method using three state-of-the-art approaches; CellProfiler, Adiposoft and floating adipocytes fractions, all run blindly on two external cohorts. We observe high concordance between our method and the state-of-the-art approaches (Adipocyte U-net vs. CellProfiler: R2visceral = 0.94, P < 2.2 × 10-16, R2subcutaneous = 0.91, P < 2.2 × 10-16), and faster run times (10,000 images: 6mins vs 3.5hrs). We applied the Adipocyte U-Net to 4 cohorts with histology, genetic, and phenotypic data (total N = 820). After meta-analysis, we found that mean adipocyte area positively correlated with body mass index (BMI) (Psubq = 8.13 × 10-69, βsubq = 0.45; Pvisc = 2.5 × 10-55, βvisc = 0.49; average R2 across cohorts = 0.49) and that adipocytes in subcutaneous depots are larger than their visceral counterparts (Pmeta = 9.8 × 10-7). Lastly, we performed the largest GWAS and subsequent meta-analysis of mean adipocyte area and intra-individual adipocyte variation (N = 820). Despite having twice the number of samples than any similar study, we found no genome-wide significant associations, suggesting that larger sample sizes and a homogenous collection of adipose tissue are likely needed to identify robust genetic associations.
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http://dx.doi.org/10.1371/journal.pcbi.1008044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449405PMC
August 2020

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Sci Transl Med 2020 06;12(549)

Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.
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http://dx.doi.org/10.1126/scitranslmed.aay6570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116615PMC
June 2020

GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.

Am J Hum Genet 2019 01 21;104(1):157-163. Epub 2018 Dec 21.

National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Old Road, Oxford OX3 7LE, UK; Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Big Data Institute Building, Roosevelt Drive, University of Oxford, Oxford OX3 7LF, UK; Medical Research Council Population Health Research Unit at the University of Oxford, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323625PMC
January 2019

Large-scale meta-analysis highlights the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length.

Hum Mol Genet 2018 12;27(24):4323-4332

Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK.

The normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle-stimulating hormone beta-subunit (FSHB) locus. A genome-wide association study meta-analysis of menstrual cycle length in 44 871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings not only confirm the role of the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2.
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http://dx.doi.org/10.1093/hmg/ddy317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276838PMC
December 2018

The genetic underpinnings of body fat distribution.

Expert Rev Endocrinol Metab 2017 11 17;12(6):417-427. Epub 2017 Oct 17.

a Big Data Institute , Li Ka Shing Centre for Health Information and Discovery, University of Oxford , Oxford , UK.

Introduction: Obesity, defined as a body mass index (BMI) ≥ 30 kg/m, has reached epidemic proportions; people who are overweight (BMI > 25 kg/m) or obese now comprise more than 25% of the world's population. Obese individuals have a higher risk of comorbidity development including type 2 diabetes, cardiovascular disease, cancer, and fertility complications. Areas covered: The study of monogenic and syndromic forms of obesity have revealed a small number of genes key to metabolic perturbations. Further, obesity and body shape in the general population are highly heritable phenotypes. Study of obesity at the population level, through genome-wide association studies of BMI and waist-to-hip ratio (WHR), have revealed > 150 genomic loci that associate with these traits, and highlight the role of adipose tissue and the central nervous system in obesity-related traits. Studies in animal models and cell lines have helped further elucidate the potential biological mechanisms underlying obesity. In particular, these studies implicate adipogenesis and expansion of adipose tissue as key biological pathways in obesity and weight gain. Expert commentary: Further work, including a focus on integrating genetic and additional genomic data types, as well as modeling obesity-like features in vitro, will be crucial in translating genome-wide association signals to the causal mechanisms driving disease.
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http://dx.doi.org/10.1080/17446651.2017.1390427DOI Listing
November 2017

Mouse Models of Human GWAS Hits for Obesity and Diabetes in the Post Genomic Era: Time for Reevaluation.

Front Endocrinol (Lausanne) 2017 7;8:11. Epub 2017 Feb 7.

Mammalian Genetics Unit, Medical Research Council Harwell Institute , Oxfordshire , UK.

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http://dx.doi.org/10.3389/fendo.2017.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294391PMC
February 2017

Commentary: FTO obesity variant circuitry and adipocyte browning in humans.

Front Genet 2015 23;6:318. Epub 2015 Oct 23.

Mammalian Genetics Unit, Medical Research Council Harwell Oxfordshire, UK.

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http://dx.doi.org/10.3389/fgene.2015.00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617056PMC
November 2015

FTO influences adipogenesis by regulating mitotic clonal expansion.

Nat Commun 2015 Apr 17;6:6792. Epub 2015 Apr 17.

MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK.

The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity.
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http://dx.doi.org/10.1038/ncomms7792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410642PMC
April 2015

Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass.

Surg Obes Relat Dis 2014 Jul-Aug;10(4):671-8. Epub 2014 Jan 28.

Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Sweden. Electronic address:

Background: Early benefits of Roux-en Y gastric bypass (RYGB) are partly mediated by the caloric restriction that patients undergo before and acutely after the procedure. Altered DNA methylation occurs in metabolic diseases including obesity, as well as in skeletal, muscle eight months after RYGB. The objective of this study was to test whether promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1 A), pyruvate dehydrogenase kinase isozyme-4 (PDK4), transcription factor A (TFAM), interleukin-1 beta (IL1 B), interleukin-6 (IL6) and tumor necrosis factor-α (TNF) is altered in blood after a very low calorie diet (VLCD) or RYGB.

Methods: Obese nondiabetic patients (n = 18, body mass index [BMI] 42.3 ± 4.9 kg/m(2)) underwent a 14-day VLCD followed by RYGB. Nonobese patients (n = 6, BMI 25.7 ± 2.1 kg/m(2)) undergoing elective cholecystectomy served as controls. DNA methylation of selected promoter regions was measured in whole blood before and after VLCD. A subgroup of seven patients was studied 1-2 days and 12 ± 3 months after RYGB. Promoter methylation was measured using methylated DNA capture and quantitative real-time polymerase chain reaction (PCR).

Results: VLCD decreased promoter methylation of PPARGC1 A. Methylation of PPARGC1 A, TFAM, IL1 B, IL6, and TNF promoters was changed two days after RYGB. Similar changes were also seen on day one after cholecystectomy. Moreover, methylation increased in PDK4, IL1 B, IL6, and TNF promoters 12 months after RYGB.

Conclusion: RYGB induced more profound epigenetic changes than VLCD in promoters of the tested genes in whole blood. Changes in DNA methylation may contribute to the improved overall metabolic health after RYGB.
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http://dx.doi.org/10.1016/j.soard.2013.12.019DOI Listing
May 2015
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