1. |
- Bar, N., et al.
(author)
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A reference map of potential determinants for the human serum metabolome
- 2020
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In: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Journal article (peer-reviewed)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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2. |
- Walters, R G, et al.
(author)
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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 463:7281, s. 671-5
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Journal article (peer-reviewed)abstract
- Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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3. |
- Lu, Yingchang, et al.
(author)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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7. |
- Falchi, M., et al.
(author)
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Low copy number of the salivary amylase gene predisposes to obesity
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:5, s. 492-497
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Journal article (peer-reviewed)abstract
- Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10-14) and serum enzyme levels (P < 2.20 × 10-16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy =-0.15 (0.02) kg/m 2; P = 6.93 × 10-10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10-10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. © 2014 Nature America, Inc. All rights reserved.
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8. |
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9. |
- Grosche, S, et al.
(author)
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Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 6618-
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
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11. |
- Aulchenko, Yurii S, et al.
(author)
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Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:1, s. 47-55
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Journal article (peer-reviewed)abstract
- Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.
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12. |
- Moustafa, J. S. E., et al.
(author)
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Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity
- 2012
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:16, s. 3727-3738
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Journal article (peer-reviewed)abstract
- Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P-empirical 8.9 10(8) and P 3.1 10(3), respectively) which we estimate explains approximate to 0.8 of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46 of the variance (P-combined 1.6 10(3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P 0.027) and both VNTRs (P-empirical 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
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13. |
- Walley, A J, et al.
(author)
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Differential coexpression analysis of obesity-associated networks in human subcutaneous adipose tissue.
- 2012
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 36:1, s. 137-147
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Journal article (peer-reviewed)abstract
- Objective:To use a unique obesity-discordant sib-pair study design to combine differential expression analysis, expression quantitative trait loci (eQTLs) mapping and a coexpression regulatory network approach in subcutaneous human adipose tissue to identify genes relevant to the obese state.Study design:Genome-wide transcript expression in subcutaneous human adipose tissue was measured using Affymetrix U133 Plus 2.0 microarrays (Affymetrix, Santa Clara, CA, USA), and genome-wide genotyping data was obtained using an Applied Biosystems (Applied Biosystems; Life Technologies, Carlsbad, CA, USA) SNPlex linkage panel.Subjects:A total of 154 Swedish families ascertained through an obese proband (body mass index (BMI) >30kgm(-2)) with a discordant sibling (BMI>10kgm(-2) less than proband).Results:Approximately one-third of the transcripts were differentially expressed between lean and obese siblings. The cellular adhesion molecules (CAMs) KEGG grouping contained the largest number of differentially expressed genes under cis-acting genetic control. By using a novel approach to contrast CAMs coexpression networks between lean and obese siblings, a subset of differentially regulated genes was identified, with the previously GWAS obesity-associated neuronal growth regulator 1 (NEGR1) as a central hub. Independent analysis using mouse data demonstrated that this finding of NEGR1 is conserved across species.Conclusion:Our data suggest that in addition to its reported role in the brain, NEGR1 is also expressed in subcutaneous adipose tissue and acts as a central 'hub' in an obesity-related transcript network.
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15. |
- Freidin, Maxim B., et al.
(author)
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Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19
- 2023
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In: Inflammation Research. - 1023-3830. ; 72:5, s. 947-953
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Journal article (peer-reviewed)abstract
- Objective and design: Fatigue is a prominent symptom in the general population and may follow viral infection, including SARS-CoV2 infection which causes COVID-19. Chronic fatigue lasting more than three months is the major symptom of the post-COVID syndrome (known colloquially as long-COVID). The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of long-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual prior to COVID-19. Subjects and methods: We analyzed pre-pandemic plasma levels of IL-6, which plays a key role in persistent fatigue, in N = 1274 community dwelling adults from TwinsUK. Subsequent COVID-19-positive and -negative participants were categorized based on SARS-CoV-2 antigen and antibody testing. Chronic fatigue was assessed using the Chalder Fatigue Scale. Results: COVID-19-positive participants exhibited mild disease. Chronic fatigue was a prevalent symptom among this population and significantly higher in positive vs. negative participants (17% vs 11%, respectively; p = 0.001). The qualitative nature of chronic fatigue as determined by individual questionnaire responses was similar in positive and negative participants. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in negative, but not positive individuals. Raised BMI was associated with chronic fatigue in positive participants. Conclusions: Pre-existing increased IL-6 levels may contribute to chronic fatigue symptoms, but there was no increased risk in individuals with mild COVID-19 compared with uninfected individuals. Elevated BMI also increased the risk of chronic fatigue in mild COVID-19, consistent with previous reports.
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19. |
- Soranzo, Nicole, et al.
(author)
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A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:11, s. 38-1182
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Journal article (peer-reviewed)abstract
- The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
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20. |
- Svensson, Per-Arne, 1969, et al.
(author)
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CDKN2B expression and subcutaneous adipose tissue expandability: Possible influence of the 9p21 atherosclerosis locus
- 2014
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 446:4, s. 1126-1131
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Journal article (peer-reviewed)abstract
- Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis. (C) 2014 The Authors. Published by Elsevier Inc.
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21. |
- Biffi, Stefania, et al.
(author)
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Cubosomes for in vivo fluorescence lifetime imaging
- 2017
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In: Nanotechnology. - : IOP Publishing. - 0957-4484 .- 1361-6528. ; 28:5
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Journal article (peer-reviewed)abstract
- Herein we provided the first proof of principle for in vivo fluorescence optical imaging application using monoolein-based cubosomes in a healthy mouse animal model. This formulation, administered at a non-cytotoxic concentration, was capable of providing both exogenous contrast for NIR fluorescence imaging with very high efficiency and chemospecific information upon lifetime analysis. Time-resolved measurements of fluorescence after the intravenous injection of cubosomes revealed that the dye rapidly accumulated mainly in the liver, while lifetimes profiles obtained in vivo allowed for discriminating between free dye or dye embedded within the cubosome nanostructure after injection.
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22. |
- Caltagirone, Claudia, et al.
(author)
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Solvatochromic fluorescent BODIPY derivative as imaging agent in camptothecin loaded hexosomes for possible theranostic applications
- 2015
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In: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 5:30, s. 23443-23449
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Journal article (peer-reviewed)abstract
- We here discuss the potential theranostic nanomedicine application of an innovative formulation consisting of monoolein-based nanoparticles with a two-dimensional hexagonal inner structure stabilized in water using a mixture of PEO132-PPO50-PEO132 block copolymers with and without conjugated folate for targeting. The proposed tumor-cell targeted formulation was shown to be able to simultaneously host the model anticancer drug camptothecin and a pyrene-modified BODIPY fluorophore, based on dynamic light scattering, small-angle X-ray scattering, and cryogenic transmission electron microscopy. The photophysical properties of the fluorophore were studied in solution in various solvents. A marked fluorescent solvatochromism, whose origin was explained by time-dependent density functional theory theoretical calculations, was observed. Fluorescence microscopy showed that HeLa cells readily internalize these nanoparticles, and that the fluorophore localizes within the lipid droplets. In addition, cytotoxicity test revealed that these nanoparticles are not toxic at the concentration used for the imaging analysis.
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23. |
- Clark, Stephen J, et al.
(author)
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Association of Sirtuin 1 (SIRT1) Gene SNPs and Transcript Expression Levels With Severe Obesity.
- 2012
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In: Obesity. - : Wiley. - 1930-7381. ; 20:1, s. 178-85
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Journal article (peer-reviewed)abstract
- Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI >40kg/m(2) and 637 children, BMI >97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r(2) = 0.96) were significantly associated with adult obesity, rs33957861 (P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61-0.92) and rs11599176 (P value: 0.006, OR = 0.74, CI = 0.61-0.90). Expression of SIRT1 mRNA was measured in BMI-discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings (r(2) = 0.13, P value = 3.36 × 10(-7)) and lower SIRT1 expression was associated with obesity (P value = 1.56 × 10(-35)). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI (P values: 4 × 10(-4), 6 × 10(-4), 4 × 10(-4), and 2 × 10(-3)) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.
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24. |
- Eleftherohorinou, Hariklia, et al.
(author)
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famCNV: copy number variant association for quantitative traits in families.
- 2011
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In: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803. ; 27:13, s. 1873-5
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Journal article (peer-reviewed)abstract
- A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. AVAILABILITY AND IMPLEMENTATION: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. CONTACT: m.falchi@imperial.ac.uk.
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25. |
- Froguel, Philippe, et al.
(author)
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A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7
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Journal article (peer-reviewed)abstract
- Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far. We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P overall = 8.1×10 -59), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23±0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P total cholesterol = 0.002 and P LDL = 0.0008). Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact. © 2012 Froguel et al.
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