Publications
1181 results found
Bradfield JP, Vogelezang S, Felix JF, et al., 2019, A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity, Human Molecular Genetics, Vol: 28, Pages: 3327-3338, ISSN: 0964-6906
Although hundreds of GWAS-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity, and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2-18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than ten SNPs (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
Rancière F, Botton J, Slama R, et al., 2019, Exposure to Bisphenol A and Bisphenol S and Incident Type 2 Diabetes: A Case-Cohort Study in the French Cohort D.E.S.I.R., Environ Health Perspect, Vol: 127
BACKGROUND: The question of whether exposure to bisphenol A (BPA) contributes to the development of type 2 diabetes is still unresolved. Most epidemiological evidence on the association between BPA and diabetes is from cross-sectional studies or longitudinal studies with single urinary measurements. No prospective study has examined exposure to BPA analogs such as bisphenol S (BPS) in relation to incident type 2 diabetes. OBJECTIVES: We aimed to investigate whether exposure to BPA and BPS, assessed at up to two time points, was associated with the incidence of type 2 diabetes. METHODS: We performed a case-cohort study on 755 participants without diabetes at baseline and followed-up over 9 y as part of the French prospective cohort Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.). BPA-glucuronide (BPA-G) and BPS-glucuronide (BPS-G) were assessed in fasting spot urine samples collected during the health examinations at baseline and 3 y later. Associations with incident diabetes were examined using Prentice-weighted Cox regression models adjusted for potential confounders. RESULTS: A total of 201 incident cases of type 2 diabetes were diagnosed over the follow-up, including 30 in the subcohort. Compared with participants with the lowest average BPA exposure (below the first quartile), participants in the second, third, and fourth quartile groups of exposure had a near doubling of the risk of type 2 diabetes, with a hazard ratio (HR) = 2.56 (95% CI: 1.16, 5.65), 2.35 (95% CI: 1.07, 5.15), and 1.56 (95% CI: 0.68, 3.55), respectively. The detection of BPS-G in urine at one or both time points was associated with incident diabetes, with an HR = 2.81 (95% CI: 1.74, 4.53). DISCUSSION: This study shows positive associations between exposure to BPA and BPS and the incidence of type 2 diabetes, independent of traditional diabetes risk factors. Our results should be confirmed by recent, population-based observational studies in dif
Wilman HR, Parisinos CA, Atabaki-Pasdar N, et al., 2019, Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration, Journal of Hepatology, Vol: 71, Pages: 594-602, ISSN: 0168-8278
BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart
Huang T, Wang T, Zheng Y, et al., 2019, Association of Birth Weight With Type 2 Diabetes and Glycemic Traits A Mendelian Randomization Study, JAMA NETWORK OPEN, Vol: 2, ISSN: 2574-3805
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- Citations: 27
Koivula RW, Forgie IM, Kurbasic A, et al., 2019, Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium., Diabetologia, Vol: 62, Pages: 1601-1615, ISSN: 0012-186X
AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enro
Thomas CE, Haussler RS, Hong M-G, et al., 2019, Individual effects of gastric bypass surgery on longitudinal blood protein profiles: an IMI DIRECT study, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S271-S271, ISSN: 0012-186X
Baron M, Maillet J, Huyvaert M, et al., 2019, Pathogenic, loss-of function mutations in MRAP2 cause monogenic metabolic syndrome, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S146-S146, ISSN: 0012-186X
Bourouh C, Oger F, Gromada X, et al., 2019, The transcriptional activity of E2F1 is controlled through exendin-4 signalling in pancreatic beta cell, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S214-S214, ISSN: 0012-186X
Vaxillaire M, Froguel P, Bonnefond A, 2019, How Recent Advances in Genomics Improve Precision Diagnosis and Personalized Care of Maturity-Onset Diabetes of the Young, CURRENT DIABETES REPORTS, Vol: 19, ISSN: 1534-4827
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- Citations: 13
Sung YJ, de Las Fuentes L, Winkler TW, et al., 2019, A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure, Human Molecular Genetics, Vol: 28, Pages: 2615-2633, ISSN: 0964-6906
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
Marchetti P, Schulte AM, Marselli L, et al., 2019, Fostering improved human islet research: a European perspective, Diabetologia, Vol: 62, Pages: 1514-1516, ISSN: 0012-186X
Liu C-T, Merino J, Rybin D, et al., 2019, Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322
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- Citations: 6
Bonnefond A, Froguel P, 2019, High Prevalence of Pathogenic Mutations in Genes Causing Monogenic Diabetes among Patients with Common Type 2 Diabetes, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
de Vries PS, Brown MR, Bentley AR, et al., 2019, Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions, American Journal of Epidemiology, Vol: 188, Pages: 1033-1054, ISSN: 1476-6256
An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
Khamis A, Canouil M, Siddiq A, et al., 2019, Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes, MOLECULAR METABOLISM, Vol: 24, Pages: 98-107, ISSN: 2212-8778
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- Citations: 18
Wuttke M, Li Y, Li M, et al., 2019, A catalog of genetic loci associated with kidney function from analyses of a million individuals, Nature Genetics, Vol: 51, Pages: 957-972, ISSN: 1061-4036
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Bentley AR, Sung YJ, Brown MR, et al., 2019, Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids, Nature Genetics, Vol: 51, Pages: 636-648, ISSN: 1061-4036
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
Frade-Proud'Hon-Clerc S, Smol T, Frenois F, et al., 2019, A novel rare missense variation of the NOD2 gene: Evidences of implication in Crohn's Disease, International Journal of Molecular Sciences, Vol: 20, ISSN: 1422-0067
Kilpelainen TO, Bentley AR, Noordam R, et al., 2019, Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity, Nature Communications, Vol: 10, ISSN: 2041-1723
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
Chadeau M, Campanella G, Gunter MJ, et al., 2018, Epigenome-wide association study of adiposity and future risk of obesity-related diseases, International Journal of Obesity, Vol: 42, Pages: 2022-2035, ISSN: 0307-0565
BackgroundObesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.MethodsDNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.ResultsWe identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10−7), higher triglyceride levels (P = 5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10−3) and one intergenic locus on chromosome 1 was inversely associa
Parmar P, Lowry E, Cugliari G, et al., 2018, Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults, EBioMedicine, Vol: 38, Pages: 206-216, ISSN: 2352-3964
BackgroundDNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.MethodsWe meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pressure (BP).FindingsLower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10−7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10−8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels.InterpretationEpigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors.
Capel E, Vatier C, Cervera P, et al., 2018, <i>MFN2</i>-associated lipomatosis: Clinical spectrum and impact on adipose tissue, JOURNAL OF CLINICAL LIPIDOLOGY, Vol: 12, Pages: 1420-1435, ISSN: 1933-2874
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- Citations: 36
Bentley AR, Evangelou E, Zhang W, et al., 2018, Multi-ancestry genome-wide smoking interaction study of 387,272 individuals identifies novel lipid loci., Nature Genetics, ISSN: 1061-4036
Serum lipids, such as triglycerides (TG) and high- and low-density lipoprotein cholesterol (HDL and LDL), are influenced by both genetic and lifestyle factors. Over 250 lipid loci have been identified,1-6 yet, it is unclear to what extent lifestyle factors modify the effects of these variants, or those yet to be identified. Smoking is associated with an unfavorable lipid profile,7,8 warranting its investigation as a lifestyle factor that potentially modifies genetic associations with lipids. Identifying interactions using traditional 1 degree of freedom (1df) tests of SNP x smoking terms may have low power, except in very large sample sizes. To enhance the detection of loci, a 2 degree of freedom (2df) test that jointly evaluates the interaction and main effects was developed.9 The Gene-Lifestyle Interactions Working Group, under the aegis of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium10, was formed to conduct analyses of lifestyle interactions in the genetic basis of cardiovascular traits. As both genetic and lifestyle factors differ across populations with different ancestry backgrounds, and to address the underrepresentation of non-European populations in genomic research, great effort went into creating a large, multi-ancestry resource for these investigations.11 Here, we report a genome-wide interaction study that uses both the 1df test of interaction and the 2df joint test of main and interaction effects to test the hypothesis that genetic associations of serum lipids differ by smoking status.
Mahajan A, Taliun D, Thurner M, et al., 2018, Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps, Nature Genetics, Vol: 50, Pages: 1505-1515, ISSN: 1061-4036
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
Ligthart S, Vaez A, Vosa U, et al., 2018, Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders, American Journal of Human Genetics, Vol: 103, Pages: 691-706, ISSN: 0002-9297
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
Cousminer DL, Ahlqvist E, Mishra R, et al., 2018, First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes, DIABETES CARE, Vol: 41, Pages: 2396-2403, ISSN: 0149-5992
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- Citations: 85
Lesne E, Coutte L, Solans L, et al., 2018, Distinct virulence ranges for infection of mice by Bordetella pertussis revealed by engineering of the sensor-kinase BvgS, PLoS ONE, Vol: 13, ISSN: 1932-6203
The whooping cough agent Bordetella pertussis coordinately regulates the expression of its virulence factors with the two-component system BvgAS. In laboratory conditions, specific chemical modulators are used to trigger phenotypic modulation of B. pertussis from its default virulent Bvg+ phase to avirulent Bvg- or intermediate Bvgi phases, in which no virulence factors or only a subset of them are produced, respectively. Whether phenotypic modulation occurs in the host remains unknown. In this work, recombinant B. pertussis strains harboring BvgS variants were tested in a mouse model of infection and analyzed using transcriptomic approaches. Recombinant BP-BvgΔ65, which is in the Bvgi phase by default and can be up-modulated to the Bvg+ phase in vitro, could colonize the mouse nose but was rapidly cleared from the lungs, while Bvg+-phase strains colonized both organs for up to four weeks. These results indicated that phenotypic modulation, which might have restored the full virulence capability of BP-BvgΔ65, does not occur in mice or is temporally or spatially restricted and has no effect in those conditions. Transcriptomic analyses of this and other recombinant Bvgi and Bvg+-phase strains revealed that two distinct ranges of virulence gene expression allow colonization of the mouse nose and lungs, respectively. We also showed that a recombinant strain expressing moderately lower levels of the virulence genes than its wild type parent was as efficient at colonizing both organs. Altogether, genetic modifications of BvgS generate a range of phenotypic phases, which are useful tools to decipher host-pathogen interactions.
Kaakinen M, Prelot L, Draisma H, et al., 2018, Machine learning in multi-omics data to assess longitudinal predictors of glycaemic trait levels, 27th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 709-709, ISSN: 0741-0395
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Karamitri A, Plouffe B, Bonnefond A, et al., 2018, Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling, SCIENCE SIGNALING, Vol: 11, ISSN: 1945-0877
Imatoh T, Yengo L, Rocheleau G, et al., 2018, <i>ALDH2</i> Polymorphism rs671, but Not <i>ADH1B</i> Polymorphism rs1229984, Increases Risk for Hypo-HDL-Cholesterolemia in a/a Carriers Compared to the G/G Carriers, LIPIDS, Vol: 53, Pages: 797-807, ISSN: 0024-4201
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- Citations: 6
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