| 1. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Journal article (peer-reviewed)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 2. |
- Penell, Johanna, et al.
(author)
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Genetic variation in the CYP2B6 Gene is related to circulating 2,2 ',4,4 '-tetrabromodiphenyl ether (BDE-47) concentrations : an observational population-based study
- 2014
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In: Environmental Health. - London : BioMed Central (BMC). - 1476-069X. ; 13, s. 34-
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Journal article (peer-reviewed)abstract
- Background: Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample.Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS).Results: Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10(- 4) to 10(-9)). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals.Conclusion: Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.
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| 3. |
- Allesøe, Rosa Lundbye, et al.
(author)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Journal article (peer-reviewed)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 4. |
- Gaulton, Kyle J, et al.
(author)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Journal article (peer-reviewed)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 5. |
- Kilpeläinen, Tuomas O, et al.
(author)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 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
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 6. |
- Lind, Lars, et al.
(author)
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Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p '-dde levels in a population-based sample
- 2017
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In: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 98, s. 212-218
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Journal article (peer-reviewed)abstract
- Objectives: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p, p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.Results: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472 ng/g lipid, while the corresponding level for those being homozygote for the T allelewas 192 ng/g lipid (p= 1.5x10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19: 41520351; p= 2.2 x 10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p= 6.2 x 10(-9)) located 7 kb downstreamthe CYP2B6 gene (cg27089200, position chr19: 41531976). This CpG-sitewas also related to the lead SNP (p = 3.8 x 10(-35)), but mediated only 4% of the effect of the lead SNP on p, p'-DDE levels.Conclusion: Circulating levels of p, p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p, p'-DDE levels.
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| 7. |
- 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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| 8. |
- Marouli, Eirini, et al.
(author)
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Rare and low-frequency coding variants alter human adult height
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 9. |
- Ng, Esther, et al.
(author)
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Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample
- 2015
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In: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 140, s. 95-101
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Journal article (peer-reviewed)abstract
- Background: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level.Objectives: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs.Methods: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model.Results: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7 x 10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8 x 10(-12)) for PCB-118, rs4802104 (p= 1.4 x 10(-9)) for PCB-74 and rs4803413 (p=2.5 x 10(-9)) for PCB-105, all of which map to CYP2B6.Conclusions: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity. (C) 2015 The Authors. Published by Elsevier Inc.
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| 10. |
- Scott, Robert A., et al.
(author)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Journal article (peer-reviewed)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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