| 41. |
- Morris, John A, et al.
(författare)
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An atlas of genetic influences on osteoporosis in humans and mice.
- 2019
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 51, s. 258-266
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR)=58, P=1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P<0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
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| 42. |
- Nica, Alexandra C, et al.
(författare)
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The architecture of gene regulatory variation across multiple human tissues : the MuTHER study.
- 2011
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
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| 43. |
- Paternoster, Lavinia, et al.
(författare)
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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
- 2013
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n=5,878) followed by replication (n=1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p=3.6×10⁻¹⁴; LOC285735, rs271170, p=2.7×10⁻¹²; OPG, rs7839059, p=1.2×10⁻¹⁰; and ESR1/C6orf97, rs6909279, p=1.1×10⁻⁹). The trabecular vBMD GWA meta-analysis (n=2,500) followed by replication (n=1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p=1.9×10⁻⁹). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n=729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
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| 44. |
- Penno, Hendrik, 1962-, et al.
(författare)
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Polymorphic variations in the gene for osteoprotegerin are associated with bone mineral density and predict fractures in elderly men: Data from Mr OS Sweden. :
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Osteoporosis is a polygenetic disorder where several genes are known to be involved. In this report we investigated the association between polymorphic variations in the gene for osteoprotegerin (OPG) and bone mineral density (BMD) and fragility fractures in elderly men. Methods: The study was performed in Mr OS Sweden, a cohort consisting of 3014 randomly selected men between 69 and 81 years of age, where at baseline BMD was measured at hip and spine by dual energy X ray absorbtiometry (DXA) and blood samples extracted. DNA was then isolated and the OPG gene was characterised. Prospective fractures, all verified by X-rays, were recorded for 5 years following baseline. Common variants in the 3’ and 5’UTR of the OPG gene was typed using Sequenom technology. Results: There was a significant association between common genetic variants in the gene for OPG and BMD at both hip (top SNP rs10955908, p<0.0008) and spine (top SNP rs10955908, p<0.0008) . The differences in BMD related to presence of various OPG alleles were between 0.5-3.5%. There was also an association with fragility fractures with odds ratio for rs6993813 reaching statistical significance (p=0.03) For five other SNPs were tested were the association with fractures did not reach statistical significance (p=0.12 - 0.19). Conclusion: Polymorphic variations in the gene for OPG are associated with BMD and fragility fractures in elderly men. The data support the view that variation in the OPG gene is a determinant for BMD and fragility fracture risk also in men.
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| 45. |
- Penno, Hendrik, 1962-, et al.
(författare)
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Polymorphic variations in the gene for osteoprotegerin do not predict prostate cancer incidence: Data from MrOS Sweden.
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background Prostate cancer cells have been shown to produce and secrete osteoprotegerin (OPG), that inhibits tumor cell death by binding to TNF-related anti apoptotic ligand (TRAIL), and also is a key regulator of bone turnover . Bone metastases play a central role in prostate cancer spreading. However, the mechanisms underlying the interaction between bone cells and prostate cancer cells are not known. The aim of this study was therefore to investigate whether polymorphic variations in the gene for OPG affect prostate cancer incidence, or extra prostatic disease and metastasis. Methods The study was performed in the MrOS-Sweden cohort consisting of 3,014 men aged 69-81 years. DNA was collected at the start of the study and the gene for OPG was investigated concerning SNPs previously shown to regulate bone mineral density (BMD), and therefore of biological importance. Data on prostate cancer prevalence at baseline, and incidence during a 3-year follow-up were collected from the Swedish Cancer Register. The association of six OPG polymorphisms with prostate cancer was evaluated. Results The association between six OPG polymorphisms and prostate cancer was evaluated. In these analyses there were no significant genotype differences between prostate cancer patients and controls. A tendency for an association between OPG genotypes and more severe disease (p=0.08-0.09) was found however regarding OPG genotypes. Conclusion Polymorphic variations in the gene for OPG are not associated with prostate cancer incidence. Our data on staging of prostate cancer at the diagnose according to the TNM system in regard to the variations in the OPG gene gave some tendencies to possible involvement but further studies are required to investigate the potential role of the OPG/RANK/RANKL system in the metastatic skeletal prostate cancer spreading, and growth, in bone.
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| 46. |
- Ribom, Eva L, et al.
(författare)
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Estimation of physical performance and measurements of habitual physical activity may capture men with high risk to fall--data from the Mr Os Sweden cohort.
- 2009
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Ingår i: Archives of gerontology and geriatrics. - : Elsevier BV. - 1872-6976 .- 0167-4943. ; 49:1
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate if clinically usable estimates of physical performance and level of habitual physical activity are associated with fall risk in elderly men. A population-based sample of 3014 randomly selected men aged 69-80 years was recruited to medical centers in Gothenburg, Malmoe, or Uppsala. The level of physical activity and self-reported falls during the preceding 12 months was evaluated using a questionnaire. The physical performance ability was estimated by measurements of handgrip strength, a timed stands test, a 6-m walking test and a 20-cm narrow walk test. Falls were reported in 16.5% of the men. Fallers performed 6.2+/-19.0% (mean+/-standard deviations; S.D.) less in right handgrip measures, 8.8+/-40.6% slower in the timed stands test, 6.8+/-30.8% slower in the 6-m walking test, and 5.3+/-28.8% slower in the 20-cm narrow walk test (all p<0.001, respectively). The odds ratio for falls among men who performed <-3 S.D. or failed compared to the mean (+1 S.D. to -1 S.D.) in the timed stands test was 3.41 (95% CI 2.31-5.02; p<0.001) and 2.46 (95% CI 1.80-3.34; p<0.001) in 20-cm narrow walk test. There were more fallers that never were physical active (73.0% vs. 65.4%, p<0.001) and who were sitting more (6.4+/-2.5 h/day vs. 6.0+/-2.3 h/day, p<0.05) than among the non-fallers. Fallers scored less than non-fallers in all the estimates of physical performance and they were more sedentary in their life style. The report suggests that clinical usable tests of physical performance and evaluation of habitual physical activity in the clinical situation possibly can be used to predict risk of falls in elderly men.
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| 47. |
- Sigurdsson, Snaevar, et al.
(författare)
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A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:18, s. 2868-2876
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene.
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| 48. |
- Strandberg, Louise, 1981, et al.
(författare)
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IL6 and IL1B polymorphisms are associated with fat mass in older men: the MrOS Study Sweden.
- 2008
-
Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-7381 .- 1930-739X. ; 16:3, s. 710-3
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Tidskriftsartikel (refereegranskat)abstract
- There is growing evidence that immune functions are linked to the regulation of body fat. Our studies of knockout mice indicate that both endogenous interleukin (IL)-6 and IL-1 can suppress mature-onset obesity. We now investigated whether four common polymorphisms of the IL6 and IL1 systems are associated with the fat mass measured with dual-energy X-ray absorptiometry (DXA) in elderly men (n = 3,014). The study subjects were from the Swedish part of the MrOS multicenter population study and 69-81 years of age. The IL6 -174 G>C (Minor allele frequency (MAF) = 48%) gene promoter polymorphism was associated with the primary outcome total fat mass (P = 0.006) and regional fat masses, but not with lean body mass. The IL1B -31T>C (MAF = 34%) polymorphism was also associated with total fat (P = 0.007) and regional fat masses, but not lean body mass. The IL-1 receptor antagonist (IL-1ra) gene (IL1RN) +2018 T>C (MAF = 27%) polymorphism (in linkage disequilibrium (LD) with a well-studied variable number tandem repeat of 86 base pair (bp)) and IL1B +3953 C>T (MAF = 26%) polymorphism were not associated with total fat mass. In conclusion, the IL-1 and IL-6 systems, shown to suppress mature-onset obesity in experimental animals, contain gene polymorphisms that are associated with fat, but not lean, mass in elderly men.
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| 49. |
- Verlaan, Dominique J., et al.
(författare)
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Targeted screening of cis-regulatory variation in human haplotypes
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:1, s. 118-127
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory cis-acting variants account for a large proportion of gene expression variability in populations. Cis-acting differences can be specifically measured by comparing relative levels of allelic transcripts within a sample. Allelic expression (AE) mapping for cis-regulatory variant discovery has been hindered by the requirements of having informative or heterozygous single nucleotide polymorphisms (SNPs) within genes in order to assign the allelic origin of each transcript. In this study we have developed an approach to systematically screen for heritable cis-variants in common human haplotypes across >1,000 genes. In order to achieve the highest level of information per haplotype studied, we carried out allelic expression measurements by using both intronic and exonic SNPs in primary transcripts. We used a novel RNA pooling strategy in immortalized lymphoblastoid cell lines (LCLs) and primary human osteoblast cell lines (HObs) to allow for high-throughput AE. Screening hits from RNA pools were further validated by performing allelic expression mapping in individual samples. Our results indicate that >10% of expressed genes in human LCLs show genotype-linked AE. In addition, we have validated cis-acting variants in over 20 genes linked with common disease susceptibility in recent genome-wide studies. More generally, our results indicate that RNA pooling coupled with AE read-out by second generation sequencing or by other methods provides a high-throughput tool for cataloging the impact of common noncoding variants in the human genome.
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| 50. |
- Weibrecht, Irene, et al.
(författare)
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In situ detection of individual mRNA molecules and protein complexes or post-translational modifications using padlock probes combined with the in situ proximity ligation assay
- 2013
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Ingår i: Nature Protocols. - : Springer Science and Business Media LLC. - 1754-2189 .- 1750-2799. ; 8:2, s. 355-372
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Tidskriftsartikel (refereegranskat)abstract
- Analysis at the single-cell level is essential for the understanding of cellular responses in heterogeneous cell populations, but it has been difficult to perform because of the strict requirements put on detection methods with regard to selectivity and sensitivity (i.e., owing to the cross-reactivity of probes and limited signal amplification). Here we describe a 1.5-d protocol for enumerating and genotyping mRNA molecules in situ while simultaneously obtaining information on protein interactions or post-translational modifications; this is achieved by combining padlock probes with in situ proximity ligation assays (in situ PLA). In addition, we provide an example of how to design padlock probes and how to optimize staining conditions for fixed cells and tissue sections. Both padlock probes and in situ PLA provide the ability to directly visualize single molecules by standard microscopy in fixed cells or tissue sections, and these methods may thus be valuable for both research and diagnostic purposes.
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