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1.
  • Berndt, Sonja I., et al. (författare)
  • Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
  • 2013
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
  • Tidskriftsartikel (refereegranskat)abstract
    • Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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2.
  • van de Vegte, Yordi, et al. (författare)
  • Genetic insights into resting heart rate and its role in cardiovascular disease
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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3.
  • Estrada, Karol, et al. (författare)
  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
  • 2012
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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4.
  • Locke, Adam E, et al. (författare)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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5.
  • Morris, John A, et al. (författare)
  • An atlas of genetic influences on osteoporosis in humans and mice.
  • 2019
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 51, s. 258-266
  • 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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6.
  • Speliotes, Elizabeth K., et al. (författare)
  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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7.
  • Zheng, Hou-Feng, et al. (författare)
  • Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
  • Tidskriftsartikel (refereegranskat)abstract
    • The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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8.
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9.
  • Ben-Avraham, Dan, et al. (författare)
  • The complex genetics of gait speed : Genome-wide meta-analysis approach
  • 2017
  • Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 9:1, s. 209-246
  • Tidskriftsartikel (refereegranskat)abstract
    • Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
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10.
  • Coviello, Andrea D, et al. (författare)
  • A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.
  • 2012
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 8:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p=1.8×10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4×10(-11)), GCKR (rs780093, 2p23.3, p=2.2×10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4×10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1×10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9×10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3×10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5×10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1×10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3×10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7×10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5×10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p=2.5×10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
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11.
  • Kanoni, Stavroula, et al. (författare)
  • Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
  • 2022
  • Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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12.
  • Lango Allen, Hana, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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13.
  • Wang, Thomas J, et al. (författare)
  • Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
  • 2010
  • Ingår i: Lancet. - 1474-547X. ; 376:9736, s. 180-8
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
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14.
  • Heid, Iris M, et al. (författare)
  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
  • Tidskriftsartikel (refereegranskat)abstract
    • Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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15.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)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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16.
  • Lu, Yingchang, et al. (författare)
  • New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)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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17.
  • Ried, Janina S., et al. (författare)
  • A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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18.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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19.
  • Yang, Jian, et al. (författare)
  • FTO genotype is associated with phenotypic variability of body mass index
  • 2012
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
  • Tidskriftsartikel (refereegranskat)abstract
    • There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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20.
  • Zheng, Hou-Feng, et al. (författare)
  • WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk
  • 2012
  • Ingår i: PLoS genetics. - SAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE. - 1553-7404. ; 8:7, s. e1002745-
  • Tidskriftsartikel (refereegranskat)abstract
    • We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10(-12), and -0.16 SD per G allele, P = 1.2×10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10(-6) and rs2707466: OR = 1.22, P = 7.2×10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10(-13)
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21.
  • Abele, H., et al. (författare)
  • Particle physics at the European Spallation Source
  • 2023
  • Ingår i: Physics reports. - : Elsevier. - 0370-1573 .- 1873-6270. ; 1023, s. 1-84
  • Forskningsöversikt (refereegranskat)abstract
    • Presently under construction in Lund, Sweden, the European Spallation Source (ESS) will be the world’s brightest neutron source. As such, it has the potential for a particle physics program with a unique reach and which is complementary to that available at other facilities. This paper describes proposed particle physics activities for the ESS. These encompass the exploitation of both the neutrons and neutrinos produced at the ESS for high precision (sensitivity) measurements (searches).
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22.
  • Baird, Denis A., et al. (författare)
  • Identification of Novel Loci Associated With Hip Shape : A Meta-Analysis of Genomewide Association Studies.
  • 2019
  • Ingår i: Journal of Bone and Mineral Research. - : Wiley-Blackwell. - 0884-0431 .- 1523-4681. ; 34:2, s. 241-251
  • Tidskriftsartikel (refereegranskat)abstract
    • We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2  > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
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23.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
  • 2011
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:8, s. 753-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
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24.
  • Liu, Ching-Ti, et al. (författare)
  • Assessment of gene-by-sex interaction effect on bone mineral density
  • 2012
  • Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 27:10, s. 2051-2064
  • Tidskriftsartikel (refereegranskat)abstract
    • Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p?
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25.
  • Lyons, Paul A, et al. (författare)
  • Genetically Distinct Subsets within ANCA-Associated Vasculitis
  • 2012
  • Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 367:3, s. 214-223
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)
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26.
  • Marriott, Ross J., et al. (författare)
  • Factors Associated With Circulating Sex Hormones in Men
  • 2023
  • Ingår i: Annals of Internal Medicine. - 0003-4819. ; 176:9, s. 1221-1234
  • Forskningsöversikt (refereegranskat)abstract
    • Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. Purpose: To clarify factors associated with variations in sex hormone concentrations. Data Sources: Systematic literature searches (to July 2019). Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. Data Extraction: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone–binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.
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27.
  • Marriott, Ross J, et al. (författare)
  • Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.
  • 2023
  • Ingår i: Annals of internal medicine. - 1539-3704. ; 176:9, s. 1221-1234
  • Forskningsöversikt (refereegranskat)abstract
    • Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.To clarify factors associated with variations in sex hormone concentrations.Systematic literature searches (to July 2019).Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.Individual participant data (IPD) (9 studies; n= 21074) and aggregate data (2 studies; n= 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
  •  
28.
  • Ohlsson, Claes, 1965, et al. (författare)
  • Genetic determinants of serum testosterone concentrations in men.
  • 2011
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 7:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n=871) and two de novo replication cohorts (n=4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p=1.2×10(-41) and rs6258, p=2.3×10(-22)). Subjects with ≥ 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p=5.6×10(-16)). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
  •  
29.
  • Samelson, Elizabeth J, et al. (författare)
  • Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study.
  • 2019
  • Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595. ; 7:1, s. 34-43
  • Tidskriftsartikel (refereegranskat)abstract
    • Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score.We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX.7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture.HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture.National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.
  •  
30.
  • Sarwar, Nadeem, et al. (författare)
  • Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
  • 2012
  • Ingår i: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
  •  
31.
  • Surendran, Praveen, et al. (författare)
  • Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
  • 2016
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1151-1161
  • Tidskriftsartikel (refereegranskat)abstract
    • High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
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32.
  • van Meurs, Joyce B, et al. (författare)
  • Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
  • 2008
  • Ingår i: JAMA : the journal of the American Medical Association. - Chicago : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 299:11, s. 1277-90
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
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33.
  • Vandenput, Liesbeth, et al. (författare)
  • A meta-analysis of previous falls and subsequent fracture risk in cohort studies
  • 2024
  • Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 35:3, s. 469-494
  • Tidskriftsartikel (refereegranskat)abstract
    • SummaryThe relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm.IntroductionPrevious falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD).MethodsThe resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients.ResultsFalls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51) and men (HR 1.53, 95% CI 1.41–1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27–1.84) in men vs. HR 1.32 (95% CI 1.20–1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men.ConclusionsA previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.
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34.
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35.
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36.
  • Abrahamson, Magnus, et al. (författare)
  • Human cystatin C: Role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase
  • 1991
  • Ingår i: Biochemical Journal. - 0264-6021. ; 273:3, s. 621-626
  • Tidskriftsartikel (refereegranskat)abstract
    • Leucocyte elastase in catalytic amounts was observed to rapidly cleave the Val-10-Gly-11 bond of the human cysteine-proteinase inhibitor cystatin C at neutral pH. The resulting modified inhibitor had size and amino acid composition consistent with a cystatin C molecule devoid of the N-terminal Ser-1-Val-10 decapeptide. Leucocyte-elastase-modified cystatin C had more than 240-fold lower affinity than native cystatin C for papain. Removal of the N-terminal decapeptide of human cystatin C also decreased inhibition of human cathepsins B and L by three orders of magnitude, but decreased inhibition of cathepsin H by only 5-fold. A tripeptidyldiazomethane analogue of of the N-terminal portion of cystatin C was a good inhibitor of cathepsins B and L but a poor inhibitor of cathepsin H. It therefore appears that amino acid side chains of the N-terminal segment of cystatin C bind in the substrate-binding pockets of cathepsins B and L but not in those of cathepsin H. It is argued that the N-terminal cystatin C interaction with cathepsin B is physiologically important and hence that leucocyte elastase could have a function as a regulator of extracellular cysteine-proteinase inhibitory activity at sites of inflammation.
  •  
37.
  • Aguilar, J., et al. (författare)
  • Study of nonstandard interactions mediated by a scalar field at the ESSnuSB experiment
  • 2024
  • Ingår i: Physical Review D. - : American Physical Society. - 2470-0010 .- 2470-0029. ; 109:11
  • Tidskriftsartikel (refereegranskat)abstract
    • In this paper, we study scalar mediator induced nonstandard interactions (SNSIs) in the context of the ESSnuSB experiment. In particular, we study the capability of ESSnuSB to put bounds on the SNSI parameters and also study the impact of SNSIs in the measurement of the leptonic CP phase δCP. Existence of SNSIs modifies the neutrino mass matrix and this modification can be expressed in terms of three diagonal real parameters (ηee, ημμ, and ηττ) and three off-diagonal complex parameters (ηeμ, ηeτ, and ημτ). Our study shows that the upper bounds on the parameters ημμ and ηττ depend upon how Δm312 is minimized in the theory. However, this is not the case when one tries to measure the impact of SNSIs on δCP. Further, we show that the CP sensitivity of ESSnuSB can be completely lost for certain values of ηee and ημτ for which the appearance channel probability becomes independent of δCP.
  •  
38.
  • Agyemang, Alex Adusei, et al. (författare)
  • Cerebellar Exposure to Cell-Free Hemoglobin Following Preterm Intraventricular Hemorrhage: Causal in Cerebellar Damage?
  • 2017
  • Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 8:5, s. 461-473
  • Tidskriftsartikel (refereegranskat)abstract
    • Decreased cerebellar volume is associated with intraventricular hemorrhage (IVH) in very preterm infants and may be a principal component in neurodevelopmental impairment. Cerebellar deposition of blood products from the subarachnoid space has been suggested as a causal mechanism in cerebellar underdevelopment following IVH. Using the preterm rabbit pup IVH model, we evaluated the effects of IVH induced at E29 (3 days prior to term) on cerebellar development at term-equivalent postnatal day 0 (P0), term-equivalent postnatal day 2 (P2), and term-equivalent postnatal day 5 (P5). Furthermore, the presence of cell-free hemoglobin (Hb) in cerebellar tissue was characterized, and cell-free Hb was evaluated as a causal factor in the development of cerebellar damage following preterm IVH. IVH was associated with a decreased proliferative (Ki67-positive) portion of the external granular layer (EGL), delayed Purkinje cell maturation, and activated microglia in the cerebellar white matter. In pups with IVH, immunolabeling of the cerebellum at P0 demonstrated a widespread presence of cell-free Hb, primarily distributed in the white matter and the molecular layer. Intraventricular injection of the Hb scavenger haptoglobin (Hp) resulted in a corresponding distribution of immunolabeled Hp in the cerebellum and a partial reversal of the damaging effects observed following IVH. The results suggest that cell-free Hb is causally involved in cerebellar damage following IVH and that blocking cell-free Hb may have protective effects.
  •  
39.
  • Alves, Marco, et al. (författare)
  • Thin ply sheet molding compound enables thin laminates with properties as of continuous fibers
  • 2020
  • Ingår i: International SAMPE Technical Conference. ; 2020-June
  • Konferensbidrag (refereegranskat)abstract
    • In a research collaboration with Chalmers University of Technology, KTH Royal Institute of Technology (SWE) and Imperial College (UK), Oxeon AB has developed ultrathin carbon fiber sheet molding compound (SMC) products for high performance, thin laminate and ease of manufacture composite applications. Said SMC products are based on ultrathin (0.02 mm or 0.0008 in) Spread Tow Tapes that are cut by length and randomly distributed in order to obtain a preform with an in-plane isotropy in either dry or pre-impregnated form displaying the previously never seen minimum cured plate thickness of about 0.5 mm. Recent work has demonstrated that these SMC materials can reach high stiffness and strength making them good alternatives to metal alloys or even continuous fiber composites. In the conduced work, SMC composites were manufactured using ultra-thin tapes of high modulus and ultrahigh modulus fibers having a large length-to-thickness ratio. The paper will describe how these SMC products lead to high stiffness and to significant increase in strength compared to commercially available SMC materials.
  •  
40.
  • Alves, Marco, et al. (författare)
  • Ultra-strong and stiff randomly-oriented discontinuous composites: closing the gap to quasi-isotropic continuous-fibre laminates
  • 2020
  • Ingår i: Composites Part A: Applied Science and Manufacturing. - : Elsevier BV. - 1359-835X. ; 132
  • Tidskriftsartikel (refereegranskat)abstract
    • Conventional randomly-oriented Tow Based Discontinuous Composites (TBDCs) are materials which combine good mechanical properties, lightweight and high manufacturability, and are therefore interesting for high-volume transport industries. This paper proposes, designs and successfully demonstrates a pathway to produce TBDCs with outstanding stiffness and tensile strength, by using ultra-thin tapes of (ultra-) high modulus carbonfibres. Numerical models are used to explore the design space of discontinuous composite materials, in order to identify the optimal microstructural design to maximise stiffness and strength. Selected microstructures are manufactured and tested under tension; the experimental results show good agreement with the numerical predictions, and demonstrate a significant increase in the tensile strength and Young's modulus of TBDCs by reducing the tow thickness and increasing the modulus of the fibres. Strength and stiffness increases of over 100% compared with the commercially available TBDC systems are achieved, resulting in mechanical properties that match the strength and overcome the stiffness of aerospace-graded continuous-fibre laminates.
  •  
41.
  • Alves, Marco, et al. (författare)
  • Ultra-Thin and Stiff Randomly-Oriented Discontinuous Composites
  • 2019
  • Ingår i: Proceedings of the American Society for Composites - 34th Technical Conference, ASC 2019. - Lancaster, PA : DEStech Publications, Inc..
  • Konferensbidrag (refereegranskat)abstract
    • This paper presents experimental and numerical results for tensile strength of tow based discontinues composite (TBDC) plates manufactured using ultra-thin fibre tapes of high stiffness carbon fibres. Numerical models were used to explore the design space of these materials, in order to identify the optimal tow properties that maximise the strength of TBDCs. The experimental show good agreement with the numerical predictions and demonstrate a significant increase in the tensile strength by reducing the tow thickness and increasing the stiffness of the fibres. Strength increases of up to 100%, compared with a commercially available material system, are found, illustrating the highly promising potential of this type of material.
  •  
42.
  • Ansari, David, et al. (författare)
  • Analysis of the Influence of HLA-A Matching Relative to HLA-B and -DR Matching on Heart Transplant Outcomes
  • 2015
  • Ingår i: Transplantation direct. - 2373-8731. ; 1:9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There are conflicting reports on the effect of donor-recipient HLA matching on outcomes in heart transplantation. The objective of this study was to investigate the effects of HLA-A matching relative to HLA-B and -DR matching on long-term survival in heart transplantation.METHODS: A total of 25 583 patients transplanted between 1988 and 2011 were identified from the International Society for Heart and Lung Transplantation registry. Transplants were divided into 2 donor-recipient matching groups: HLA-A-compatible (no HLA-A mismatches) and HLA-A-incompatible (1-2 HLA-A mismatches). Primary outcome was all-cause mortality. Secondary outcomes were graft failure-, cardiovascular-, infection-, or malignancy-related deaths.RESULTS: The risk of all-cause mortality 15 years after transplantation was higher for HLA-A-compatible (vs HLA-A-incompatible) grafts in patients who had HLA-B-, HLA-DR-, or HLA-B,DR-incompatible grafts (P = 0.027, P = 0.007, and P = 0.002, respectively) but not in HLA-B- and/or HLA-DR-compatible grafts. This was confirmed in multivariable Cox regression analysis where HLA-A compatibility (vs HLA-A incompatibility) was associated with higher mortality in transplants incompatible for HLA-DR or HLA-B and -DR (hazard ratio [HR], 1.59; 95% confidence interval [95% CI], 1.11-2.28; P = 0.012 and HR, 1.69; 95% CI, 1.17-2.43; P = 0.005, respectively). In multivariable analysis, the largest compromise in survival for HLA-A compatibility (vs HLA-incompatibility) was for chronic rejection in HLA-B- and -DR-incompatible grafts (HR, 1.91; 95% CI, 1.22-3.01; P = 0.005).CONCLUSIONS: Decreased long-term survival in heart transplantation was associated with HLA-A compatibility in HLA-B,DR-incompatible grafts.
  •  
43.
  • Astrand, Annika, et al. (författare)
  • Mice lacking melanin-concentrating hormone receptor 1 demonstrate increased heart rate associated with altered autonomic activity.
  • 2004
  • Ingår i: American journal of physiology. Regulatory, integrative and comparative physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 287:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Melanin-concentrating hormone (MCH) plays an important role in energy balance. The current studies were carried out on a new line of mice lacking the rodent MCH receptor (MCHR1(-/-) mice). These mice confirmed the previously reported lean phenotype characterized by increased energy expenditure and modestly increased caloric intake. Because MCH is expressed in the lateral hypothalamic area, which also has an important role in the regulation of the autonomic nervous system, heart rate and blood pressure were measured by a telemetric method to investigate whether the increased energy expenditure in these mice might be due to altered autonomic nervous system activity. Male MCHR1(-/-) mice demonstrated a significantly increased heart rate [24-h period: wild type 495 +/- 4 vs. MCHR1(-/-) 561 +/- 8 beats/min (P < 0.001); dark phase: wild type 506 +/- 8 vs. MCHR1(-/-) 582 +/- 9 beats/min (P < 0.001); light phase: wild type 484 +/- 13 vs. MCHR1(-/-) 539 +/- 9 beats/min (P < 0.005)] with no significant difference in mean arterial pressure [wild type 110 +/- 0.3 vs. MCHR1(-/-) 113 +/- 0.4 mmHg (P > 0.05)]. Locomotor activity and core body temperature were higher in the MCHR1(-/-) mice during the dark phase only and thus temporally dissociated from heart rate differences. On fasting, wild-type animals rapidly downregulated body temperature and heart rate. MCHR1(-/-) mice displayed a distinct delay in the onset of this downregulation. To investigate the mechanism underlying these differences, autonomic blockade experiments were carried out. Administration of the adrenergic antagonist metoprolol completely reversed the tachycardia seen in MCHR1(-/-) mice, suggesting an increased sympathetic tone.
  •  
44.
  • Baussan, E., et al. (författare)
  • A very intense neutrino super beam experiment for leptonic CP violation discovery based on the European spallation source linac
  • 2014
  • Ingår i: Nuclear Physics B. - : Elsevier BV. - 0550-3213 .- 1873-1562. ; 885, s. 127-149
  • Tidskriftsartikel (refereegranskat)abstract
    • Very intense neutrino beams and large neutrino detectors will be needed in order to enable the discovery of CP violation in the leptonic sector. We propose to use the proton linac of the European Spoliation Source currently under construction in Lund, Sweden, to deliver, in parallel with the spoliation neutron production, a very intense, cost effective and high performance neutrino beam. The baseline program for the European Spoliation Source linac is that it will be fully operational at 5 MW average power by 2022, producing 2 GeV 2.86 ms long proton pulses at a rate of 14 Hz. Our proposal is to upgrade the linac to 10 MW average power and 28 Hz, producing 14 pulses/s for neutron production and 14 pulses/s for neutrino production. Furthermore, because of the high current required in the pulsed neutrino horn, the length of the pulses used for neutrino production needs to be compressed to a few mu s with the aid of an accumulator ring. A long baseline experiment using this Super Beam and a megaton underground Water Cherenkov detector located in existing mines 300-600 km from Lund will make it possible to discover leptonic CP violation at 5 sigma significance level in up to 50% of the leptonic Dirac CP-violating phase range. This experiment could also determine the neutrino mass hierarchy at a significance level of more than 3 sigma if this issue will not already have been settled by other experiments by then. The mass hierarchy performance could be increased by combining the neutrino beam results with those obtained from atmospheric neutrinos detected by the same large volume detector. This detector will also be used to measure the proton lifetime, detect cosmological neutrinos and neutrinos from supernova explosions. Results on the sensitivity to leptonic CP violation and the neutrino mass hierarchy are presented.
  •  
45.
  • Beyder, Arthur, et al. (författare)
  • Loss-of-Function of the Voltage-Gated Sodium Channel Na(V)1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome
  • 2014
  • Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 146:7, s. 1659-1668
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na(V)1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
  •  
46.
  • Beyder, Arthur, et al. (författare)
  • Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
  • 2014
  • Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 146:7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
  •  
47.
  • Bi, Zhaoxia, et al. (författare)
  • High In-content InGaN nano-pyramids : Tuning crystal homogeneity by optimized nucleation of GaN seeds
  • 2018
  • Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 123:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Uniform arrays of submicron hexagonal InGaN pyramids with high morphological and material homogeneity, reaching an indium composition of 20%, are presented in this work. The pyramids were grown by selective area metal-organic vapor phase epitaxy and nucleated from small openings in a SiN mask. The growth selectivity was accurately controlled with diffusion lengths of the gallium and indium species, more than 1 μm on the SiN surface. High material homogeneity of the pyramids was achieved by inserting a precisely formed GaN pyramidal seed prior to InGaN growth, leading to the growth of well-shaped InGaN pyramids delimited by six equivalent 10 1 ̄ 1 facets. Further analysis reveals a variation in the indium composition to be mediated by competing InGaN growth on two types of crystal planes, 10 1 ̄ 1 and (0001). Typically, the InGaN growth on 10 1 ̄ 1 planes is much slower than on the (0001) plane. The formation of the (0001) plane and the growth of InGaN on it were found to be dependent on the morphology of the GaN seeds. We propose growth of InGaN pyramids seeded by 10 1 ̄ 1-faceted GaN pyramids as a mean to avoid InGaN material grown on the otherwise formed (0001) plane, leading to a significant reduction of variations in the indium composition in the InGaN pyramids. The InGaN pyramids in this work can be used as a high-quality template for optoelectronic devices having indium-rich active layers, with a potential of reaching green, yellow, and red emissions for LEDs.
  •  
48.
  • Bi, Zhaoxia, et al. (författare)
  • InN quantum dots on GaN nanowires grown by MOVPE
  • 2014
  • Ingår i: physica status solidi (c). - : Wiley. - 1862-6351 .- 1610-1642 .- 1610-1634. ; 11, s. 421-424
  • Tidskriftsartikel (refereegranskat)abstract
    • In this work, growth of InN quantum dots (QDs) on GaN nanowires (NWs) by metal-organic vapour phase epitaxy is demonstrated, illustrating the feasibility to combine 0D and 1D structures for nitride semiconductors. Selective area growth was used to generate arrays of c-oriented GaN NWs using Si3N4 as the mask material. In general, InN QDs tend to form at the NW edges between the m-plane side facets, but the QD growth can also be tuned to the side facets by controlling the growth temperature and the growth rate. TEM characterization reveals that I1-type stacking faults are formed in the QDs and originate from the misfit dislocations at the InN/GaN interface. Photoluminescence measurement at 4 K shows that the peak shifts to high energy with reduced dot size. (C) 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
  •  
49.
  •  
50.
  • Bi, Zhaoxia, et al. (författare)
  • Self-assembled InN quantum dots on side facets of GaN nanowires
  • 2018
  • Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 123:16
  • Tidskriftsartikel (refereegranskat)abstract
    • Self-assembled, atomic diffusion controlled growth of InN quantum dots was realized on the side facets of dislocation-free and c-oriented GaN nanowires having a hexagonal cross-section. The nanowires were synthesized by selective area metal organic vapor phase epitaxy. A 3 Å thick InN wetting layer was observed after growth, on top of which the InN quantum dots formed, indicating self-assembly in the Stranski-Krastanow growth mode. We found that the InN quantum dots can be tuned to nucleate either preferentially at the edges between GaN nanowire side facets, or directly on the side facets by tuning the adatom migration by controlling the precursor supersaturation and growth temperature. Structural characterization by transmission electron microscopy and reciprocal space mapping show that the InN quantum dots are close to be fully relaxed (residual strain below 1%) and that the c-planes of the InN quantum dots are tilted with respect to the GaN core. The strain relaxes mainly by the formation of misfit dislocations, observed with a periodicity of 3.2 nm at the InN and GaN hetero-interface. The misfit dislocations introduce I1 type stacking faults (...ABABCBC...) in the InN quantum dots. Photoluminescence investigations of the InN quantum dots show that the emissions shift to higher energy with reduced quantum dot size, which we attribute to increased quantum confinement.
  •  
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