| 1. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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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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| 2. |
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| 3. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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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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| 4. |
- Moayyeri, Alireza, et al.
(författare)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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| 5. |
- Daniel, Thomas F., et al.
(författare)
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The "Tetramerium Lineage" (Acanthaceae : Acanthoideae : Justicieae) : Delimitation and intra-lineage relationships based on cp and nrITS sequence data
- 2008
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Ingår i: Systematic Botany. - 0363-6445 .- 1548-2324. ; 33:2, s. 416-436
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Tidskriftsartikel (refereegranskat)abstract
- We used DNA sequence data from five genic regions (nrITS; chloroplast trnL-F, trnT-L, rps16, trnS-G) to study phylogenetic relationships of the Tetramerium lineage (Acanthaceae: Justicieae). From a sample of 70 species (representing 25 genera) previously affiliated with the Tetramerium lineage, 68 are included therein. Our analyses excluded Papuasian Calycacanthus and Neotropical Streblacanthus monospermus from the Tetramerium lineage; however, two species described in Justicia (J. gonzalezii and J. medranoi) and a Malagasy species of uncertain generic affinities are nested within the lineage. A monophyletic Tetramerium lineage consists of 23 currently recognized genera with at least 168 species, more than 70% of which occur in the New World. Old World Chlamydocardia and Clinacanthus are serially sister to all other members of the lineage. Other Old World taxa consist of: Ecbolium clade (all sampled species of Ecbolium plus Malagasy Populina richardii), Megalochlamys clade (Megalochlamys, Trichaulax and the unidentified Malagasy species), and two isolated taxa (Angkalanthus and Chorisochora). All analyses strongly support monophyly of the New World Tetramerium lineage. The basal clades of New World plants, all with nototribic flowers, are: 1) the taxonomically heterogeneous but palynologically consistent Mirandea clade, and 2) the Pachystachys clade + the South American Anisacanthus clade. The second is sister to all other NW plants, referred to here as the core Tetramerium lineage. We recognize five clades within the core Tetramerium lineage related as follows: (Henrya clade (Carlowrightia parviflora clade (North American Anisacanthus clade (core Carlowrightia clade + Tetramerium)))). Macromorphological synapomorphies are unknown for the Tetramerium lineage and for many of its constituent clades. However, we propose sternotribic flowers as synapomorphic for the core Tetramerium lineage, and flowers with the lower-central lobe of the corolla modified into a keel as a synapomorphy for a lineage consisting of Tetramerium and the core Carlowrightia clade. Palynological characters provide putative synapomorphies for some clades (e.g. Ecbolium clade, Mirandea clade) and autapomorphies for several species (e.g. Mexacanthus mcvaughii, Trichalux mwasumbii). An Old World origin is postulated for the Tetramerium lineage, and we posit a single dispersal event to America and subsequent extensive radiation there, especially in arid zones of Mexico and adjacent regions. Taxonomic implications of our results are extensive. Notably, many traditionally recognized genera (e.g. Anisacanthus, Carlowrightia, Mirandea) are not monophyletic and emphasis on floral form often has been phylogenetically misleading; for example, floral adaptations to pollination by hummingbirds have evolved at least eight times in the New World Tetramerium lineage.
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| 6. |
- McDade, Lucinda A., et al.
(författare)
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Phylogenetic placement, delimitation, and relationships among genera of the enigmatic Nelsonioideae (Lamiales: Acanthaceae)
- 2012
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Ingår i: Taxon. - : Wiley. - 0040-0262 .- 1996-8175. ; 61:3, s. 637-651
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Tidskriftsartikel (refereegranskat)abstract
- We took a two-tiered approach to test monophyly of Nelsonioideae and place the group within Lamiales, and to determine relationships among taxa within the group. Phylogenetic analysis of a molecular dataset (ndhF+trnL-F) for a broad sample of Lamiales supports monophyly of Nelsonioideae and places the clade with strong support as sister to a lineage composed of all other plants treated as Acanthaceae (Avicennia, Thunbergioideae, Acanthoideae). We propose to treat this entire group as Acanthaceae s.l. and hypothesize that indurate, explosively dehiscent capsules are a synapomorphy for the family, albeit with autapomorphic fruit types in Avicennia and Mendoncia. These results further support monophyly of family-level groups that have emerged from recent studies of Lamiales but are largely unsuccessful in resolving relationships among these groups, as also encountered by other workers. Our results contradict some aspects of relationships that have seemed resolved by earlier studies, notably among Byblidaceae, Scrophulariaceae, Thomandersia, and other Lamiales. Among Nelsonioideae, analysis of sequence data from rapidly evolving genic regions (trnS-G, ndhF-rpl32+rpl32-trnL((UAG)), nrITS) and a larger sample of nelsonioids (i.e., all genera and multiple taxa to represent the diversity of species-rich genera) indicates that Nelsonia and Elytraria are monophyletic with strong support, but with only moderate support for Nelsonia as the first branching clade and Elytraria sister to the remaining nelsonioids. An African clade comprising monospecific Saintpauliopsis sister to Anisosepalum (two of three species sampled) is sister to a clade that includes all sampled members of pantropical Staurogyne plus New World Gynocraterium and Asian Ophiorrhiziphyllon. Gynocraterium is sister to all sampled members of New World Staurogyne; this last clade is sister to a clade comprising the other sampled Staurogyne plus Ophiorrhiziphyllon, which is nested among Asian Staurogyne. The taxonomic implications of these patterns of relationship are discussed. Our results suggest that Nelsonioideae have a complex history of inter-continental dispersals compared to other lineages of Acanthaceae of similar to much larger size in terms of number of species, making it an interesting group for biogeographic study.
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| 7. |
- McDade, Lucinda A, et al.
(författare)
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Phylogenetic placement, delineation, and relationships among genera of the enigmatic Nelsonioideae (Lamiales: Acanthaceae)
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We took a two-tiered approach to test monophyly of Nelsonioideae and place the group within Lamiales, and to determine relationships among taxa within the group. Phylogenetic analysis of a molecular data set (ndhF + trnLF) for a broad sample of Lamiales supports monophyly of Nelsonioideae and places the clade with strong support as sister to a lineage composed of all other plants treated as Acanthaceae (i.e., Avicennia, Thunbergioideae, Acanthoideae). We propose to treat this entire group as Acanthaceae s.l. and advance indurate, explosively dehiscent capsules as a synapomorphy for the family, albeit with autapomorphic fruit types in Avicennia and Mendoncia. These results further support monophyly of family level groups that have emerged from recent studies of Lamiales but are largely not successful in resolving relationships among these groups, as also encountered by other workers. In fact, our results contradict some aspects of relationships that have seemed resolved by earlier studies, notably among Byblidaceae, Scrophulariaceae, Thomandersia, and other Lamiales. Among Nelsonioideae, analysis of sequence data from more rapidly evolving genic regions (i.e., trnS-G, ndhF-rpl32 + rpl32-trnL(UAG), nrITS) and a larger sample of nelsonioids (i.e., all genera and multiple taxa to represent the diversity of species-rich genera) indicates that Nelsonia and Elytraria are monophyletic with strong support but with only moderate support for Nelsonia as the first branching clade and Elytraria sister to the remaining nelsonioids. An African clade comprising monospecific Saintpauliopsis sister to Anisosepalum (2 of 3 species sampled) is sister to a clade that includes all sampled members of pantropical Staurogyne plus New World Gynocraterium and Asian Ophiorrhiziphyllon. Gynocraterium is sister to all sampled members of New World Staurogyne; this last clade is sister to a clade comprising the other sampled Staurogyne plus Ophiorrhiziphyllon which is nested among Asian Staurogyne. The taxonomic implications of these patterns of relationship are discussed. Our results suggest that Nelsonioideae have a complex history of inter-continental dispersals compared to other acanth lineages of similar to much larger size in terms of number of species, making it an interesting group for biogeographic study.
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| 8. |
- Nielson, Carrie M., et al.
(författare)
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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2
- 2016
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 31:12, s. 2085-2097
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (β=0.22, p=1.9×10-8) and decreased risk of radiographic vertebral fracture (odds ratio [OR]=0.75; false discovery rate [FDR] p=0.01). In 1p36.12, rs12742784 (MAF=21%) was associated with higher vBMD (β=0.09, p=1.2×10-10) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4×10-4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β=0.28, FDR p=0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β=0.12, FDR p=1.7×10-3, functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence.
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| 9. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.
- 2018
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
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Tidskriftsartikel (refereegranskat)abstract
- Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.To investigate the genetic regulation of serum E2 and E1 in men.Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Genetic determinants of serum E2 and E1 levels.Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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