| 1. |
- Horikoshi, Momoko, et al.
(författare)
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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| 2. |
- Koller, Daniel L., et al.
(författare)
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Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women
- 2013
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 28:3, s. 547-558
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n=4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p=1.7x109) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p=1.3x108) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5597 for femoral neck; n=4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3x1011; ESR1/C6orf97 joint p=1.4x1010). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1x105). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. (c) 2013 American Society for Bone and Mineral Research.
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| 3. |
- Paternoster, Lavinia, et al.
(författare)
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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
- 2013
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n=5,878) followed by replication (n=1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p=3.6×10⁻¹⁴; LOC285735, rs271170, p=2.7×10⁻¹²; OPG, rs7839059, p=1.2×10⁻¹⁰; and ESR1/C6orf97, rs6909279, p=1.1×10⁻⁹). The trabecular vBMD GWA meta-analysis (n=2,500) followed by replication (n=1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p=1.9×10⁻⁹). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n=729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
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| 4. |
- Petherick, L., et al.
(författare)
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Climatic records over the past 30 ka from temperate Australia - a synthesis from the Oz-INTIMATE workgroup
- 2013
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 74, s. 58-77
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Tidskriftsartikel (refereegranskat)abstract
- Temperate Australia sits between the heat engine of the tropics and the cold Southern Ocean, encompassing a range of rainfall regimes and falling under the influence of different climatic drivers. Despite this heterogeneity, broad-scale trends in climatic and environmental change are evident over the past 30 ka. During the early glacial period (similar to 30-22 ka) and the Last Glacial Maximum (similar to 22-18 ka), climate was relatively cool across the entire temperate zone and there was an expansion of grasslands and increased fluvial activity in regionally important Murray Darling Basin. The temperate region at this time appears to be dominated by expanded sea ice in the Southern Ocean forcing a northerly shift in the position of the oceanic fronts and a concomitant influx of cold water along the southeast (including Tasmania) and southwest Australian coasts. The deglacial period (similar to 18-12 ka) was characterised by glacial recession and eventual disappearance resulting from an increase in temperature deduced from terrestrial records, while there is some evidence for climatic reversals (e.g. the Antarctic Cold Reversal) in high resolution marine sediment cores through this period. The high spatial density of Holocene terrestrial records reveals an overall expansion of sclerophyll woodland and rainforest taxa across the temperate region after similar to 12 ka, presumably in response to increasing temperature, while hydrological records reveal spatially heterogeneous hydro-climatic trends. Patterns after similar to 6 ka suggest higher frequency climatic variability that possibly reflects the onset of large scale climate variability caused by the El Nino/Southern Oscillation.
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