8 research outputs found
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (Pâ<â5âĂâ10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and Îł-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition
Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis
Aim: To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis
(RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis
(NMA). Materials & methods: Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-
month confirmed disability progression (3mCDP and 6mCDP) were conducted. Results: For each outcome,
the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies:
alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for
3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP
definition used for included ofatumumab trials) for 6mCDP. Conclusion: The most efficacious DMTs for RMS
were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious
treatments (for ARR)
Serum- and Glucocorticoid-Inducible Kinase 1 Mediates Salt Sensitivity of Glucose Tolerance
Gene flow in the European coal tit, Periparus ater (Aves: Passeriformes): Low among Mediterranean populations but high in a continental contact zone
Extant phylogeographical patterns of Palearctic terrestrial vertebrates are generally believed to have originated from glacial range fragmentation. Post-Pleistocene range expansions have led to the formation of secondary contact zones among genetically distinct taxa. For coal tits (Periparus ater), such a contact zone has been localized in Germany. In this study, we quantified gene flow between Fennoscandian and southern European coal tits using a set of 13 microsatellite loci. STRUCTURE analysis revealed four genetic clusters, two occurring on Mediterranean islands. German populations were genetically admixed but introgression of southern alleles was evident for Fennoscandian populations. In the south, we found negligible introgression of northern alleles (and haplotypes) but slight admixture of two southern genetic clusters in the Pyrenees and on the Balkan Peninsula and near complete sorting of these two allelic lineages on the islands of Corsica and Sardinia. Genetic distinctiveness of the Mediterranean island populations reflects general patterns of endemism in the Corso-Sardinian fauna and the Cypriot fauna. Wide-range gene flow in Central Europe suggests a broad zone of intergradation between subspecies of the coal tit rather than a narrow contact zone. This is in accordance with low morphological and bioacoustic differentiation of European coal tit populations
Determination of the androgen receptor status of circulating tumour cells in metastatic breast cancer patients
Gene flow in the European coal tit, Periparus ater (Aves: Passeriformes): low among Mediterranean populations but high in a continental contact zone
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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (Pâ<â5âĂâ10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and Îł-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition