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  • 1
    Keywords: CANCER ; IDENTIFICATION ; MUTATIONS ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; LAMB2
    Abstract: More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only approximately 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P〈5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 x 10(-13)) and FAAH2 (rs5914101, P=4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain approximately 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
    Type of Publication: Journal article published
    PubMed ID: 26239645
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  • 2
    Keywords: CELLS ; DISEASE ; GENE-EXPRESSION ; VARIANTS ; REVEALS ; BREAST-CANCER RISK ; METAANALYSIS ; WIDE ASSOCIATION ; CENTRAL PRECOCIOUS PUBERTY ; HUMAN PREFRONTAL CORTEX
    Abstract: 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-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), 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 (P 〈 5 x 10(-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 gamma-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.
    Type of Publication: Journal article published
    PubMed ID: 25231870
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  • 3
    ISSN: 1573-739X
    Keywords: Beclomethasone ; Chromatography, high pressure liquid ; Chromatography, thin layer ; Drug compounding ; Drug stability ; Enema ; Mesalazine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A beclomethasone dipropionate (BDP) enema and a BDP/mesalazine combination enema (containing 2 mg BDP and 1 g mesalazine and 2 mg BDP, respectively per 40 ml) were formulated. BDP and mesalazine were suspended in a carbomer-water gel. No degradation of BDP was measured during the storage period of the BDP enema (4 weeks at 20°C) and of the BDP/mesalazine enema (44 days at 4°C, 20°C and 37°C, respectively). Progressive darkening of colour occurred for the BDP/mesalazine enema during storage at 20°C and at 37°C, probably induced by mesalazine degradation products. Only very slight colouring was observed at 4°C. Hardly any precipitation of BDP and mesalazine was seen during the storage period and the enemas could easily be resuspended.
    Type of Medium: Electronic Resource
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