Biology subjects

Frayling, T. M.

Publications and source records attributed to Frayling, T. M..

22 records · Page 2Linked to original sources

bioRxiv2017

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

Fibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21s therapeutic potential.

genetics↗

bioRxiv2017

Phenotypes associated with female X chromosome aneuploidy in UK Biobank: an unselected, adult, population-based cohort

Women with X chromosome aneuploidy such as 45,X (Turner syndrome) or 47,XXX (Triple X syndrome) present with characteristics including differences in stature, increased cardiovascular disease risk and primary ovarian insufficiency. Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the phenotypic penetrance is overestimated. Studies of prenatally ascertained X chromosome aneuploidy cases have limited follow-up data and so the long-term consequences into adulthood are often not reported. We aimed to characterise the prevalence and phenotypic consequences of X chromosome aneuploidy in a large population of women over 40 years of age. We detected 30 women with 45,X, 186 with mosaic 45,X/46,XX and 110 with 47,XXX among 244,848 UK Biobank women, using SNP array data. The prevalence of non-mosaic 45,X (1/8,162) and 47,XXX (1/2,226) was lower than expected, but was higher for mosaic 45,X/46,XX (1/1,316). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognised Turner syndrome phenotype, including a 17.2cm shorter stature (SD = 5.72cm; P = 1.5 x 10-53) and 16/30 did not report an age at menarche. The phenotype of women with 47,XXX included taller stature (5.3cm; SD = 5.52cm; P = 5.8 x 10-20), earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 x 10-14) and a lower fluid intelligence score (24%; SD = 29.7%; P = 3.7 x 10-8). In contrast, the characteristics of women with mosaic 45,X/46,XX were much less pronounced than expected. Women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. In conclusion, the availability of data from 244,848 women allowed us to assess the phenotypic penetrance of traits associated with X chromosome aneuploidy in an adult population setting. Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.\n\nFundingNone

genetics↗

bioRxiv2017

Genetic architecture of early childhood growth phenotypes gives insights into their link with later obesity

Early childhood growth patterns are associated with adult metabolic health, but the underlying mechanisms are unclear. We performed genome-wide meta-analyses and follow-up in up to 22,769 European children for six early growth phenotypes derived from longitudinal data: peak height and weight velocities, age and body mass index (BMI) at adiposity peak (AP ~9 months) and rebound (AR ~5-6 years). We identified four associated loci (P< 5x10-8): LEPR/LEPROT with BMI at AP, FTO and TFAP2B with Age at AR and GNPDA2 with BMI at AR. The observed AR-associated SNPs at FTO, TFAP2B and GNPDA2 represent known adult BMI-associated variants. The common BMI at AP associated variant at LEPR/LEPROT was not associated with adult BMI but was associated with LEPROT gene expression levels, especially in subcutaneous fat (P<2x10-51). We identify strong positive genetic correlations between early growth and later adiposity traits, and analysis of the full discovery stage results for Age at AR revealed enrichment for insulin-like growth factor 1 (IGF-1) signaling and apolipoprotein pathways. This genome-wide association study suggests mechanistic links between early childhood growth and adiposity in later childhood and adulthood, highlighting these early growth phenotypes as potential targets for the prevention of obesity.

genomics↗

bioRxiv2017

Red Blood Cell Distribution Width: genetic evidence for aging pathways in 116,666 volunteers

Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 166,666 UK Biobank human volunteers.\n\nA large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%). RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimers disease, longevity, age at menopause, bone density, myositis, Parkinsons disease, and age-related macular degeneration. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA and apoptosis.\n\nAlthough increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.

genomics↗