Genetic Regulation of Puberty Timing in Humans.

Understanding the regulation of puberty timing has relevance to developmental and human biology and to the pathogenesis of various diseases. Recent large-scale genome-wide association studies on puberty timing and adult height, body mass index (BMI) and central body shape provide evidence for shared biological mechanisms that regulate these traits. There is a substantial genetic overlap between age at menarche in women and BMI, with almost invariable directional consistency with the epidemiological associations between earlier menarche and higher BMI. By contrast, the genetic loci identified for age at menarche are largely distinct from those identified for central body shape, while alleles that confer earlier menarche can be associated with taller or shorter adult height. The findings of population-based studies on age at menarche show increasing relevance for other studies of rare monogenic disorders and enrich our understanding of the mechanisms that regulate the timing of puberty and reproductive function.This work was supported by the MRC.This is the author accepted manuscript. The final version is available from Karger at http://www.karger.com/Article/Abstract/43102

SAM68 is required for regulation of Pumilio by the NORAD long noncoding RNA

The number of known long noncoding RNA (lncRNA) functions is rapidly growing, but how those functions are encoded in their sequence and structure remains poorly understood. NORAD (noncoding RNA activated by DNA damage) is a recently characterized, abundant, and highly conserved lncRNA that is required for proper mitotic divisions in human cells. NORAD acts in the cytoplasm and antagonizes repressors from the Pumilio family that bind at least 17 sites spread through 12 repetitive units in NORAD sequence. Here we study conserved sequences in NORAD repeats, identify additional interacting partners, and characterize the interaction between NORAD and the RNA-binding protein SAM68 (KHDRBS1), which is required for NORAD function in antagonizing Pumilio. These interactions provide a paradigm for how repeated elements in a lncRNA facilitate function.</jats:p

Elucidating the genetic basis of social interaction and isolation.

The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study participants, we perform genome-wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P < 5 × 10-8) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation

Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study.

Early puberty timing is associated with higher risks for type 2 diabetes (T2D) and cardiovascular disease in women and therefore represents a potential target for early preventive interventions. We characterised the range of diseases and other adverse health outcomes associated with early or late puberty timing in men and women in the very large UK Biobank study. Recalled puberty timing and past/current diseases were self-reported by questionnaire. We limited analyses to individuals of White ethnicity (250,037 women; 197,714 men) and to disease outcomes with at least 500 cases (~ 0.2% prevalence) and we applied stringent correction for multiple testing (corrected threshold P < 7.48 × 10(-5)). In models adjusted for socioeconomic position and adiposity/body composition variables, both in women and men separately, earlier puberty timing was associated with higher risks for angina, hypertension and T2D. Furthermore, compared to the median/average group, earlier or later puberty timing in women or men was associated with higher risks for 48 adverse outcomes, across a range of cancers, cardio-metabolic, gynaecological/obstetric, gastrointestinal, musculoskeletal, and neuro-cognitive categories. Notably, both early and late menarche were associated with higher risks for early natural menopause in women. Puberty timing in both men and women appears to have a profound impact on later health.This research has been conducted using the UK Biobank Resource. This work was supported by the Medical Research Council [Unit Programme number MC_UU_12015/2].This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/srep1120

Identifying genetic variants that affect viability in large cohorts

A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.Medical Research Council (Unit Programme number MC_UU_12015/2). This grant supported FRD and JRBP. National Institutes of Health (NIH) (grant number R01GM121372). This grant is to MP and JKP. National Institutes of Health (NIH) (grant number R01MH106842). This grant is to JKP. Columbia University. This research was funded in part by a Research Initiative in Science and Engineering grant to MP and JKP. National Institutes of Health (NIH) (grant number R01GM115889). This grant is to Guy Sella, provided partial support for HM

Events in Early Life are Associated with Female Reproductive Ageing: A UK Biobank Study.

The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence ('early-life risk factors') could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006-2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls (menopause/pre-menopausal at ≥ 45 years), in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82, P = 8.0 × 10(-9), fully-adjusted model). Earlier age at menarche (odds ratio = 1.03, confidence interval: 1.01, 1.06, P = 2.5 × 10(-6)) and earlier year of birth were also associated with EM (odds ratio = 1.02, confidence interval: 1.00, 1.04, P = 8.0 × 10(-6)). We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.This research has been conducted using the UK Biobank Resource. This work was generously supported by a Wellcome Trust Institutional Strategic Support Award [WT097835MF to University of Exeter].This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2471

Exploring the genetic correlations of antisocial behaviour and life history traits.

UNLABELLED: Prior evolutionary theory provided reason to suspect that measures of development and reproduction would be correlated with antisocial behaviours in human and non-human species. Behavioural genetics has revealed that most quantitative traits are heritable, suggesting that these phenotypic correlations may share genetic aetiologies. We use genome-wide association study data to estimate the genetic correlations between various measures of reproductive development (N = 52 776-318 863) and antisocial behaviour (N = 31 968). Our genetic correlation analyses demonstrate that alleles associated with higher reproductive output (number of children ever born, r g = 0.50, P = 0.0065) were positively correlated with alleles associated with antisocial behaviour, whereas alleles associated with more delayed reproductive onset (age at first birth, r g = -0.64, P = 0.0008) were negatively associated with alleles linked to antisocial behaviour. Ultimately, these findings coalesce with evolutionary theories suggesting that increased antisocial behaviours may partly represent a faster life history approach, which may be significantly calibrated by genes. DECLARATION OF INTEREST: None

Confronting Standard Models of Proto–Planetary Disks With New Mid–Infrared Sizes from the Keck Interferometer

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.The accepted author manuscript is in ORE at http://hdl.handle.net/10871/21611We present near- and mid-infrared (MIR) interferometric observations made with the Keck Interferometer Nuller and near-contemporaneous spectro-photometry from the infrared telescope facilities (IRTFs) of 11 well-known young stellar objects, several of which were observed for the first time in these spectral and spatial resolution regimes. With au-level spatial resolution, we first establish characteristic sizes of the infrared emission using a simple geometrical model consisting of a hot inner rim and MIR disk emission. We find a high degree of correlation between the stellar luminosity and the MIR disk sizes after using near-infrared data to remove the contribution from the inner rim. We then use a semi-analytical physical model to also find that the very widely used "star + inner dust rim + flared disk" class of models strongly fails to reproduce the spectral energy distribution (SED) and spatially resolved MIR data simultaneously; specifically a more compact source of MIR emission is required than results from the standard flared disk model. We explore the viability of a modification to the model whereby a second dust rim containing smaller dust grains is added, and find that the 2-rim model leads to significantly improved fits in most cases. This complexity is largely missed when carrying out SED modeling alone, although detailed silicate feature fitting by McClure et al. recently came to a similar conclusion. As has been suggested recently by Menu et al., the difficulty in predicting MIR sizes from the SED alone might hint at "transition disk"-like gaps in the inner au; however, the relatively high correlation found in our MIR disk size versus stellar luminosity relation favors layered disk morphologies and points to missing disk model ingredients instead.M.S. was supported by NASA ADAP grant NNX09AC73G. R.W.R. was supported by the IR&D program of The Aerospace Corporation

Technology mediator: a new role for the reference librarian?

The Arizona Health Sciences Library has collaborated with clinical faculty to develop a federated search engine that is useful for meeting real-time clinical information needs. This article proposes a technology mediation role for the reference librarian that was inspired by the project, and describes the collaborative model used for developing technology-mediated services for targeted users