Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10(-8)), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10(-12)) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10(-10)). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants;thirteen of the chronotype signals remained associated at P<5x10(-8) on meta-analysis and eleven of these reached P< 0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10(-8)). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10(-16)) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10(-9);and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10(-9)). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05);undersleeping and BMI (rG = 0.147, P = 1x10(-5)) and over-sleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans

Testing mutual exclusivity of ETS rearranged prostate cancer

Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 5′ fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements

Symptoms in the lives of terminal cancer patients: which is the most important?

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LocusZoom plot of chronotype associations in the <i>PER2</i> locus.

<p>Variants are coloured by their LD r² with lead variant rs75804782 and those with association <i>P</i>-values > 0.01 were omitted for clarity.</p

LocusZoom plots of sleep duration associations in the <i>VRK2</i> locus.

<p>Both plots show the same locus but each highlights a different lead variant: rs1380703 (left) and rs17190618 (right). Variants with association <i>P</i>-values > 0.01 were omitted for clarity. The two leads variants represent separate signals.</p

Genetic variants associated with chronotype (as either a continuous or binary trait) at <i>P</i><5x10^-8 in the UK Biobank study.

<p>Variants highlighted in bold were not identified by the 23andMe study, those in italic did not reach genome-wide significance on meta-analysis and those not highlighted replicate previously reported loci from 23andMe. Genes listed are candidate or nearest genes within 250Kb of the lead SNP. Odds ratios correspond to risk of morningness over eveningness. Beta, OR and frequency refers to A1. Replication data is based on continuous data and as the replication beta is in different units to the discovery GWAS beta, a P-value meta-analysis was performed.</p

Manhattan and quantile-quantile (QQ) plots for chronotype.

<p>Summary information plots for inverse-normalised (self-report) Sleep Duration vs. ~16.8 million imputed genetic variants in 127,573 White British individuals in the UK Biobank study. The Manhattan plot (top) shows association test (-log₁₀ <i>P</i>-value on the y-axis against physical autosomal location on the x-axis with the standard genome-wide significance cutoff of <i>P</i> = 5x10^-8 shown by the horizontal black line. Variants tested had imputation R²>0.4, a Hardy-Weinberg Equilibrium (HWE) <i>P</i>-value > 1x10^-6 and minor allele frequency (MAF) > 0.1%. The Sleep Duration QQ plot (bottom) identifies some inflation (λ_GC = 1.097) but, as with Chronotype, this is consistent with expected inflation from a highly polygenic trait in such a large sample size [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006125#pgen.1006125.ref015" target="_blank">15</a>].</p