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Meta-Analysis
. 2016 Aug 5;12(8):e1006125.
doi: 10.1371/journal.pgen.1006125. eCollection 2016 Aug.

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

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Free PMC article
Meta-Analysis

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

Samuel E Jones et al. PLoS Genet. .
Free PMC article

Abstract

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 oversleeping 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.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: DH and YH are current or former employees of and own stock or stock options in 23andMe, Inc. There are no other competing interests.

Figures

Fig 1
Fig 1. Manhattan and quantile-quantile (QQ) plots for chronotype.
Summary information plots for inverse-normalised (self-report) chronotype score vs. ~16.8 million imputed genetic variants in 127,898 White British individuals in the UK Biobank study. The Manhattan plot (top) shows association test (-log10 P-value on the y-axis against physical autosomal location on the x-axis. The standard genome-wide significance cutoff of P = 5x10-8 is shown by the horizontal black line. Variants tested had imputation R2>0.4, a Hardy-Weinberg Equilibrium (HWE) P-value > 1x10-6 and minor allele frequency (MAF) > 0.1%. The QQ (quantile-quantile) plot (bottom) identifies some inflation (λGC = 1.097) but this is consistent with expected inflation from a highly polygenic trait in such a large sample size [15].
Fig 2
Fig 2. LocusZoom plot of chronotype associations in the RGS16 locus.
The plot displays -log10 P-value on the y-axis and physical position on the x-axis. Points identify individual variants whose colour indicates their LD r2 with lead variant rs516134. The blue line indicates pre-calculated recombination rates (in cM/Mb) at each position. Variants with association P-values > 0.01 were omitted for clarity.
Fig 3
Fig 3. LocusZoom plot of chronotype associations in the PER2 locus.
Variants are coloured by their LD r2 with lead variant rs75804782 and those with association P-values > 0.01 were omitted for clarity.
Fig 4
Fig 4. Manhattan and quantile-quantile (QQ) plots for chronotype.
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 P-value on the y-axis against physical autosomal location on the x-axis with the standard genome-wide significance cutoff of P = 5x10-8 shown by the horizontal black line. Variants tested had imputation R2>0.4, a Hardy-Weinberg Equilibrium (HWE) P-value > 1x10-6 and minor allele frequency (MAF) > 0.1%. The Sleep Duration QQ plot (bottom) identifies some inflation (λGC = 1.097) but, as with Chronotype, this is consistent with expected inflation from a highly polygenic trait in such a large sample size [15].
Fig 5
Fig 5. LocusZoom plots of sleep duration associations in the VRK2 locus.
Both plots show the same locus but each highlights a different lead variant: rs1380703 (left) and rs17190618 (right). Variants with association P-values > 0.01 were omitted for clarity. The two leads variants represent separate signals.

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