Mixed-model Genome-wide Association Analysisof Sleep Duration in a Japanese Large Cohort
YuyaTamai ∗,Takeshi Nishiyama †Abstract — Though there have been several GWASof sleep duration, a small number of lociwerereplicated forthe association with sleep duration such as PAX8, CBWD2 and VPK2. Therefore, we conducted a GWAS ofsleep duration using a large Japanese cohort. In our linear mixed-model analysis of sleep duration, any locihave neither reached genome-wide significancepresumably due to limitations in sample size.Considering that
only two loci were discovered in a large-scale GWAS of sleep duration in 128,266 individuals, a GWAS orGWAS meta-analysis using more sample size will need to find further associated variants with sleep duration.

Keyword: Linear Mixed-model; genome-wide association study
1 Introduction
Usual sleep duration is heritable with heritability estimates being around 40%. Candidate gene association
studies for sleep duration identified a number of potential loci, though the results were inconsistent. A
GWAS of sleep duration have identified and replicated two SNPs near PAX8 and CBWD2 (Gottlieb et al.,2015). Recently, a large-scale GWAS using the UK biobank replicated association with PAX8 andidentified new loci, VPK2, and confirmed the association with VPK2 in other samples (Jones SEet al.,2016). However, the identified variants only account for a small amount of the variation in sleep duration.
Therefore, we conducted a GWAS of sleep duration using data from the Japan Multi-Institutional
Collaborative Cohort Study (J-MICC study) using a linear mixed-model (LMM).
2 Methods
2.1 Sample
The J-MICC study is one of the largest population-based cohort studies in Japan. The participants wereenrolled in 10 study areas throughout Japan except for the northern region. Phenotype information wasobtained from self-administered questionnaires at study entry. The ethics committees of all participating
institutions approved the protocol for the J-MICC study, and all participants provided written informedconsent. Genotyping was performed with the Illumina Infinium OmniExpressExome-8 BeadChip. In total,
513,776 SNPs in 14,088 participants passed our quality control criteria (MAF≥ 5%, HWE p-value ≥0.001 and call rate ≥ 95% for both individuals and markers).
2.2 Analysis
To perform LMM analysis of sleep duration adjusted for age and gender we used BOLT-LMM (Lohet al.,2015). BOLT-LMM reported no improvement of the non-infinitesimal mixed model test over thestandard infinitesimal test and thus we report the results based on the latter.
3 Results
Any loci have neither reached genome-wide significance (Table1 and Figure 1).

∗Dept. of Public Health, Nagoya City Univ. Graduate School of Medicine, 1Kawasumi, Mizuho-ku,Nagoya, 467-8601, Japan, E-mail: yuyatamai@gmail.com, Tel: +81-52-853-8176†Dept. of Public Health, Aichi Medical Univ. School of Medicine, 480-1195, Japan

Table 1: Results for the Top 10 SNPs
SNP

Chromosome

BetaP-value

exm-rs12229654

12-0.08

1.30E-07

exm329750

35.09

2.20E-07

rs2188380

12-0.08

2.20E-07

rs13153325

50.07

3.40E-07

rs4764852

12-0.06

9.90E-07

exm313929

34.76

1.30E-06

exm792711

94.76

1.30E-06

rs197146

194.76

1.30E-06

rs11874550

180.084.70E-06

rs6028312

200.06

5.20E-06

Figure 1: Manhattan Plot
4 Discussions and summary
We performed a GWAS of sleep duration in 14,088 individuals from the JMICC study but we could not
find any genome-wide significant signals. Considering that only two loci were discovered in a large-scale
GWAS of sleep duration in 128,266 individuals, this non-significant finding is presumably due tolimitations in sample size. A GWAS or GWAS meta-analysis using more sample size will need to findfurther associated variants with sleep duration.
AcknowledgmentThis work was partly supported by KAKENHI (15K06915; Grant-in-Aid (C)).
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