Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases.

PER3gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess:i) the frequency of allelic variants at twoPER3polymorphic sites (rs57875989 length polymorphism:PER3⁴,PER3⁵; rs228697 SNP:PER3^C,PER3^G) in relation to sleep-wake timing;ii) the effect of morning light on behavioural/circadian variables inPER3⁴/PER3⁴andPER3⁵/PER3⁵homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/mood questionnaires. 19PER3⁴/PER3⁴and 11PER3⁵/PER3⁵homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between thePER3^Gvariant and morningness (OR = 2.10), and between thePER3^G-PER3⁴haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/aMT6s rhythms betweenPER3⁵/PER3⁵andPER3⁴/PER3⁴subjects at baseline. After light administration,PER3⁴/PER3⁴subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed betweenPER3polymorphic variants/their combinations and both diurnal preference and the response to light.