Daily and seasonal rhythms in the endocrine system are co-ordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei (SCN) that is synchronised to solar time by inputs from the eyes. The SCN neurons act as circadian clocks and incorporate Period (Per) and Cryptochrome (Cry) genes. Mutations that alter the rate of transcription of Per and Cry genes or the stability of Per and Cry proteins affect clock speed 1. In Framingham off-spring study, clock variants have been associated with time of going to bed, sleepiness and sleep duration 2. There is also evidence of a role for clock variants in major depressive illness (where sleep disturbance is a feature), seasonal affective disorder (winter depression) 3, bipolar mental illness but little evidence for anxiety states 4.

Alcohol consumption has been shown to be linked to altered circadian rhythmicity in a complex bidirectional way. On one hand, animal studies suggest that "fetal exposure to ethanol significantly alters the clock mechanism governing the circadian function of beta-endorphin neurons"5, and increased drinking in adulthood has been suggested as a consequence of night-shift work 6 or severe jet lag 7. On the other hand, Spanagel et al published evidence on mPer2 mutant mice presenting increased consumption of self-administered ethanol, which was supported by a study among 215 patients with confirmed alcohol dependence 8. The effect seems to be specific to Per2, as no evidence was found for a differential ethanol reinforcement, seeking, or relapse behaviour in mPer1-mutant mice, compared to the wild type 9. Moreover, alterations of glutamatergic components resulted from deletion of mPer2 8 but not mPer1 9. The evidence on efficacy of acamprosate for relapse prevention in alcoholics 10, 11 and mPer2 mutant mice 8 supports a direct effect of hyperglutamatergic states in the brain on alcohol addiction. A haplotype composed of 4 SNPs (including the rare allele of the proposed SNP rs2304674) was found to be associated with lower alcohol consumption among Western European alcoholics (less than 300 g/d compared to (cubed)300 g/d), with one SNP in the haplotype possibly regulating transcriptional activation of Per2 8. However it is not clear whether the differential ethanol intake in mPer2 mutant mice and in the patients with the lower alcohol consumption haplotype was specifically due to altered circadian rhythmicity 12.

No further published evidence is available to date to confirm these findings in humans. We have recently investigated the association between Per2 variants rs56013895 and rs2304674 (two of those in Spanagel's paper 8) and alcohol consumption in the British Women Heart and Health Study (BWHHS). This is a cohort of British women aged 60-80 years, whose alcohol consumption is remarkably low. Excluding women of ethnicity different from 'white', we noted that the presence of the rare allele for the latter SNP was associated with lower alcohol consumption, and the effect was more pronounced for rare allele homozygotes Vs heterozygotes. Notably our results are in the same direction as those reported in 8, but are based on a population sample characterised by extremely different phenotype (moderate drinkers Vs alcoholics). This variant is common among Europeans (HapMap CEU minor allele frequency: 0.233). The other SNP (rs56013895) showed similar results, but is much more rare.

Given the initial evidence that this SNP is associated with alcohol drinking in groups with such different levels of the phenotype, we aim at replicating such findings in ALSPAC using genotype and alcohol data collected from the mothers. Moreover, since variations in hPer2 gene have been linked to morning preference and/or sleeping patterns, we will analyse independently offspring genotype in relation to detailed sleep data in the children.