In the present study, to explore the potential influence of maternal smoking during pregnancy on sleep duration in female offspring, we conducted an observation study and GEWIS in UK Biobank cohort. Our results showed that maternal smoking during pregnancy can effect sleep duration in offspring, which were consistent with the previous study [16, 23].
We found that ankyrin repeat and LEM domain containing 2 (ANKLE2) achieved significant threshold in the GWGEIS for short sleep duration in females. ANKLE2 encodes a member of the LEM family of inner nuclear membrane proteins. The encoded protein functions as a mitotic regulator through postmitotic formation of the nuclear envelope. Previous research suggested that ANKLE2 regulates C. elegans nuclear envelope reassembly through barrier-to-autointegration factor (BAF) dehosphorylation . Mutations in this gene cause BAF hyperphosphorylation, which is an important DNA-binding protein that interacts with a unique structural motif called LAP2-Emerin-MAN1 (LEM) domain to establish a connection between chromatin and a family of proteins containing LEM domains . Now there is striking evidence that decreased number of glial cells and neuronal within the brain can lead to microcephaly [26, 27], sleep is associated with decreased neurons . And more recently studies have shown that ANKLE2 gene associated with Congenital microcephaly [29, 30], and it has been proved that genetic mutations can cause short sleep phenotype. Based on our study results, ANKLE2 may contribute to the dysfunction of female sleep regulation.
Myelin transcripyion factor 1 like (MYT1L) is another identified candidate gene, which encodes a member of the zinc finger superfamily of transcription factors. The encoded protein is part of a novel class of cystein-cystein-histidine-cystein zinc finger proteins that function in the animal central nervous system. It associated with neuronal cells and via indirect methods exerts its pro-neuronal function . MYT1L only expresses in the human brain, and plays a critical role in the developing central nervous system, which has been related to schizophrenia, intellectual disability, autism . Our results suggest that MYT1L can be considered as a potential gene affecting sleep, consistent with previous study . Enlarging the comparative analysis of MYT1L and other diseases, we found that several diseases regulated by MYT1L are related to sleep. For example, fibromyalgia associated with sleep disturbance and gene MYT1L is candidate gene fibromyalgia [33, 34]. Serpin family E member 2 (SERPINE2) is a member of the serpin family, a group of proteins that inhibit serine proteases. It is a susceptibility gene for chronic obstructive pulmonary disease and human tumors [35, 36]. It is well known that many chronic diseases are associated with sleep disorders, studies shown a significant association between short-term sleep and chronic obstructive pulmonary disease in female.
Until now, the biological mechanism of maternal smoking affecting offspring development remains largely known, but established studies could enhance our understanding of the relationship between maternal smoking during pregnancy and sleep duration in female offspring. On the one hand, smoking during pregnancy can have a long-term effect on offspring through hypothalamic-pituitary-adrenal axis [38, 39], and effects developing brain’s acetycholine neurotransmitter systems [40, 41]. On the other hand, smoking during pregnancy might affect early morphological changes of the placenta, resulting in a decreased surface area and volume of fetal capillaries [42, 43], inducing smaller head circumference at birth, and the identified gene ANKLE2 in our further confirmed this in a certain degree. These mechanisms may partly explain the effect of maternal smoking during pregnancy on the offspring's sleep duration.
With the development of science and technology in recent years, it has been commonly known that many diseases are affected by both the environment and genes. Own to the large sample and the rigorous design of UK Biobank, our results are credible and representative. Nevertheless, several limitations should be noticed. Firstly, though we could detect the influence of maternal smoking during pregnancy on offspring sleep duration, the information of indirect exposure to smoking is missing, such as, second-hand smoke. Secondly, the data of maternal smoking during pregnancy were driven from online questionnaire surveys, retrospective measurements and which may increase the possibility of recall bias and measurement. In addition, UK Biobank subjects were European whites, it should be cautious when popularize current studies results to other-race.
In summary, our results suggested effect that maternal smoking during pregnancy has effects on sleep duration in offspring, especially on short-term sleep, which may provide an essential information with the pregnancy health, and highlight the detrimental effect of smoking in health from new perspective.