Type 2 Diabetes (T2D) is an increasingly prevalent health problem and better understanding of its etiology is vital for improved prevention and treatment. It is known that T2D has multifactorial origin and mental health problems seem to accompany this progressive disorder. Of note, there is a bidirectional association between T2D and depression. One explanation for this relationship between T2D and depression could be the presence of pleiotropic genetic variants and possibly shared biological pathways. However, the underlying mechanisms remain poorly understood. Another possible common biological mechanism underlying T2D and depression comorbidity is related to disrupted circadian rhythms. It has been well established that many common disorders have seasonal fluctuations and it has been hypothesized that the amount of daylight might play an important role in seasonal fluctuations of both mental health conditions, glucose metabolism and T2D. The amount of daylight varies substantially throughout the year in Finland, making it one of the best locations to study this phenomenon. This research explores the shared genetic basis of T2D and depression as limited information exists on shared genetic risk of these conditions. Furthermore, another possible biological mechanism associated with both T2D and depression – circadian rhythm – has received limited research attention and is thus one of the focus areas of current thesis in relation to glucose metabolism. This research aims to provide better understanding in the genetic basis of increasingly prevalent health problems of T2D depression. The indicated knowledge together with understanding environmental effects of these prevalent conditions is needed in development of intervention strategies in light of the diabetes epidemic. Thus, this thesis focuses on four objectives. The first objective of this doctoral thesis is to examine whether there is a common genetic basis of T2D, glycemic indices related to T2D, and depressive symptoms. The second objective is to examine which specific genetic variants show common variation between glycemic indices and depressive symptoms. The third aim is to study if a common diabetes risk variant rs10830963 in the Melatonin Receptor 1B (MTNR1B) gene influences the relationship between depressive symptoms and glycemic indices. The final aim of this doctoral thesis is to investigate to what extent the amount of daylight moderates the associations between MTNR1B rs10830963 and glycemic indices. The first two objectives are addressed in Study I, objective three in Study II and objective four in study III. Study I is based on the summary statistics data from previously published Genome-Wide Association Studies (GWAS) of depressive symptoms by CHARGE consortium, T2D by Diagram consortium and glycemic traits by MAGIC consortium. GWAS on depressive symptoms involved 51,258 participants, GWAS on T2D involved 34,840 cases and 114,981 controls, GWAS on glycemic traits involved up to 58,074 participants. Studies II-III are conducted within the same Prevalence, Prediction and Prevention of Diabetes, the PPP-Botnia Study cohort. This prospective study cohort comprises 5,208 individuals at baseline visit and 3,850 individuals at follow-up, on average 6.8 years later. The analytic sample of Study II involved 4,455 non-diabetic participants from the baseline visit who were genotyped for MTNR1B rs10830963, had data on glycemic indices available based on an Oral Glucose Tolerance Test (OGTT) and additionally had data on depressive symptoms measured using Mental Health Inventory (MHI). The analytic sample of Study III involved 3,422 participants who had data on glycemic indices at both time points, were genotyped for MTNR1B rs10830963 and had no diabetes at baseline. The results of Study I showed that there was very low SNP-based heritability of the traits of interest and no overall SNP-based genetic correlation between glycemic traits or T2D and depressive symptoms. Yet, pleiotropic genetic variation for depressive symptoms and T2D was found in the IGF2BP2, CDKAL1, CDKNB-AS, and PLEKHA1 genes. Pleiotropic genetic variation for depressive symptoms and fasting glucose was found in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes. The results of Study II showed that the common diabetes risk variant rs10830963 in the MTNR1B gene and depressive symptoms are independently associated with glycemic traits. The associations between glycemic traits and depressive symptoms were not influenced by the variation in diabetes risk variant rs10830963. The results of Study III showed that each addition of the risk allele G of rs10830963 was associated with an increasingly worse glycemic profile across the 6.8-year follow-up. Additionally, more daylight was associated with worse glycemic response across the follow-up. Finally, the risk genotype GG of the MTNR1B rs10830963 became more insulin resistant during the follow-up, if the amount of daylight was less at the follow-up than at the baseline. Based on these findings, there are differences in underlying genetic background of glycemic traits, T2D and depressive symptoms. Additionally, on a candidate gene level, the known diabetes risk variant rs10830963 does not contribute significantly to the comorbidity between depression and diabetes. Yet, the rs10830963 and daylight are associated with glucose metabolism and the longitudinal glycemic profiles vary according to the amount of daylight, MTNR1B rs10830963 genotype and their interaction. This study contributes to the research literature in several ways. The findings provide valuable insights into the relationship of T2D and depression by addressing the common genetic background of these conditions. Furthermore, it emphasizes the importance of the amount of daylight in glucose metabolism and consequently T2D genesis.
|Status||Publicerad - 2019|
|MoE-publikationstyp||G5 Doktorsavhandling (artikel)|
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