Investigating the shared genetic basis and causal relationships between mucosa-associated lymphoid tissue inflammation and psychiatric disorders.

Background: Chronic and acute inflammation of the mucosa-associated lymphoid tissue have been positively linked to the development of psychiatric disorders in observational studies. However, it remains unclear whether this association is causal. In the present study, we investigated this association, using as proxies genetically predicted tonsillectomy, appendectomy and appendicitis on psychiatric disorders including major depressive disorder (MDD), schizophrenia (SCZ), bipolar depression (BD) and anxiety (ANX) via a two-sample Mendelian randomization (MR) analysis. Methods: Genetic association summary statistics for tonsillectomy, appendectomy and appendicitis were sourced from FinnGen Consortium, comprising data from 342,000 participants. Genetic correlations between all exposures and outcome were calculated with Linkage Disequilibrium Score (LDSC) Regression analysis. MR estimates were then calculated to assess their impact on the risk of developing psychiatric disorders. Sensitivity analysis was employed to test for any directional pleiotropy. Results: Our results suggest that there is no direct causal association between tonsillectomy, appendectomy or appendicitis with a heightened risk for development of psychiatric disorders. The robustness of the results of the main MR analysis was further confirmed with additional sensitivity analyses. However, a moderate inverse genetic correlation was observed between tonsillectomy and MDD traits (rg=-0.39, p-value (P)=7.5x10-5). Conclusion: Our findings provide, for the first time, evidence that there is no causal association between tonsillectomy or appendectomy on subsequent vulnerability of developing psychiatric disorders. Future studies using larger sample size GWAS should focus on unraveling the confounding factors and mediators to investigate this relationship further.

Palaeogenomic insights into the origins of early settlers on the island of Cyprus.

Archaeological evidence supports sporadic seafaring visits to the Eastern Mediterranean island of Cyprus by Epipaleolithic hunter-gatherers over 12,000 years ago, followed by permanent settlements during the early Neolithic. The geographical origins of these early seafarers have so far remained elusive. By systematically analysing all available genomes from the late Pleistocene to early Holocene Near East (c. 14,000-7000 cal BCE), we provide a comprehensive overview of the genetic landscape of the early Neolithic Fertile Crescent and Anatolia and infer the likely origins of three recently published genomes from Kissonerga-Mylouthkia (Cypriot Late Pre-Pottery Neolithic B, c. 7600-6800 cal BCE). These appear to derive roughly 80% of their ancestry from Aceramic Neolithic Central Anatolians residing in or near the Konya plain, and the remainder from a genetically basal Levantine population. Based on genome-wide weighted ancestry covariance analysis, we infer that this admixture event took place roughly between 14,000 and 10,000 BCE, coinciding with the transition from the Cypriot late Epipaleolithic to the Pre-Pottery Neolithic A (PPNA). Additionally, we identify strong genetic affinities between the examined Cypro-LPPNB individuals and later northwestern Anatolians and the earliest European Neolithic farmers. Our results inform archaeological evidence on prehistoric demographic processes in the Eastern Mediterranean, providing important insights into early seafaring, maritime connections, and insular settlement.

Appraising the Causal Role of Risk Factors in Coronary Artery Disease and Stroke: A Systematic Review of Mendelian Randomization Studies.

BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease and stroke. METHODS AND RESULTS MR studies investigating the association of any genetically predicted exposure with coronary artery disease or stroke were identified. Studies were classified into 4 categories built on the significance of the main MR analysis results and its concordance with sensitivity analyses, namely, robust, probable, suggestive, and insufficient. Studies reporting associations that did not perform any sensitivity analysis were classified as nonevaluable. We identified 2725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive, and 926 had insufficient evidence. The most robust associations were observed for anthropometric traits, lipids, and lipoproteins and type 2 diabetes with coronary artery; disease and clinical measurements with coronary artery disease and stroke; and thrombotic factors with stroke. CONCLUSIONS Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. Approximately half of the studies reporting associations presented an MR sensitivity analysis along with the main analysis that further supported the causality of associations. Future research should focus on more thorough assessments of sensitivity MR analyses and further assessments of mediation effects or nonlinearity of associations.

Genetic Study of Early Onset Parkinson's Disease in Cyprus.

Parkinson's Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)-the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus.

Prediction of Parkinson's Disease Risk Based on Genetic Profile and Established Risk Factors.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with already established PD-environmental/lifestyle factors. METHODS: Genotypic and lifestyle/environmental data on 235 PD-patients and 464 controls were obtained from a previous study carried out in the Cypriot population. A PRS was calculated for each individual. Univariate logistic-regression analysis was used to assess the association of PRS and each risk factor with PD-status. Stepwise-regression analysis was used to select the best predictive model for PD combining genetic and lifestyle/environmental factors. RESULTS: The 12-SNPs PRS was significantly increased in PD-cases compared to controls. Furthermore, univariate analyses showed that age, head injury, family history, depression, and Body Mass Index (BMI) were significantly associated with PD-status. Stepwise-regression suggested that a model which includes PRS and seven other independent lifestyle/environmental factors is the most predictive of PD in our population. CONCLUSIONS: These results suggest an association between both genetic and environmental factors and PD, and highlight the potential for the use of PRS in combination with the classical risk factors for risk prediction of PD.

Incidence of mild cognitive impairment in the elderly population in Greece: results from the HELIAD study.

BACKGROUND: There are no published data on Mild Cognitive Impairment (MCI) incidence in people over 65 years of age in Greece, relevant literature is scarce for Southern Europe, and reported rates worldwide show great variability. AIMS: To investigate the incidence and risk factors of MCI and its subtypes in the elderly population in Greece. METHODS: The incidence cohort of the HELIAD study (Hellenic Epidemiological Longitudinal Investigation of Aging and Diet) comprised 955 individuals who received full neurological and neuropsychological evaluation on two separate occasions about three years apart. RESULTS: The MCI incidence rate in our cohort is 54.07 new cases per 1000 person-years, standardized by age and sex to 59.99. Each additional year of age over 65 raises the probability of novel MCI by 6.2%, while lower educational attainment more than doubles the risk for incident MCI. Apolipoprotein E-ε4 (APOE-ε4) carriage results in increased risk for MCI by more than 1.7 times. Incidence rates for amnestic MCI are slightly higher than for the non-amnestic subtype, and AD is the most common potential underlying etiology. DISCUSSION: The MCI incidence rate in the Greek population over 65 years of age is 54/1000 person-years. Advanced age and APOE-ε4 carriage are predisposing factors, while higher educational attainment was found to exert a protective effect. CONCLUSIONS: MCI incidence in people over 65 years-old in Greece is consistent with reported rates around the world. Larger studies encompassing neuroimaging and cerebrospinal fluid biomarkers will hopefully shed more light on MCI epidemiology in Greece in the future.

Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn's Disease and Ulcerative Colitis: A Mendelian Randomization Study.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC. METHODS: We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances-nicotine, alcohol, and caffeine-to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy. RESULTS: We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P > 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found. CONCLUSIONS: We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.

Dementia Incidence in the Elderly Population of Greece: Results From the HELIAD Study.

OBJECTIVES: Recently a declining trend in dementia incidence rates has been reported in high-income countries. We investigated dementia incidence in a representative sample of the Greek population in the age group of 65 years and above. METHODS: This research is part of the Hellenic Epidemiological Longitudinal Investigation of Aging and Diet (HELIAD). The incidence cohort consisted of 1072 participants who were reevaluated after a mean period of 3.09 years. RESULTS: The incidence rate of dementia was 19.0 cases per 1000 person-years (age-standardized and sex-standardized incidence: 25.4/1000 person-years), of which 16.3 per 1000 person-years were attributable to Alzheimer disease. Each additional year of age increased dementia risk by 19.3% and each additional year of education decreased dementia risk by 12.1%. Apolipoprotein E (APOE)-ε4 homozygous participants were 18 times more likely to be diagnosed with dementia. A baseline diagnosis of mild cognitive decline (MCI) resulted in a risk for dementia increased by 3.7 times compared with the cognitively normal; in participants with MCI at baseline, APOE-ε4 carriage increased dementia risk by 4.5 times. CONCLUSIONS: The incidence rate of dementia in people 65 years and above in Greece is generally consistent with recently published rates in Europe and North America. Advancing age, baseline MCI, and APOE-ε4 homozygosity are risk factors, while higher educational attainment seems protective.