The Effect of Mediterranean Diet on Thyroid Gland Activity.

The main goal of this research was to determine whether there is a correlation between adherence to the Mediterranean diet (assessed by the Mediterranean Diet Serving Score (MDSS)) and parameters indicating thyroid gland activity, such as concentration of thyroid-stimulating hormone (TSH), thyroid hormones (free triiodothyronine (fT3), free thyroxine (fT4)), thyroglobulin (Tg), antibodies to thyroid proteins (thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb)), and calcitonin (CT) in plasma and serum samples. An additional objective was to investigate whether there are differences in the values of the MDSS among clinical groups (euthyroid individuals, euthyroid individuals with positive TgAb and/or TPOAb, and hypothyroid and hyperthyroid participants). This cross-sectional study included 4620 participants over 18 years of age from the islands of Korcula and Vis, and the mainland city of Split. The MDSS was assessed from a food frequency questionnaire (FFQ). MDSS values were significantly higher in females compared to males and showed a positive association with the age of the participants. There was no significant difference in the MDSS values among the examined clinical groups. In the group of subjects with euthyroidism, a significant positive association was found between fT3 and the MDSS, while in the group of subjects with subclinical hypothyroidism, a significant positive association was observed between the MDSS and both fT3 and fT4. CT levels were also positively associated with the MDSS. Considering the significant positive association of the MDSS and both fT3 and fT4 levels in patients with subclinical hypothyroidism, the results of this study could be used to create guidelines for selecting an appropriate, potentially protective diet for these patients.

Vitamin D and the Thyroid: A Critical Review of the Current Evidence.

Vitamin D is necessary for the normal functioning of many organs, including the thyroid gland. It is, therefore, not surprising that vitamin D deficiency is considered a risk factor for the development of many thyroid disorders, including autoimmune thyroid diseases and thyroid cancer. However, the interaction between vitamin D and thyroid function is still not fully understood. This review discusses studies involving human subjects that (1) compared vitamin D status (primarily determined by serum calcidiol (25-hydroxyvitamin D [25(OH)D]) levels) with thyroid function assessed by thyroid stimulating hormone (TSH), thyroid hormones, and anti-thyroid antibody levels; and (2) evaluated the effect of vitamin D supplementation on thyroid function. Due to the many inconsistencies in the results between the studies, it is still difficult to draw a definite conclusion on how vitamin D status affects thyroid function. Studies in healthy participants observed either a negative correlation or no association between TSH and 25(OH)D levels, while the results for thyroid hormones showed high variability. Many studies have observed a negative association between anti-thyroid antibodies and 25(OH)D levels, but equally many studies have failed to observe such an association. Regarding the studies that examined the effect of vitamin D supplementation on thyroid function, almost all observed a decrease in anti-thyroid antibody levels after vitamin D supplementation. Factors that could contribute to the high variability between the studies are the use of different assays for the measurement of serum 25(OH)D levels and the confounding effects of sex, age, body-mass index, dietary habits, smoking, and the time of year when the samples were collected. In conclusion, additional studies with larger numbers of participants are needed to fully understand the effect of vitamin D on thyroid function.

Role of ST6GAL1 in Thyroid Cancers: Insights from Tissue Analysis and Genomic Datasets.

Thyroid cancer is the predominant endocrine-related malignancy. ST6 ß-galactoside α2,6-sialyltransferase 1 (ST6GAL1) has been studied in various types of cancers; however, the expression and function of ST6GAL1 in thyroid cancer has not been investigated so far. Previously, we conducted two genome-wide association studies and have identified the association of the ST6GAL1 gene with plasma thyroglobulin (Tg) levels. Since Tg levels are altered in thyroid pathologies, in the current study, we wanted to evaluate the expression of ST6GAL1 in thyroid cancer tissues. We performed an immunohistochemical analysis using human thyroid tissue from 89 patients and analyzed ST6GAL1 protein expression in papillary thyroid cancer (including follicular variant and microcarcinoma) and follicular thyroid cancer in comparison to normal thyroid tissue. Additionally, ST6GAL1 mRNA levels from The Cancer Genome Atlas (TCGA, n = 572) and the Genotype-Tissue Expression (GTEx) project (n = 279) were examined. The immunohistochemical analysis revealed higher ST6GAL1 protein expression in all thyroid tumors compared to normal thyroid tissue. TCGA data revealed increased ST6GAL1 mRNA levels in both primary and metastatic tumors versus controls. Notably, the follicular variant of papillary thyroid cancer exhibited significantly higher ST6GAL1 mRNA levels than classic papillary thyroid cancer. High ST6GAL1 mRNA levels significantly correlated with lymph node metastasis status, clinical stage, and reduced survival rate. ST6GAL1 emerges as a potential cancer-associated glycosyltransferase in thyroid malignancies, offering valuable insights into its diagnostic and prognostic significance.

Genome-Wide Association Analysis and Genomic Prediction of Thyroglobulin Plasma Levels.

Thyroglobulin (Tg) is an iodoglycoprotein produced by thyroid follicular cells which acts as an essential substrate for thyroid hormone synthesis. To date, only one genome-wide association study (GWAS) of plasma Tg levels has been performed by our research group. Utilizing recent advancements in computation and modeling, we apply a Bayesian approach to the probabilistic inference of the genetic architecture of Tg. We fitted a Bayesian sparse linear mixed model (BSLMM) and a frequentist linear mixed model (LMM) of 7,289,083 variants in 1096 healthy European-ancestry participants of the Croatian Biobank. Meta-analysis with two independent cohorts (total n = 2109) identified 83 genome-wide significant single nucleotide polymorphisms (SNPs) within the ST6GAL1 gene (p<5×10-8). BSLMM revealed additional association signals on chromosomes 1, 8, 10, and 14. For ST6GAL1 and the newly uncovered genes, we provide physiological and pathophysiological explanations of how their expression could be associated with variations in plasma Tg levels. We found that the SNP-heritability of Tg is 17% and that 52% of this variation is due to a small number of 16 variants that have a major effect on Tg levels. Our results suggest that the genetic architecture of plasma Tg is not polygenic, but influenced by a few genes with major effects.

Environmental Factors That Affect Parathyroid Hormone and Calcitonin Levels.

Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate homeostasis in the body. Therefore, an understanding of environmental and genetic factors influencing PTH and calcitonin levels is crucial. Genetic factors are estimated to account for 60% of variations in PTH levels, while the genetic background of interindividual calcitonin variations has not yet been studied. In this review, we analyzed the literature discussing the influence of environmental factors (lifestyle factors and pollutants) on PTH and calcitonin levels. Among lifestyle factors, smoking, body mass index (BMI), diet, alcohol, and exercise were analyzed; among pollutants, heavy metals and chemicals were analyzed. Lifestyle factors that showed the clearest association with PTH levels were smoking, BMI, exercise, and micronutrients taken from the diet (vitamin D and calcium). Smoking, vitamin D, and calcium intake led to a decrease in PTH levels, while higher BMI and exercise led to an increase in PTH levels. In terms of pollutants, exposure to cadmium led to a decrease in PTH levels, while exposure to lead increased PTH levels. Several studies have investigated the effect of chemicals on PTH levels in humans. Compared to PTH studies, a smaller number of studies analyzed the influence of environmental factors on calcitonin levels, which gives great variability in results. Only a few studies have analyzed the influence of pollutants on calcitonin levels in humans. The lifestyle factor with the clearest relationship with calcitonin was smoking (smokers had increased calcitonin levels). Given the importance of PTH and calcitonin in maintaining calcium and phosphate homeostasis and bone mineral metabolism, additional studies on the influence of environmental factors that could affect PTH and calcitonin levels are crucial.

Environmental Factors Affecting Thyroid-Stimulating Hormone and Thyroid Hormone Levels.

Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that alters the levels of thyroid-stimulating hormone (TSH) and thyroid hormones is crucial. Genetic factors contribute up to 65% of interindividual variations in TSH and thyroid hormone levels, but many environmental factors can also affect thyroid function. This review discusses studies that have analyzed the impact of environmental factors on TSH and thyroid hormone levels in healthy adults. We included lifestyle factors (smoking, alcohol consumption, diet and exercise) and pollutants (chemicals and heavy metals). Many inconsistencies in the results have been observed between studies, making it difficult to draw a general conclusion about how a particular environmental factor influences TSH and thyroid hormone levels. However, lifestyle factors that showed the clearest association with TSH and thyroid hormones were smoking, body mass index (BMI) and iodine (micronutrient taken from the diet). Smoking mainly led to a decrease in TSH levels and an increase in triiodothyronine (T3) and thyroxine (T4) levels, while BMI levels were positively correlated with TSH and free T3 levels. Excess iodine led to an increase in TSH levels and a decrease in thyroid hormone levels. Among the pollutants analyzed, most studies observed a decrease in thyroid hormone levels after exposure to perchlorate. Future studies should continue to analyze the impact of environmental factors on thyroid function as they could contribute to understanding the complex background of gene-environment interactions underlying the pathology of thyroid diseases.

Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians.

Autoimmune thyroid diseases (AITD) are multifactorial endocrine diseases most frequently accompanied by Tg and TPO autoantibodies. Both antibodies have a higher prevalence in females and act under a strong genetic influence. To identify novel variants underlying thyroid antibody levels, we performed GWAS meta-analysis on the plasma levels of TgAb and TPOAb in three Croatian cohorts, as well as gender specific GWAS and a bivariate analysis. No significant association was detected with the level of TgAb and TPOAb in the meta-analysis of GWAS or bivariate results for all individuals. The bivariate analysis in females only revealed a genome-wide significant association for the locus near GRIN3A (rs4457391, P = 7.76 × 10-9). The same locus had borderline association with TPOAb levels in females (rs1935377, P = 8.58 × 10-8). In conclusion, we identified a novel gender specific locus associated with TgAb and TPOAb levels. Our findings provide a novel insight into genetic and gender differences associated with thyroid antibodies.

Thyroid hormone levels are associated with metabolic components: a cross-sectional study.

AIM: To analyze the association of thyroid function and hormone levels with metabolic syndrome (MetS) and its components. METHODS: This cross-sectional population-based study involved 2183 Croatian individuals with no history of thyroid disease, hypertension, diabetes, and hyperlipidemia. MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III criteria. RESULTS: We found no association between thyroid function groups and the prevalence of MetS and its components. Clinically hypothyroid participants showed significantly higher triceps skinfold measurements than subclinically hypothyroid and euthyroid participants. Furthermore, clinically hypothyroid participants had higher abdominal skinfold thickness than subclinically hypothyroid participants. Otherwise, suprailiac and abdominal skinfold measurements were higher in the subclinically and clinically hyperthyroid group of participants compared with euthyroid and subclinically hypothyroid participants. A strong positive association of thyroid-stimulating hormone (TSH) and strong negative association of free triiodothyronine (fT3) and free thyroxine (fT4) levels with HOMA-IR and cholesterol levels were found. Furthermore, the fT4 level also showed a strong negative association with HDL and triceps skinfold thickness. CONCLUSIONS: This study supports the standing that TSH, fT3, and fT4 levels are important variables to determine the association of thyroid function with MetS.

Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population.

Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10-7). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10-8) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.

Thyroglobulin Antibodies are Associated with Symptom Burden in Patients with Hashimoto's Thyroiditis: A Cross-Sectional Study.

BACKGROUND: Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid disorders characterized by lower production of thyroid hormones and positivity to autoantibodies to thyroglobulin (TgAb) and/or thyroid peroxidase (TPOAb). We performed a comprehensive phenotypic characterization of patients with HT, with specific focus on thyroid autoimmunity, to get better understanding of disease manifestation. METHODS: We collected information on thyroid-specific phenotypes (TSH, T3, T4, fT4, TgAb, TPOAb, thyroid volume) and other clinical phenotypes (age, body surface area, number of hypothyroidism symptoms, blood pressure) from 290 patients with HT without levothyroxine (LT4) therapy with the aim to test for correlations between thyroid-specific and clinical phenotypes. RESULTS: Our key and novel finding is the existence of significant positive correlation between TgAb levels and the number of symptoms (r = 0.25, p = 0.0001) in HT patients without LT4 therapy that remained significant after adjustment for TPOAb, T3, TSH levels and thyroid volume (ß = 0.66, SE = 0.3, p = 0.0299). Increased TgAb levels are significantly associated with fragile hair (p = 0.0043), face edema (p = 0.0061), edema of the eyes (p = 0.0293) and harsh voice (p = 0.0349). CONCLUSIONS: Elevated TgAb levels are associated with symptom burden in HT patients, suggesting a role of thyroid autoimmunity in clinical manifestations of HT. Based on these results, we recommend screening for TgAb antibodies in HT patients with symptom burden. We also suggest that further work on understandings of symptoms appearance due to their autoimmune or hypothyroid causation is needed.

The effect of multiple nutrients on plasma parathyroid hormone level in healthy individuals.

Although the effect of isolated nutrients on plasma parathyroid hormone (PTH) is somewhat familiar, the effect of multiple nutrients on plasma PTH level has not yet been studied. The aim of this study was to identify groups of food items that are associated with the plasma PTH level in healthy individuals. This cross-sectional study enrolled 1180 healthy individuals from Croatia with plasma PTH levels inside the referent values. A food frequency questionnaire containing 58 food items was completed to evaluate the dietary intake. We used principal component analysis to reduce food items into dietary groups, followed by linear regression analysis to test the association between dietary groups and the level of PTH. The results indicate that different sorts of vegetables (p = .006), sausages, salami, mushrooms, eggs (p = .033), as well as white bread (p = .009) are associated with the increase, while bran bread (p = .009) is associated with the decreased plasma PTH level.

Genome-wide meta-analysis identifies novel loci associated with parathyroid hormone level.

BACKGROUND: Parathyroid hormone (PTH) is one of the principal regulators of calcium homeostasis. Although serum PTH level is mostly accounted by genetic factors, genetic background underlying PTH level is insufficiently known. Therefore, the aim of this study was to identify novel genetic variants associated with PTH levels. METHODS: We performed GWAS meta-analysis within two genetically isolated Croatian populations followed by replication analysis in a Croatian mainland population and we also combined results across all three analyzed populations. The analyses included 2596 individuals. A total of 7,411,206 variants, imputed using the 1000 Genomes reference panel, were analysed for the association. In addition, a sex-specific GWAS meta-analyses were performed. RESULTS: Polymorphisms with the lowest P-values were located on chromosome 4 approximately 84 kb of the 5' of RASGEF1B gene. The most significant SNP was rs11099476 (P = 1.15 × 10-8). Sex-specific analysis identified genome-wide significant association of the variant rs77178854, located within DPP10 gene in females only (P = 2.21 × 10- 9). There were no genome-wide significant findings in the meta-analysis of males. CONCLUSIONS: We identified two biologically plausible novel loci associated with PTH levels, providing us with further insights into the genetics of this complex trait.

Association of Established Thyroid-stimulating Hormone and Free Thyroxine Genetic Variants with Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT), the most frequent autoimmune thyroid disease (AITD), is characterized by chronic inflammation of the thyroid gland that usually results in hypothyroidism. Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels are used as clinical determinants of thyroid function. The main aim of this study was to explore the association of established TSH and FT4 genetic variants with HT. We performed a case-control analysis using 23 genetic markers in 200 HT patients and 304 controls. Additionally, we tested the association of selected variants with several thyroid-related quantitative traits in HT cases only. Two genetic variants showed nominal association with HT: rs11935941 near NR3C2 gene (p = 0.0034, OR = 0.57, 95% CI = 0.39-0.83) and rs1537424 near MBIP gene (p = 0.0169, OR = 0.72, 95% CI = 0.55-0.94). Additionally, three SNPs showed nominal association with thyroglobulin antibody (TgAb) levels: rs4804416 in INSR gene (p = 0.0073, ß = -0.51), rs6435953 near IGFBP5 gene (p = 0.0081, ß = 0.75), and rs1537424 near MBIP gene (p = 0.0117, ß = 0.49). GLIS3 genetic variant rs10974423 showed nominal association with thyroid peroxidase antibody (TPOAb) levels (p = 0.0465, ß = -0.56) and NRG1 genetic variant rs7825175 was nominally associated with thyroid gland volume (p = 0.0272, ß = -0.18). All detected loci were previously related to thyroid function or pathology. Findings from our study suggest biological relevance of NR3C2 and MBIP with HT, although these loci require additional confirmation in a larger replication study.

Meta-analysis of 49†549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Molecular Characterization of Glucose-6-phosphate Dehydrogenase Deficiency in Families from the Republic of Macedonia and Genotype-phenotype Correlation.

INTRODUCTION: Glucose-6-phospahte dehydrogenase deficiency (G6PD) is one of the most common inherited disorders affecting around 400 million people worldwide. Molecular analysis of the G6PD gene identified more than 140 distinct mutations, the majority being single base missense mutations. G6PD Mediterranean is the most common variant found in populations of the Mediterranean area. AIM: The aim of our study was to perform molecular characterization of G6PD deficiency in families from the Republic of Macedonia and correlate the findings to disease phenotype. PATIENTS AND METHODS: Six patients and seven other family members were selected for genetic characterization, the selection procedure involved clinical evaluation and G6PD quantitative testing. All patients were first screened for the Mediterranean mutation, and subsequently for the Seattle mutation. Mutations were detected using PCR amplification and appropriate restriction endonuclease cleavage. RESULTS: Four hemizygote and 3 heterozygous carriers for G6PD Mediterranean were detected. All G6PD deficient patients from this group showed clinical picture of hemolysis, and in 66.6% neonatal jaundice was confirmed based on history data. To our knowledge, this is the first study concerned with molecular aspects of the G6PD deficiency in R. Macedonia. CONCLUSION: This study represents a step towards a more comprehensive genetic evaluation in our population and better understanding of the health issues involved.

Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

The OSR1 rs12329305 polymorphism contributes to the development of congenital malformations in cases of stillborn/neonatal death.

BACKGROUND: Involvement of development-related gene polymorphisms in multifactorial/polygenic etiology of stillborn/neonatal deaths due to malformations has been insufficiently tested. Since these genes showed evolutional stability and their mutations are very rare, we can assume that their polymorphic variants may be a risk factor associated with the occurrence of developmental disorders of unknown etiology or can enhance the phenotypic variability of known genetic disorders. MATERIAL AND METHODS: To determine the association of 3 polymorphisms involved in the regulation of the early embryonic development of different organs, we conducted an association study of their relation to the particular malformation. We selected 140 samples of archived paraffin tissue samples from deceased patients in which fetal/neonatal autopsy examination had shown congenital abnormalities as the most likely cause of death. The polymorphisms of OSR1 rs12329305, rs9936833 near FOXF1, and HOXA1 rs10951154 were genotyped using the TaqMan allelic discrimination assay. RESULTS: After Bonferroni correction for multiple testing, significant allelic association with stillborn/neonatal deaths was observed for rs12329305 (p=7×10-4). In addition, association analysis for the same polymorphism was shown in the subgroup with isolated anomalies (1.25×10^-5), particularly in the subgroup of cases with kidney and heart anomalies (p=4.18×10^-5, p=5.12×10^-8, respectively). CONCLUSIONS: The findings of the present study showed, for the first time, the role of the OSR1 rs12329305 polymorphism in the development of congenital malformations in cases of stillborn/neonatal death, particularly in those with congenital kidney and heart developmental defects.

Vitamin D and thyroid function: A mendelian randomization study.

BACKGROUND: Numerous organs, including the thyroid gland, depend on vitamin D to function normally. Insufficient levels of serum 25-hydroxyvitamin D [25(OH)D] are seen as a potential factor contributing to the emergence of several thyroid disorders, however, the causal relationship remains unclear. Here we use a Mendelian randomization (MR) approach to investigate the causal effect of serum 25(OH)D concentration on the indicators of thyroid function. METHODS: We conducted a two-sample MR analysis utilizing summary data from the most extensive genome-wide association studies (GWAS) of serum 25(OH)D concentration (n = 443,734 and 417,580), thyroid-stimulating hormone (TSH, n = 271,040), free thyroxine (fT4, n = 119,120), free triiodothyronine (fT3, n = 59,061), total triiodothyronine (TT3, n = 15,829), as well as thyroid peroxidase antibody levels and positivity (TPOAb, n = 12,353 and n = 18,297), low TSH (n = 153,241), high TSH (n = 141,549), autoimmune hypothyroidism (n = 287,247) and autoimmune hyperthyroidism (n = 257,552). The primary analysis was conducted using the multiplicative random-effects inverse variance weighted (IVW) method. The weighted mode, weighted median, MR-Egger, MR-PRESSO, and Causal Analysis Using Summary Effect estimates (CAUSE) were used in the sensitivity analysis. RESULTS: The IVW, as well as MR Egger and CAUSE analysis, showed a suggestive causal effect of 25(OH)D concentration on high TSH. Each 1 SD increase in serum 25(OH)D concentration was associated with a 12% decrease in the risk of high TSH (p = 0.02). Additionally, in the MR Egger and CAUSE analysis, we found a suggestive causal effect of 25(OH)D concentration on autoimmune hypothyroidism. Specifically, each 1 SD increase in serum 25(OH)D concentration was associated with a 16.34% decrease in the risk of autoimmune hypothyroidism (p = 0.02). CONCLUSIONS: Our results support a suggestive causal effect which was negative in direction across all methods used, meaning that higher genetically predicted vitamin D concentration possibly lowers the odds of having high TSH or autoimmune hypothyroidism. Other thyroid parameters were not causally influenced by vitamin D serum concentration.

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.