Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

The aims of this study were to evaluate: (1) associations of vitamin D with the presence/severity of Hashimoto’s thyroiditis (HT) and (2) correlations of vitamin D with thyroid-related phenotypes. Total 25(OH)D (vitamin D in the text) was measured from stored serum samples of 461 HT patients and 176 controls from a Croatian Biobank of HT patients (CROHT). (1) Vitamin D levels, and proportions of vitamin D deficiency, were compared between HT cases and controls. HT patients were additionally divided into two groups (MILD and OVERT) to take into account HT severity. (2) Correlations between vitamin D and 10 clinical phenotypes in all HT patients and two subgroups of HT patients were tested using the Spearman correlation test. Our analyses were adjusted for age, gender, BMI, smoking status and seasonality of blood sampling. (1) No significant differences in vitamin D levels, or proportions of vitamin D deficiency, were detected between HT patients of all disease stages and controls. However, a nominally significant difference in vitamin D levels between MILD and OVERT subgroups (OR = 1.038, p = 0.023) was observed. Proportions of individuals with vitamin D deficiency during winter–spring were high: all HT cases (64.69%), MILD (60.64%), OVERT (68.7%), controls (60.79%). (2) A nominally significant negative correlation between vitamin D and TSH in all HT patients (r = −0.113, p = 0.029) and a positive correlation between vitamin D and systolic blood pressure in OVERT HT patients (r = 0.205, p = 0.025) were identified. Our study indicates that there is no association between vitamin D and HT; however, there may be a subtle decrease in vitamin D levels associated with overt hypothyroidism.

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10⁻⁸) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

The TNF/LTA locus has been a long-standing T2D candidate gene. Several studies have examined association of TNF/LTA SNPs with T2D but the majority have been small-scale and produced no convincing evidence of association. The purpose of this study is to examine T2D association of tag SNPs in the TNF/LTA region capturing the majority of common variation in a large-scale sample set of UK/Irish origin. This study comprised a case-control (1520 cases and 2570 control samples) and a family-based component (423 parent-offspring trios). Eleven tag SNPs (rs928815, rs909253, rs746868, rs1041981 (T60N), rs1800750, rs1800629 (G-308A), rs361525 (G-238A), rs3093662, rs3093664, rs3093665, and rs3093668) were selected across the TNF/LTA locus and genotyped using a fluorescence-based competitive allele specific assay. Quality control of the obtained genotypes was performed prior to single- and multi-point association analyses under the additive model. We did not find any consistent SNP associations with T2D in the case-control or family-based datasets. The present study, designed to analyse a set of tag SNPs specifically selected to capture the majority of common variation in the TNF/LTA gene region, found no robust evidence for association with T2D. To investigate the presence of smaller effects of TNF/LTA gene variation with T2D, a large-scale meta-analysis will be required.

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 (β = 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.

Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development. A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study. Diagnosis of HT cases was based on clinical examination, measurement of thyroid hormones (TSH and fT4) and antibodies (TgAb, TPOAb) and ultrasound examination. We selected and genotyped 14 known TPOAb-associated genetic variants. Case–control logistic regression model was used to test the association of selected genetic variants with HT. Additionally, we tested association of the same genetic variants with thyroid related quantitative traits (TPOAb levels, TgAb levels and thyroid gland volume) using linear regression. Three genetic variants showed nominal association with HT; rs10774625 in ATXN2 gene (p = 0.0149, OR = 0.73, CI = 0.56–0.94), rs7171171 near RASGRP1 gene (p = 0.0356, OR = 1.4, CI = 1.02–1.92) and rs11675434 in TPO gene (p = 0.041, OR = 1.31, CI = 1.01–1.69). Two of these SNPs (rs1077462, rs11675434) also showed association with TPOAb levels (p = 0.043, β = −0.39; p = 0.042, β = 0.40, respectively) and one (rs7171171) was associated with thyroid gland volume (p = 0.0226, β = −0.21). Our findings suggest that variants inside or near TPO, ATXN2 and RASGRP1 genes are associated with HT. Identified loci are novel to HT and represent good basis for further exploration of HT susceptibility.