Background Left-right hippocampal volumetric asymmetry and atrophy are implicated in neurodegenerative and neuropsychiatric disorders, yet their molecular basis in healthy adults remains poorly understood. Methods We conducted a meta-analysis of epigenome-wide association studies across six population-based cohorts (n = 8156; 53% women; mean age = 60.7 years) to identify DNA methylation signatures associated with left and right hippocampal volumes (LHCV, RHCV) and hippocampal asymmetry (i.e, differences between left and right volumes divided by their sums). Findings We identified five CpGs and 262 differentially methylated regions associated with LHCV, nine CpGs and 246 regions with RHCV, one CpG and 16 regions with asymmetry. Cross-omics integration uncovered 15 LHCV-related and 13 RHCV-related methylation-gene expression pairs, with five overlapping genes primarily involved in immune regulation. LHCV-specific genes were involved in cellular signalling, and Mendelian randomisation (MR) analyses supported a potential causal association between brain expression of DIP2C and increased risk of major depressive disorder. RHCV-specific genes were involved in neuronal differentiation pathways, with MR analyses suggesting that brain-tissue expression of BAIAP2, MACF1, SLC16A5, and CORO1B was associated with neuropsychiatric disorders. We also identified sex-specific patterns with hippocampal asymmetry. Notably, baseline methylation at these sites predicted hippocampal atrophy rates, explaining >10% of the variation. Associations with multiple healthy dietary patterns suggest modifiable influences on hippocampal structure. Interpretation These findings highlight distinct methylation profiles as potential biomarkers or therapeutic targets for neuropsychiatric and neurodegenerative conditions. Funding Institutional funds, Federal Ministry of Education and Research of Germany, Alzheimer's Association.

Fatty liver is associated with increased all-cause mortality. Organic cation transporter 1 (OCT1) is a polyspecific hepatic uptake transporter. OCT1 mediates hepatic uptake of vitamin B1 (thiamine); thus, OCT1 deficiency may impair thiamine availability and consequently reduce glucose-derived energy. Consequently, OCT1-knockout mice exhibit significantly reduced liver fat. In 2% of Europeans and White Americans, common genetic variants markedly reduce OCT1 function. In this study, we used these naturally occurring variants to investigate the influences of reduced OCT1 function on liver fat in humans. We analyzed 2512 whole-body MRI datasets from the Study of Health in Pomerania (SHIP) and validated the findings using 31,594 datasets from the UK Biobank. In both cohorts, OCT1 deficiency was associated with lower fat content in the liver (p = 0.027 in SHIP; p = 2.9 × 10-6 in the UK Biobank), but not in other body compartments. OCT1 deficiency remained an independent predictor after adjustment for age, BMI, daily alcohol consumption, and biological sex. To investigate underlying mechanisms, we used Seahorse assays to show that OCT1-overexpressing cells exhibited increased mitochondrial metabolic activity when glucose was the sole energy source. Our findings warrant further investigation of OCT1 as a potential contributor to the pathogenesis of fatty liver.

BACKGROUND:Bipolar disorder (BD) is a major mood disorder influenced by both genetic and environmental factors. While DNA methylation from peripheral tissues can reflect both genetic and environmental influences and reveal insights into disease biology, it remains understudied in BD. DNA methylation signatures may complement polygenic scores (PGS) and hold potential as biomarkers. Here, we conducted the largest epigenome-wide association study (EWAS) of BD to date and evaluated the predictive value of polymethylation scores (PMS) in classifying case-control status. METHODS:DNA methylation from peripheral blood of 1729 cases and 1747 controls, comprising twelve cohorts, was obtained. We performed meta-analyses for the total sample, male-only, and female-only analyses. Differentially methylated regions (DMRs) were identified using the comb-p method. Polymethylation scores for BD (BD-PMS) were tested for association with BD, and in combination with PGS. FINDINGS:We identified 47 differentially methylated CpG positions (DMPs) in the total and four in the female-only analysis. Ninety, fourteen and six DMRs were identified in the total sample, female-only, and male-only analyses, respectively. Genes annotated to the top DMPs were enriched for immune activation and phosphorylation pathways. DMRs were annotated to genes relevant to neurotransmission, including GABBR1 and CACNA2D4. BD-PMS explained 2% of the variance in BD case-control status, and improved the variance explained from 7.9 to 8.5% when combined with PGS. For bipolar I disorder, BD-PMS explained 4.9% of the variance, and improved the variance explained by PGS from 15.9 to 18.5%. Association of BD with PMS for schizophrenia and major depression suggests pleiotropic epigenetic effects. INTERPRETATION:DNA methylation signatures of BD are detectable in blood using adequately powered data and may reveal novel BD biology that is not captured by genetic studies. PMS from large cohorts have the potential to facilitate the development of prediction tools to aid clinical decision-making. FUNDING:This investigation was primarily funded by the Research Council of Norway (RCN #250299, #273446, #223273) and the University of Bergen. A complete list of funding organisations is provided in the Acknowledgements.

Periodontitis is a complex inflammatory disease in which chronic immune activation drives destruction of periodontal soft tissues and alveolar bone. Although early-onset forms show high heritability, much genetic risk remains unresolved. To identify shared genetic signals across early- and later-onset periodontitis, we combined two European genome-wide association study datasets (3183 cases, 10 326 controls) and applied Fisher's combined probability test (FCOMB) and effect-size-based genome-wide association meta-analysis (GWAMA) across > 7 million variants to capture shared signals with either heterogeneous or more concordant effect sizes. We confirmed known associations at SIGLEC5 and DEFA1A3 and identified several additional suggestive loci. Among these, FCOMB highlighted the strongest signal at the long non-coding RNA LINC01541 (rs11876034, P = 1.7 × 10-6). We evaluated the biological relevance of LINC01541 by repressing it in gingival fibroblasts using CRISPR interference. Knockdown led to significant downregulation of inflammatory mediators, including CSF2 and CSF3, regulators of neutrophil recruitment, members of the interleukin (IL) family (IL1B, IL36B, IL36RN), and chemokines (CXCL5, CXCL8, CCL20). Six of the top ten differentially expressed genes belonged to an epithelial keratinization expression cluster. Gene-set enrichment analyses following linc01541 knockdown demonstrated repression of cytokine signaling, with IL-10 signaling most affected (padj = 5.3 × 10-14; AUC = 0.81), alongside activation of cell-cycle pathways (padj = 3.3 × 10-24; AUC = 0.73). We demonstrated the utility of aggregating heterogeneous samples to detect modest but biologically meaningful genetic effects. The convergence of the genetic association at LINC01541 with functional evidence suggests that this lncRNA modulates an upstream mucosal inflammatory axis relevant to periodontal pathogenesis.

Background:Carotid-intima media-thickness (cIMT) predicts cardiovascular events and informs mechanistic research on cardiovascular diseases. However, cardiovascular disease research remains Eurocentric despite etiological differences across ancestries. Incorporating Asian populations who face substantial cardiovascular disease burden with distinct etiological landscape can enhance our understanding of cIMT biology and subclinical processes linked to CVD. This study aims to elucidate methylation-based mechanisms of cIMT through DNA methylation profiling integrated with multi-omics data and clinically informative cIMT thresholds, leveraging an Asian cohort to enhance discovery. Methods:We conducted an epigenome-wide association study (EWAS) of cIMT using peripheral blood DNA methylation at ~850,000 CpG sites in the Asian Health for Life in Singapore (HELIOS) cohort (n=1,357), followed by targeted trans-ancestry meta-analysis with European cohorts (overall n=2,765). Causal inference analyses (summary data-based Mendelian Randomisation [SMR] and colocalisation) evaluated methylation-mediated effects on cIMT, cardiovascular disease and proximal gene expression. We derived a methylation risk score (MRS) and tested its association with cIMT thresholds indicative of elevated cardiovascular risk (≥75th percentile for age, sex and ethnicity). Results:Three novel CpG-cIMT associations were identified (P<9.35E-07). Causal analyses supported cg08227773 methylation-mediated effects on both coronary artery disease risk (PSMR=2.91E-05, coloc PP.H4 =0.91) and NBEAL2 (Neurobeachin-like 2) expression (PSMR=9.13E-08, coloc PP.H4=0.69), a gene implicated in immune dysregulation. MRS of cIMT aggregating the three sentinel CpGs was associated with clinically-informative cIMT elevation (Odds Ratio=2.75 for Q4 vs Q1, 95% CI: 1.47-5.13). Conclusions:Through Asian-led discovery, this study identifies three novel DNA methylation markers for cIMT that are linked to cIMT elevation above clinically meaningful risk thresholds. Causal inference analyses suggest methylation-mediated coronary artery disease risk via NBEAL2 regulation, nominating biologically relevant targets while underscoring the need for larger multi-omics resources to refine mechanisms.

Autoimmune hypothyroidism (Hashimoto's thyroiditis) is common and has a strong genetic component. Here we performed multi-ancestry genome-wide association meta-analyses encompassing 48,694 Hashimoto's thyroiditis cases, using a precise case definition, and 1,044,134 controls. We identified 155 significant (P < 5 × 10-8) independent genetic associations, of which 45 variants and 19 loci were not previously associated with hypothyroidism. Six loci were specific for individuals of European ancestry reference populations. Functional enrichment analyses of Hashimoto's thyroiditis-associated genes highlighted immune cells and the spleen, underpinning the importance of T cells in Hashimoto's thyroiditis development. This observation was further supported by 161 significant colocalizations with expression quantitative trait loci in immune cells and 40 in thyroid tissue (for example, TG, VAV3, IRF5), highlighting the interplay between the immune system and the thyroid. Mendelian randomization indicated causal effects of Hashimoto's thyroiditis on cardiovascular traits and expected associations with thyroid hormone levels.

BACKGROUND AND AIM:Genetic susceptibility plays a particularly important role in early-onset (EO) and severe periodontitis (PD). The genetic risk remains largely unexplained because of limited sample sizes and heterogeneous phenotypes in genome-wide association studies (GWAS). This study investigates whether current GWAS data can be used to construct a polygenic score (PGS) capturing genetic susceptibility to severe PD. MATERIALS AND METHODS:A PGS was developed in a three-step design, using a German EO-III/IV-C-PD GWAS (n = 692 cases, ≤ 35 years at diagnosis) as the base dataset, a Spanish EO-III/IV-C-PD GWAS (n = 441 cases) to optimise the score, and as validation a Dutch EO-III/IV-C-PD GWAS (n = 171 cases) and a German population-based GWAS with later-onset III/IV-PD (Studies of Health in Pomerania [SHIP], n = 2941 cases). RESULTS:The PGS showed a trend towards association with disease status in the Spanish sample (Nagelkerke R2 = 0.4%, p = 0.06; AUC = 0.52; 95% confidence interval [CI]: 0.49-0.56), but not in the smaller Dutch dataset (R2 = 0.2%, p = 0.18; AUC = 0.52; 95% CI: 0.48-0.57) or in the SHIP dataset (AUC = 0.50, 95% CI: 0.48-0.52). Case-control distributions overlapped substantially. Genetic correlation analyses revealed no strong overlap with other associated traits. CONCLUSIONS:Current PGS models have limited case-control discriminative ability for PD. Larger harmonised studies are needed to enhance genetic risk prediction and clarify pleiotropic relationships.

IntroductionA recent two-sample Mendelian randomization study suggested a possible causal association between hypothyroidism and selected sepsis types. We address this knowledge gap by examining the association between thyroid-stimulating hormone (TSH) levels and risk of sepsis and severe infectious diseases, using triangulation between traditional observational and Mendelian randomization (MR) analyses.MethodsBaseline characteristics and TSH-measurements were collected from adults (>20 years) at the time of participation in the prospective, population-based Trøndelag Health Study (The HUNT Study), and linked to hospital records for ascertainment of infectious diseases. Time-to-event analyses with Cox regression was used to assess the association between TSH levels and risk of sepsis, adjusting for confounders. Next, we extracted uncorrelated (R2 < 0.01) single-nucleotide polymorphisms strongly associated (p-value < 5e-8) with TSH levels from genome-wide association studies of European ancestry participants in the ThyroidOmics Consortium. Genetic associations with risk of sepsis were extracted from European ancestry participants in the UK Biobank. Secondary genetic analyses examined other measures of thyroid function (FT4, FT3, autoimmune thyroid disease and deiodinase activity) with sepsis risk, along with genetic and observational analyses of risk of lower respiratory tract infections (LRTI) and upper urinary tract infections (UUTI).ResultsIn the observational analyses of 45,364 subjects in HUNT there was no association between baseline normal-range TSH and sepsis risk [HR 0.98 (95% CI 0.93–1.04) per mU/L unit increase]. TSH levels <0.5 mU/L was associated with higher sepsis risk (HR 1.50, 95% CI 1.19–1.90). In the MR analyses (271,040 subjects with TSH-measurements, and 10,154 cases with sepsis), there was no association between normal-range TSH and sepsis risk [OR 1.04 (95% CI 0.98–1.10), per SD increase]. Secondary analyses supported no link between thyroid function and risk of sepsis, LRTI or UUTI.ConclusionVariation in baseline thyroid function in the general adult population does not causally influence the risk of sepsis, LRTI or UUTI. In contrast to earlier MR work based on genetic liability to overt hypothyroidism in clinical populations, our findings indicate that mild deviations in thyroid function within and around the reference range are unlikely to be useful targets for sepsis prevention or risk stratification.

Abstract Background It is an everyday observation that people of the same chronological age differ with respect to their physical and mental capacity. However, assessing these differences in biological age remains challenging. Methods Here, we aggregate 89 age-associated variables from the Berlin Aging Study II (BASE-II, n=1,631) to generate MultiAge, a new marker of biological age that summarizes information from ten domains reflecting organ health and global biological age. We then used methylation data obtained from an Illumina MethylationEPIC array and supervised machine learning to translate MultiAge into a DNA methylation signature, MultiAgeEpi (309 CpGs), which was subsequently validated in four independent external validation cohorts (KORA FF4, KORA Age, SHIP-TREND, BiDirect, total n=4,339). MultiAgeEpi results were compared with previously published epigenetic clocks (GrimAge, DunedinPACE, SystemsAge). Results We report that MultiAgeEpi showed similar, and in several cases, stronger associations with age-associated outcomes such as diabetes, metabolic syndrome, multimorbidity, frailty and mortality (q < 0.05) compared to the other clocks. Conclusions MultiAge and MultiAgeEpi thus provide a comprehensive assessment of biological age through aggregation of numerous age-associated variables and the use of the high-resolution methylomics data makes transfer of this marker to other cohorts possible.

Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries - collectively known as the circle of Willis (CoW) - influences the risk of IA development and rupture. Although CoW variation is known to be heritable, its genetic underpinnings and contribution to IA remain poorly understood. Here, we aimed to investigate the genetic architecture of CoW variation and its potential link with IA. Using a semi-automated detection tool, we characterized the diameters, bifurcation angles, and presence of arterial segments of the CoW in 1078 participants from a population-based cohort and 682 IA patients. Composite traits capturing variation in all CoW characteristics were generated through principal component analysis. We conducted a genome-wide association study (GWAS) on these composite traits and identified four loci with suggestively significant associations. Lead single-nucleotide polymorphisms (SNPs) were located in or near the genes DPYSL2, CSMD3, TRPC6, and PKD1L2. Notably, PKD1L2 is closely related to PKD1, a gene implicated in autosomal dominant polycystic kidney disease, a connective tissue disorder that increases IA susceptibility. We observed statistically significant SNP-based heritability for the second principal component of CoW variation (heritability estimate = 0.95, standard error = 0.25). All lead SNPs demonstrated nominal association (p < 0.05) with multiple CoW characteristics and other vascular traits. Our findings highlight a substantial genetic contribution to CoW morphology and offer new insights into the molecular mechanisms underlying CoW variation and its role in IA pathogenesis.

BACKGROUND:Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. METHODS:In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were estimated per individual and categorised into quintiles, with the highest and lowest quintiles defined as increasing and decreasing, respectively, and the rest as stable. Patterns of thyroid function change were identified based on combined TSH and FT4 evolution. We used cohort-stratified Cox models to assess associations between changing patterns and all-cause mortality. This study is registered with PROSPERO, CRD42023408086. FINDINGS:In this IPD analysis, we analysed data collected between Jan 1, 2011, and Oct 13, 2022, from 31 cohorts across Europe (n=19), the USA (n=5), Asia (n=3), Brazil (n=2), and Australia (n=2; 137 488 participants; 68 322 [49·7%] were female and 69 166 [50·3%] were male; median age 60 years [range 18-106]). Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and with lower TSH in iodine-insufficient regions. Longitudinal analyses showed that TSH increased with increasing age regardless of iodine status. The overall increase in TSH from age 18 years to 100 years was 0·61 mIU/L (0·52 SD) for female participants and 0·99 mIU/L (0·76) for male participants from iodine-sufficient regions. Greater variability in population distribution and longitudinal TSH changes was observed in adults aged 65 years or older. Higher FT4 with older age was suggested cross-sectionally, but longitudinally FT4 increased in iodine-sufficient regions and decreased in iodine-insufficient regions. Compared with stable thyroid function, all changing patterns were associated with increased all-cause mortality: hazard ratios of 1·80 (95% CI 1·57-2·06) for increasing TSH with stable or decreasing FT4; 2·45 (2·01-2·97) for increasing TSH and increasing FT4; 2·45 (1·99-3·01) for decreasing TSH with decreasing FT4; and 1·94 (1·68-2·24) for decreasing TSH with stable or increasing FT4. INTERPRETATION:Ageing-related changes in thyroid function varied by sex and iodine status. Most individuals had stable thyroid function during ageing with a slight increase in TSH, although older adults displayed greater variability. Patterns of changing thyroid function were associated with an increased all-cause mortality risk, warranting further exploration of the underlying mechanisms and clinical management. FUNDING:None.

Cytokine dysregulation contributes to chronic inflammation and immune-mediated diseases, yet population-level determinants of pro- and anti-inflammatory cytokines remain poorly characterized. We aimed to identify demographic and lifestyle determinants of plasma cytokine levels and evaluate reproducibility of inflammatory patterns across European populations. In the population-based Rotterdam Study cohort (n = 3,456; mean age 57 years; 56

Environmental exposures influence the risk of psychiatric disorders, yet the biological mechanisms by which such experiences become embedded in brain structure remain poorly understood. The human cerebral cortex is crucial for cognition and emotional regulation, and variation in cortical thickness (CT) and surface area (SA) is linked to various behavioural and psychiatric traits. Here, we present a large-scale epigenome-wide association study that combines peripheral blood DNA methylation (DNAm) with MRI-derived cortical measures in over 7,400 individuals across 20 cohorts within the ENIGMA consortium. We identify mostly non-overlapping DNAm signatures associated with CT and SA, consistent with their distinct developmental and regulatory architectures. CT-associated CpGs are replicated across independent cohorts and are enriched for environmentally responsive regulatory elements and pathways associated with stress, metabolism, and immune signalling. In contrast, SA-associated CpGs cluster within chromatin-regulatory regions involved in early cortical development. Phenome-wide and Mendelian randomisation analyses reveal pleiotropic associations between DNAm, cortical structure, and psychiatric and cognitive traits. These findings suggest that peripheral DNAm captures environmentally sensitive biological processes that link exposure, cortical organisation, and behavioural vulnerability.

Many non-coding variants influence complex traits and diseases through gene regulation, yet the mechanisms linking these variants to downstream biology remain poorly understood. Here, we present eQTLGen Phase 2, a comprehensive genome-wide analysis of gene expression quantitative trait loci (eQTLs) in 43,301 blood samples from 52 datasets. Beyond local ciseffects, this sample size enabled the first systematic mapping of trans-eQTLs at scale. We identify cis-eQTLs for nearly all expressed genes (94.7%) and trans-eQTLs for over half (56.2%). Second, by colocalizing cis-eQTLs with trans-eQTLs, we infer a directed gene regulatory network comprising 47,554 directed gene regulatory relationships. These networks reveal how genetic perturbations in upstream regulators produce dose-dependent downstream effects, supported by Perturb-seq and ChIP-seq data. Third, integrating this network with 87 genome-wide association studies allows us to systematically prioritize trait-relevant pathways and candidate genes. Variants exerting both cis- and trans-effects are markedly more likely to colocalize with trait associations than cis-only variants, delineating a subset of functionally active cis-eQTLs from a large group with limited downstream impact. This distinction provides a conceptual framework for identifying regulatory variants that truly mediate complex trait biology. Together, these results provide a publicly available resource of cis- and trans-eQTLs and an in vivo scaffold for human gene-regulatory networks, elucidating how propagation of cis-effects modulates complex disease.

Ewing sarcoma (EwS) is a rare, aggressive pediatric malignancy driven by FET::ETS family fusions (EWSR1::FLI1 in >85% of cases) with no established environmental risk factors. To investigate germline predisposition, we analyzed 2,014 EwS cases and 10,525 cancer-free controls in a two-stage analysis that combined an international genome-wide association study and a case parent trio study. The combined meta-analysis identified 18 variants at 14 susceptibility loci (9 novel, 5 replicated) with moderate effect sizes (odds ratios≥1.25). Integrative analyses of the EwS loci revealed enrichment of expanded GGAA microsatellites, with evidence for binding of the EWSR1::FLI1 chimeric oncogenic activator. EWSR1::ETS knockdown in EwS cell lines resulted in dysregulated genes at susceptibility loci related to skeletal/muscle development, RNA binding/processing, and chromatin regulation. Our findings provide insights into the inherited component of EwS, highlighting a genetic architecture in which common germline variations with moderate effects interact with somatic EWSR1::FLI1 fusions to promote sarcomagenesis by dysregulating local genes.

ABSTRACT Chronic kidney disease is characterized by decreased glomerular filtration rate (eGFR, estimated from serum creatinine or cystatin C) or increased urinary albumin-to-creatinine-ratio (UACR). Genome-wide association studies provided the genetic make-up of these traits, but their overlap remained largely unknown. Our multi-trait GWAS (N=1M) identified 812 signals and multi-trait fine-mapping sharpened the identification of likely causal variants. Of 333 signals classified for filtration function or albuminuria, only 11 overlapped. Their effects on eGFR and UACR were directionally concordant, dominated by eGFR and independent of HbA1c or mean arterial pressure. Mapped genes pinpointed mechanisms related to glomerular filtration area ( SHROOM3 , EPB41L5 ) and sodium-mediated intraglomerular pressure ( NRBP1 , DPEP1 / CHMP1A ). Genetics of fluid intake resulted in shadow effects on UACR without albumin leakage into urine. Our multi-trait approach sharpened the identification of likely causal genes for kidney traits, demonstrated largely distinct genetics for filtration function versus albuminuria, and provided new biological insights into the overlap.

There is increasing evidence that even a small variation in thyroid function, even within the reference range, is associated with adverse clinical outcomes. Furthermore, there exists a substantial interindividual variation of thyroid function even within euthyroid individuals suggesting an individual hypothalamus-pituitary-thyroid (HPT) axis setpoint. Here we assess potential contributions of the HPT axis organ volumes to the variation of thyroid hormones in the general population. Using linear regression models, we analyzed the association of circulating free T3, free T4, and log-transformed TSH levels with hypothalamus, pituitary gland, and log-transformed thyroid volume in a subsample of up to n = 3438 participants from the population-based Study of Health in Pomerania with a mean age 50.6 years, 44.6% female, and a mean TSH 1.38mU/L. Performing cross-sectional analyses at baseline, we observed inverse associations of pituitary volume with free T4 levels ( β = - 0.74 , P = 0.017 , n = 1 , 372 ) and of thyroid volume with TSH levels ( β = - 0.72 , P = 3.1 × 10 - 147 , n = 3 , 430 ), as well as positive associations of thyroid volume with free T3 ( β = 0.11 , P = 1.3 × 10 - 4 , n = 3 , 310 ) and free T4 levels ( β = 0.81 , P = 1.2 × 10 - 18 , n = 3 , 311 ) but observed no association regarding hypothalamus volume (n ≤ 1636). The findings for free T3 and free T4 were supported by longitudinal analyses in a subsample of up to n = 2040 participants with available longitudinal data and a mean follow-up time of 7.3 years. In summary, using data from a population-based sample, we identified associations between pituitary volume and circulating free T4 as well as thyroid gland volume with circulating levels of TSH, free T3, and free T4 contributing to the variation of thyroid hormone levels.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

CONTEXT:Genetic factors are a major contributor to variation in thyroid function. Recent studies have partly identified the responsible common genetic variants and studied their application in unraveling thyroid (patho)physiology as well as their potential clinical use. EVIDENCE ACQUISITION:This review summarizes the current state of knowledge regarding the genetic architecture of thyroid function as well as its applications to improve (patho)physiological understanding and clinical management of thyroid (dys)function. EVIDENCE SYNTHESIS:Genome-wide association studies (GWAS) have been successful in detecting numerous genetic variants affecting variation in thyrotropin (TSH), free thyroxine, and triiodothyronine concentrations. Subsequent emerging high-throughput in silico and in vitro strategies are of particular value in unraveling functionality of these novel genes and its genetic variants. Translational methods such as mendelian randomization (MR) and polygenic scores (PGSs) can provide important insights into causal associations or susceptibility to disease. Moreover, PGSs show potential in adjusting personalized TSH reference ranges by distinguishing between individual hypothalamic-pituitary-thyroid-axis set-point effects and (subclinical) thyroid dysfunction. CONCLUSION:Functional characterization of the associated genes and variants in GWAS is warranted as the majority are located in genes with a yet unknown role in thyroid hormone physiology. Integration of multi-omics data and optimalization of translational applications such as MR and PGS show potential to further unravel the underlying molecular mechanisms and pave the way for incorporation of genetics in personalized management of thyroid diseases.