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To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases., (© 2024. The Author(s).)

Background: Recently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain endophenotype in people with gender dysphoria (GD). However, despite mounting neuroimaging work, brain gender differences and effects of gender-affirming hormone therapy (GAHT) at the metabolite level remain understudied., Methods: Thirty-one transgender men (TM) before and after testosterone administration (7.7 months ± 3.5 months), relative to 30 cisgender men (CM) and 35 cisgender women (CW) underwent magnetic resonance spectroscopy ( 1 H-MRS) at two time points. Two brain regions were assessed, i.e. the lateral parietal cortex and the amygdala/anterior hippocampus. Associated metabolites that were measured include N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), glutamate and glutamine (Glx), myo-inositol (mI), glycine (Gly) and their respective ratios., Results: A critical time by group interaction revealed an effect of GAHT in the lateral parietal cortex of TM. MI+Gly/Cr ratios decreased upon initiation of GAHT. In addition, NAA/Cr and Cho/Cr ratios were lower in CW when compared to CM in the lateral parietal cortex. Glx levels and Glx/Cr ratios in TM differed from those in CW in the amygdala/anterior hippocampus. Interestingly, pubertal age of onset of gender dysphoria (i.e. GD) in TM differentially affected testosterone-mediated effects on Cr concentration and NAA/Cr ratios when compared to childhood and adult GD onset in the amygdala/anterior hippocampus., Conclusion: This 1 H-MRS study demonstrated that testosterone administration shifts mI+Gly/Cr ratios in the parietal cortex. In the amygdala/anterior hippocampus, modulation of metabolite concentrations by age of onset of GD is suggestive for a possible developmental trend., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Some transgender people desire a transition through gender-affirming hormone treatment (GAHT). To date, it is unknown how GAHT changes emotion perception in transgender people., Methods: Thirty transgender men (TM), 30 cisgender men (CM), and 35 cisgender women (CW) underwent 3 Tesla functional magnetic resonance imaging (fMRI) while passively viewing emotional faces (happy, angry, surprised faces) at two timepoints (T0 and T1). At T0 all participants were hormone-naïve, while TM immediately commenced testosterone supplementation at T0. The second scanning session (T1) occurred after 6-10 months of GAHT in TM. All 3 groups completed both T0 and T1 RESULTS: GAHT in TM shifted the neural profile whilst processing emotions from a sex-assigned at birth pattern at T0 (similar to CW) to a consistent with gender identity pattern at T1 (similar to CM). Overall, the brain patterns stayed the same for the cis people at T0 and T1., Conclusions: These findings document the impact of hormone treatment, and testosterone supplementation specifically, on emotion perception in TM., Competing Interests: Conflicts of interest None of the authors has a conflict of interest to declare. In no case did the funding sources have any influence on the research design, data collection, analyses and results, or interpretation. Neither have the funding sources any influence on the writing process nor on the decision to publish the results., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The main objective was to carry out a global DNA methylation analysis in a population with gender incongruence before gender-affirming hormone treatment (GAHT), in comparison to a cisgender population., Methods: A global CpG (cytosine-phosphate-guanine) methylation analysis was performed on blood from 16 transgender people before GAHT vs. 16 cisgender people using the Illumina© Infinium Human Methylation 850k BeadChip, after bisulfite conversion. Changes in the DNA methylome in cisgender vs. transgender populations were analyzed with the Partek ® Genomics Suite program by a 2-way ANOVA test comparing populations by group and their sex assigned at birth., Results: The principal components analysis (PCA) showed that both populations (cis and trans) differ in the degree of global CpG methylation prior to GAHT. The 2-way ANOVA test showed 71,515 CpGs that passed the criterion FDR p < 0.05. Subsequently, in male assigned at birth population we found 87 CpGs that passed both criteria (FDR p < 0.05; fold change ≥ ± 2) of which 22 were located in islands. The most significant CpGs were related to genes: WDR45B, SLC6A20, NHLH1, PLEKHA5, UBALD1, SLC37A1, ARL6IP1, GRASP , and NCOA6 . Regarding the female assigned at birth populations, we found 2 CpGs that passed both criteria (FDR p < 0.05; fold change ≥ ± 2), but none were located in islands. One of these CpGs, related to the MPPED2 gene, is shared by both, trans men and trans women. The enrichment analysis showed that these genes are involved in functions such as negative regulation of gene expression (GO:0010629), central nervous system development (GO:0007417), brain development (GO:0007420), ribonucleotide binding (GO:0032553), and RNA binding (GO:0003723), among others., Strengths and Limitations: It is the first time that a global CpG methylation analysis has been carried out in a population with gender incongruence before GAHT. A prospective study before/during GAHT would provide a better understanding of the influence of epigenetics in this process., Conclusion: The main finding of this study is that the cis and trans populations have different global CpG methylation profiles prior to GAHT. Therefore, our results suggest that epigenetics may be involved in the etiology of gender incongruence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramirez, Fernández, Collet, Kiyar, Delgado-Zayas, Gómez-Gil, Van Den Eynde, T’Sjoen, Guillamon, Mueller and Pásaro.)