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... Show moreTo 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. Show less
Fuentes, L. de las; Schwander, K.L.; Brown, M.R.; Bentley, A.R.; Winkler, T.W.; Sung, Y.J.; ... ; Fornage, M. 2023
Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide... Show moreIntroduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 x 10(-8)) and suggestive (p < 1 x 10(-6)) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects. Show less
Spek, A. van der; Stewart, I.D.; Kuehnel, B.; Pietzner, M.; Alshehri, T.; Gauss, F.; ... ; Amin, N. 2023
Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify... Show moreMetabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts characterized for depression, and circulating metabolites using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) based Metabolon platform. We tested 806 metabolites covering a wide range of biochemical processes including those involved in lipid, amino-acid, energy, carbohydrate, xenobiotic and vitamin metabolism for their association with depression. In a conservative model adjusting for life style factors and cardiovascular and antidepressant medication use we identified 8 metabolites, including 6 novel, significantly associated with depression. In individuals with depression, increased levels of retinol (vitamin A), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) (lecithin) and mannitol/sorbitol and lower levels of hippurate, 4-hydroxycoumarin, 2-aminooctanoate (alpha-aminocaprylic acid), 10-undecenoate (11:1n1) (undecylenic acid), 1-linoleoyl-GPA (18:2) (lysophosphatidic acid; LPA 18:2) are observed. These metabolites are either directly food derived or are products of host and gut microbial metabolism of food-derived products. Our Mendelian randomization analysis suggests that low hippurate levels may be in the causal pathway leading towards depression. Our findings highlight putative actionable targets for depression prevention that are easily modifiable through diet interventions. Show less
BackgroundChildhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in... Show moreBackgroundChildhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence (“comorbidity”) of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood.MethodsWe carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types.ResultsChildhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types.ConclusionsThis meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288). Show less
Groenewold, N.A.; Bas, J.M.; Amod, A.R.; Laansma, M.A.; Velzen, L.S. van; Aghajani, M.; ... ; Wee, N.J.A. van der 2023
There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in... Show moreThere is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood. Show less
Groenewold, N.A.; Bas-Hoogendam, J.M.; Amod, A.R.; Laansma, M.A.; Velzen, L.S. van; Aghajani, M.; ... ; Wee, N.J.A. van der 2023
There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in... Show moreThere is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood. Show less
Dima, D.; Modabbernia, A.; Papachristou, E.; Doucet, G.E.; Agartz, I.; Aghajani, M.; ... ; Frangou, S. 2021
