Dataset Information

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

ABSTRACT: Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P?=?8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P?=?2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P?=?6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P?=?1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P?=?6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P?=?1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

SUBMITTER: Medici M

PROVIDER: S-EPMC3937134 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Medici Marco M Porcu Eleonora E Pistis Giorgio G Teumer Alexander A Brown Suzanne J SJ Jensen Richard A RA Rawal Rajesh R Roef Greet L GL Plantinga Theo S TS Vermeulen Sita H SH Lahti Jari J Simmonds Matthew J MJ Husemoen Lise Lotte N LL Freathy Rachel M RM Shields Beverley M BM Pietzner Diana D Nagy Rebecca R Broer Linda L Chaker Layal L Korevaar Tim I M TI Plia Maria Grazia MG Sala Cinzia C Völker Uwe U Richards J Brent JB Sweep Fred C FC Gieger Christian C Corre Tanguy T Kajantie Eero E Thuesen Betina B Taes Youri E YE Visser W Edward WE Hattersley Andrew T AT Kratzsch Jürgen J Hamilton Alexander A Li Wei W Homuth Georg G Lobina Monia M Mariotti Stefano S Soranzo Nicole N Cocca Massimiliano M Nauck Matthias M Spielhagen Christin C Ross Alec A Arnold Alice A van de Bunt Martijn M Liyanarachchi Sandya S Heier Margit M Grabe Hans Jörgen HJ Masciullo Corrado C Galesloot Tessel E TE Lim Ee M EM Reischl Eva E Leedman Peter J PJ Lai Sandra S Delitala Alessandro A Bremner Alexandra P AP Philips David I W DI Beilby John P JP Mulas Antonella A Vocale Matteo M Abecasis Goncalo G Forsen Tom T James Alan A Widen Elisabeth E Hui Jennie J Prokisch Holger H Rietzschel Ernst E EE Palotie Aarno A Feddema Peter P Fletcher Stephen J SJ Schramm Katharina K Rotter Jerome I JI Kluttig Alexander A Radke Dörte D Traglia Michela M Surdulescu Gabriela L GL He Huiling H Franklyn Jayne A JA Tiller Daniel D Vaidya Bijay B de Meyer Tim T Jørgensen Torben T Eriksson Johan G JG O'Leary Peter C PC Wichmann Eric E Hermus Ad R AR Psaty Bruce M BM Ittermann Till T Hofman Albert A Bosi Emanuele E Schlessinger David D Wallaschofski Henri H Pirastu Nicola N Aulchenko Yurii S YS de la Chapelle Albert A Netea-Maier Romana T RT Gough Stephen C L SC Meyer Zu Schwabedissen Henriette H Frayling Timothy M TM Kaufman Jean-Marc JM Linneberg Allan A Räikkönen Katri K Smit Johannes W A JW Kiemeney Lambertus A LA Rivadeneira Fernando F Uitterlinden André G AG Walsh John P JP Meisinger Christa C den Heijer Martin M Visser Theo J TJ Spector Timothy D TD Wilson Scott G SG Völzke Henry H Cappola Anne A Toniolo Daniela D Sanna Serena S Naitza Silvia S Peeters Robin P RP

PLoS genetics 20140227 2

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12, ...[more]

PMID: 24586183

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Project description:ContextAntibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited.ObjectiveThe purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease.Design, setting, and participantsWe studied European ancestry participants of 3 independent prospective population-based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887).ExposureSingle nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined.Main outcomesThe main outcomes were TPOAb concentrations and positivity, thyroid hormone concentrations (TSH, free T4), and clinical thyroid diseases (subclinical and overt hypothyroidism and goiter).ResultsSignificantly associated single nucleotide polymorphisms (P < 5 · 10(-8)) mapped into 4 genomic regions not previously implicated for TPOAbs (RERE, extended HLA region) and into 5 previously described loci. A higher Genetic Risk Score (GRS) based on these 9 SNPs showed strong and graded associations with higher TPOAb, TSH, and lower free T4 concentrations (P < .001). Compared with individuals in the lowest GRS quartile, those in the highest quartile had 1.80-fold higher odds of subclinical hypothyroidism (95% confidence interval, 1.27-2.55) and 1.89-fold higher odds of overt hypothyroidism (95% confidence interval, 1.24-2.87).ConclusionThe identification of 4 novel genetic loci associated with TPOAb concentrations and positivity gives further insight into the genetic underpinnings of hypothyroidism. A GRS showed strong and graded associations with markers of thyroid function and disease in independent population-based studies.

Project description:BackgroundAutoimmune thyroid disease (AITD) is induced by various factors, including inheritability, which regulates gene expression. Multiple loci correlated with AITD have been discovered utilizing genome-wide association studies (GWASs). Nevertheless, demonstrating the biological relevance and function of these genetic loci is difficult.MethodsThe FUSION software was utilized to define genes that were expressed differentially in AITD using a transcriptome-wide association study (TWAS) method in accordance with GWAS summary statistics from the largest genome-wide association study of 755,406 AITD individuals (30,234 cases and 725,172 controls) and levels of gene expression from two tissue datasets (blood and thyroid). Further analyses were performed such as colocalization, conditional, and fine-mapping analyses to extensively characterize the identified associations, using functional mapping and annotation (FUMA) to conduct functional annotation of the summary statistics of 23329 significant risk SNPs (P < 5 × 10-8) recognized by GWAS, together with summary-data-based mendelian randomization (SMR) for identifying functionally related genes at the loci in GWAS.ResultsThere were 330 genes with transcriptome-wide significant differences between cases and controls, and the majority of these genes were new. 9 of the 94 unique significant genes had strong, colocalized, and potentially causal correlations with AITD. Such strong associations included CD247, TPO, KIAA1524, PDE8B, BACH2, FYN, FOXK1, NKX2-3, and SPATA13. Subsequently, applying the FUMA approach, novel putative AITD susceptibility genes and involved gene sets were detected. Furthermore, we detected 95 probes that showed strong pleiotropic association with AITD through SMR analysis, such as CYP21A2, TPO, BRD7, and FCRL3. Lastly, we selected 26 genes by integrating the result of TWAS, FUMA, and SMR analysis. A phenome-wide association study (pheWAS) was then carried out to determine the risk of other related or co-morbid phenotypes for AITD-related genes.ConclusionsThe current work provides further insight into widespread changes in AITD at the transcriptomic level, as well as characterized the genetic component of gene expression in AITD by validating identified genes, establishing new correlations, and uncovering novel susceptibility genes. Our findings indicate that the genetic component of gene expression plays a significant part in AITD.

Project description:RationaleCoronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD.ObjectiveTo expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD.Methods and resultsWe performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P<5×10-8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising (P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance (P<5×10-8) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci (P<5×10-8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death.ConclusionsWe identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD.

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Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

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Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

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