Whole-genome sequence-based analysis of thyroid function

Taylor, Peter N.; Porcu, Eleonora; Chew, Shelby; Campbell, Purdey J; Traglia, Michela; Brown, Suzanne J.; Mullin, Benjamin H.; Shihab, Hashem A.; Min, Josine L.; Walter, Klaudia; Memari, Yasin; Huang, Jie; Barnes, Michael R.; Beilby, John; Charoen, Pimphen; Danecek, Petr; Dudbridge, Frank; Forgetta, Vincenzo; Greenwood, Celia M.T.; Grundberg, Elin; Johnson, Andrew D.; Hui, Jennie; Lim, Ee Mun; McCarthy, Shane; Muddyman, Dawn; Panicker, Vijay; Perry, John; Bell, Jordana T.; Yuan, Wei; Relton, Caroline L; Gaunt, Tom R.; Schlessinger, David; Abecasis, Gonçalo R.; Cucca, Francesco; Surdulescu, Gabriela L.; Woltersdorf, Wolfram; Zeggini, Eleftheria; Zheng, Hou-Feng; Toniolo, Daniela; Dayan, Colin; Naitza, Silvia; Walsh, John P.; Spector, Tim D.; Smith, George Davey; Durbin, Richard; Richards, J. Brent; Sanna, Serena; Soranzo, Nicole; Timpson, Nicholas J.; Wilson, Scott G.

doi:10.1038/ncomms6681

Cited by 79 publications

(92 citation statements)

References 42 publications

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“…In the future, more polymorphisms will be studied. The study by Taylor et al [46] indicated that uncommon polymorphisms (MAF <1%) may have a very large impact on the associations studied.…”

Section: Discussionmentioning

confidence: 99%

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

et al. 2017

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Objectives: In previous studies, around half of all hypothyroid patients preferred levo-thyroxine (L-T4) + levo-triiodothyronine (L-T3) combination therapy, 25% preferred T4, and 25% had no preference. The reason for this is yet to be explored. Methods: A total of 45 overtly autoimmune, hypothyroid patients – now euthyroid on ≥6 months’ L-T4 therapy – participated in a prospective, double-blind, cross-over study. The patients were randomized into 2 groups of either 3 continuous months’ L-T4 therapy followed by 3 months’ combination therapy or vice versa. In all periods, 50 μg L-T4 was blindly replaced by either (identical) 50 μg L-T4 or by 20 μg T3. L-T4 was hereafter adjusted to obtain normal serum TSH values. We investigated 3 single nucleotide polymorphisms (SNPs) on the type II iodothyronine deiodinase (DIO2) gene (rs225014 (Thr92Ala), rs225015, and rs12885300 (ORFa-Gly3Asp)) and 1 SNP on the cellular membrane transport-facilitating monocarboxylate transporter (MCT10) gene (rs17606253), and asked in which of the 2 treatment periods patients felt better (i.e., which treatment was preferred). Results: 27 out of 45 patients (60%) preferred the combination therapy. Two polymorphisms (rs225014 (DIO2, Thr92Ala) and rs17606253 (MCT10)) were combined yielding 3 groups: none vs. 1 of 2 vs. both SNPs present, and 42 vs. 63 vs. 100% of our patients in the 3 groups preferred the combined treatment (Jongheere-Terpstra trend test, p = 0.009). Conclusion: The present study indicates that the combination of polymorphisms in DIO2 (rs225014) and MCT10 (rs17606253) enhances hypothyroid patients’ preference for L-T4 + L-T3 replacement therapy. In the future, combination therapy may be restricted or may be even recommended to individuals harbouring certain polymorphisms.

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“…In the future, more polymorphisms will be studied. The study by Taylor et al [46] indicated that uncommon polymorphisms (MAF <1%) may have a very large impact on the associations studied.…”

Section: Discussionmentioning

confidence: 99%

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

et al. 2017

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“…Besides yielding the first examples of novel trait associations identified through population-based WGS 15,16, the project provided a large-scale empirical evaluation of strategies for testing associations in the low and rare allele frequency range. First, the study demonstrated an overall paucity of low-frequency alleles with high-penetrance in the space where it was powered (defined by each variant’s effect >1.2 standard deviations and MAF ~0.5%), suggesting that in this frequency range novel discoveries required larger samples with greater statistical power.…”

Section: Introductionmentioning

confidence: 99%

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Iotchkova¹,

Huang²,

Morris³

et al. 2016

Nat Genet

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Large-scale whole genome sequence datasets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole genome sequence data from the UK10K and the 1000 Genomes Projects into 35,981 study participants of European ancestry, followed by association analysis with twenty quantitative cardiometabolic and hematologic traits. We describe 17 novel associations, including six rare (minor allele frequency [MAF]<1%) or low frequency variants (1%

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“…This could be explained by a genetic influence, which has been shown to explain 65% of the variation in concentrations of thyroid stimulating hormone (TSH) and thyroxine (T4) in healthy adults [2]. Nineteen loci have been found to be associated with circulating TSH and six with free T4 (fT4) concentrations in genome-wide association studies (GWAS) in adults [3–12]. Despite a tight physiological regulation between TSH and fT4, these two hormones do not seem to share genetic influences [13].…”

Section: Introductionmentioning

confidence: 99%

“…Despite a tight physiological regulation between TSH and fT4, these two hormones do not seem to share genetic influences [13]. A recent study showed that all common variants could explain ~20% of the variation in TSH and fT4 concentrations [12]. However, the identified loci specific to TSH only explained a small part of the variation in TSH concentration, suggesting that a part of the missing heritability in relation to thyroid hormones might be explained by larger effects of rare or low-frequency variants [12].…”

Section: Introductionmentioning

confidence: 99%

A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents

et al. 2017

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BackgroundHypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.ObjectiveThis study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.MethodsGenome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5−24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2−22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.ResultsNo novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (PDE10A (rs2983511: β = 0.112SD, p = 4.8 ∙ 10−16), FOXE1 (rs7847663: β = 0.223SD, p = 1.5 ∙ 10−20), NR3C2 (rs9968300: β = 0.194SD), p = 2.4 ∙ 10−11), VEGFA (rs2396083: β = 0.088SD, p = 2.2 ∙ 10−10)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (p<0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.ConclusionIn a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.

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Whole-genome sequence-based analysis of thyroid function

Cited by 79 publications

References 42 publications

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents

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