The genetic basis of thyroid function: Novel findings and new approaches

Context: Genetic factors are major determinants of thyroid function. Over the last two decades,multiple genetic variants have been associated with variations in normal range thyroid functiontests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number ofknown variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels.Evidence Acquisition: This review summarizes the results of genetic association studies onnormal range thyroid function and explores how these genetic variants can be used in futurestudies to improve our understanding of thyroid hormone regulation and disease.Evidence Synthesis: Serum TSH and FT4 levels are determined by multiple genetic variantson virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional followup studies on top of GWAS hits has the potential to discover new key players in thyroidhormone regulation, as exemplified by the identification of the thyroid hormone transporterSLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these geneticvariants to investigate causal associations between thyroid function and various outcomes inMendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroiddysfunction, and to predict the individual HPT axis setpoint.Conclusions: Recent genetic studies have greatl

Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study

Final publication is available from Mary Ann Liebert, Inc., publishers https://doi.org/10.1089/thy.2020.0393

Comparison of genotyping using pooled DNA samples (allelotyping) and individual genotyping using the affymetrix genome-wide human SNP array 6.0

Background: Genome-wide association studies (GWAS) using array-based genotyping technology are widely used to identify genetic loci associated with complex diseases or other phenotypes. The costs of GWAS projects based on individual genotyping are still comparatively high and increase with the size of study populations. Genotyping using pooled DNA samples, as also being referred as to allelotyping approach, offers an alternative at affordable costs. In the

Limited evidence for blood eQTLs in human sexual dimorphism

The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits. To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs. Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis-eQTLs. Compensatory effects may further hamper their detection. Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs

The Composition of the Modernist Book: Ulysses, A Draft of XXX Cantos and The Making of Americans.

This is a study of the composition of three Modernist first editions: Ulysses (1922), The Making of Americans (1925) and A Draft of XXX Cantos (1930). The bibliographical and figurative commitments made to being in print by Ulysses, A Draft of XXX Cantos and The Making of Americans set a coherent program for reading Modernist texts in their perfected form: in print. The editorial reception of the Modernist book has proceeded, however, with reference to the editorial and bibliographical principles established by the New Bibliographers. In deferring to the authors and manuscripts of Modernist books as the highest source of textual authority, the vital significance of being in print to literary Modernism is obscured. The figure of the ideal Book concentrates the central aesthetic, intellectual and bibliographic problem posed the Modernist book: the making of literature. The rhyme with The Making of Americans is appropriate: this book intensifies and consolidates the propositions made about objective and autonomous composition made more hesitantly by Ulysses and A Draft of XXX Cantos. These three books display a gradual refusal to equate inscription and intention; their composition effaces all traces of a sovereign creative subjectivity. The vision of the book guides Modernist composition, and requires a critical distinction be drawn between manuscripts and printed letters. Modernism must be read in print. The vestigial nostalgia for Romantic modes of textual production and creation in Ulysses is repeated on the placards and proof-pages for the book. Printed drafts are revised and reformed by the pen of the author. The finality asserted by the printed letter is only reluctantly ceded on the publication of Ulysses. The composition of A Draft of XXX Cantos represents a further transition away from the script economy of Romanticism. The interplay between authorial typescripts, early publications and the first edition of A Draft of XXX Cantos assert an intermediate order of Modernist textuality which takes the printed page as its foundation. The Making of Americans relies on the absolute objectivity and anonymity of its composition for the effect of its narrative. Objectivity is the intellectual and aesthetic strategy which produces literature rather than the personality and memory of the author. The impersonality of the apparently automatically written manuscripts and scarcely revised typescripts for The Making of Americans severs the visible links between the writing author and her page. In their unwillingness to corroborate the modes of textual generation described by the New Bibliographers, these three books thematise their own composition as the exemplary Modernist and modern mode of textual generation. The Modernist book attenuates or denies a Romantic connection between the creative hand of the author and the surface image of the page: the mechanisms of print deliberately detach the author from the literary text. The distance of the author from the scene of textual reproduction is measured by the printed book. The composition of this analytical object is not a fallacy but an actuality, commemorated in the archive, enacted by the book. Modernism is the literature of the imprimatur rather than of authorial inscription and accordingly it is towards the first editions of Modernist texts that the attentions of editors and textual scholars must be directed

Novel associations for hypothyroidism include known autoimmune risk loci

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near _PTPN22_ and rs3184504 in _SH2B3_ (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near _VAV3_ (p-value 8.3e-11), another gene involved in immune function, and rs965513 near _FOXE1_ (p-value 3.1e-14). Of these, the association with _PTPN22_ confirms a recent small candidate gene study, and _FOXE1_ was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although _SH2B3_ has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The _VAV3_ association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1

Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome.

Comparing transcript levels between healthy and diseased individuals allows the identification of differentially expressed genes, which may be causes, consequences or mere correlates of the disease under scrutiny. We propose a method to decompose the observational correlation between gene expression and phenotypes driven by confounders, forward- and reverse causal effects. The bi-directional causal effects between gene expression and complex traits are obtained by Mendelian Randomization integrating summary-level data from GWAS and whole-blood eQTLs. Applying this approach to complex traits reveals that forward effects have negligible contribution. For example, BMI- and triglycerides-gene expression correlation coefficients robustly correlate with trait-to-expression causal effects (r <sub>BMI </sub> = 0.11, P <sub>BMI </sub> = 2.0 × 10 <sup>-51</sup> and r <sub>TG </sub> = 0.13, P <sub>TG </sub> = 1.1 × 10 <sup>-68</sup> ), but not detectably with expression-to-trait effects. Our results demonstrate that studies comparing the transcriptome of diseased and healthy subjects are more prone to reveal disease-induced gene expression changes rather than disease causing ones

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health

White Blood Cells and Blood Pressure: A Mendelian Randomization Study

Background: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. Methods: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. Results: A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. Conclusions: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP