Corrado Masciullo

A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.

Background Hepcidin is the main regulator of iron homeostasis: inappropriate production of hepcidin results in iron overload or iron deficiency and anaemia. Aims To study variation of serum hepcidin concentration in a normal population. Results Hepcidin showed age and sex dependent variations that correlated with ferritin but not with serum iron and transferrin saturation. The size of the study population was underpowered to find genome wide significant associations with hepcidin concentrations but it allowed to show that association with serum iron, transferrin saturation and erythrocyte traits of common DNA variants in HFE (rs1800562) and TMPRSS6 (rs855791) genes is not exclusively dependent on hepcidin values. When multiple interactions between environmental factors, the iron parameters and hepcidin were taken into account, the HFE variant, and to lesser extent the TMPRSS6 variant, were associated with ferritin and with hepcidin normalised to ferritin (the hepcidin/ferritin ratio). Conclusions The results suggest a mutual control of serum hepcidin and ferritin concentrations, a mechanism relevant to the pathophysiology of HFE haemochromatosis, and demonstrate that the HFE rs1800562 C282Y variant exerts a direct pleiotropic effect on the iron parameters, in part independent of hepcidin.

Increased Serum Hepcidin Levels in Subjects with the Metabolic Syndrome: A Population Study

The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS.

Evidence of Inbreeding Depression on Human Height

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

A genome-wide association study of early menopause and the combined impact of identified variants

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Heritability and Demographic Analyses in the Large Isolated Population of Val Borbera Suggest Advantages in Mapping Complex Traits Genes

Background Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South. Methodology/Principal Findings The study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits. Conclusions/Significance The data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations.

Serum levels of the hepcidin-20 isoform in a large general population: the Val Borbera study.

Hepcidin, a 25 amino-acid liver hormone, has recently emerged as the key regulator of iron homeostasis. Proteomic studies in limited number of subjects have shown that biological fluids can also contain truncated isoforms, whose role remains to be elucidated. We report, for the first time, data about serum levels of the hepcidin-20 isoform (hep-20) in a general population, taking advantage of the Val Borbera (VB) study where hepcidin-25 (hep-25) was measured by SELDI-TOF-MS. Detectable amount of hep-20 were found in sera from 854 out of 1577 subjects (54.2%), and its levels were about 14% of hep-25 levels. A small fraction of subjects (n = 30, 1.9%) had detectable hep-20 but undetectable hep-25. In multivariate regression models, significant predictors of hep-20 were hep-25 and age in males, and hep-25, age, serum ferritin and body mass index in females. Of note, the hep-25:hep-20 ratio was not constant in the VB population, but increased progressively with increasing ferritin levels. This is not consistent with the simplistic view of hep-20 as a mere catabolic byproduct of hep-25. Although a possible active regulation of hep-20 production needs further confirmation, our results may also have implications for immunoassays for serum hepcidin based on antibodies lacking specificity for hep-25. This article is part of a Special Issue entitled: Integrated omics.

Genome Wide Association Analysis of a Founder Population Identified TAF3 as a Gene for MCHC in Humans

The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5–10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E–09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.

Computer-based genealogy reconstruction in founder populations

This paper describes a software tool that reconstructs entire genealogies from data collected from different and heterogeneous sources, including municipal and parish records archived over centuries. The tool exploits a record linkage algorithm relying on a rule-based data matching approach. It applies a general strategy for managing the ambiguities due to missing, imprecise or erroneous input data. The process follows an iterative approach that combines automatic pedigree reconstruction with software-empowered human data revision to improve the quality and the accuracy of the results and to optimize the matching rules. The paper discusses the results obtained by reconstructing the entire genealogy of the population of the Val Borbera, a geographically isolated valley in Northern Italy. The genealogy could be reconstructed from data going back as far as the XVI century. The resulting pedigree includes 75,994 trios, 58.9% of which belonging to a unique big family, reconstructed over 13 generations.