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2.
Nat Genet ; 50(5): 652-656, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29662168

RESUMO

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

3.
Ann Hum Biol ; 45(1): 44-56, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29382284

RESUMO

BACKGROUND: Due to its central and strategic position in Europe and in the Mediterranean Basin, the Italian Peninsula played a pivotal role in the first peopling of the European continent and has been a crossroad of peoples and cultures since then. AIM: This study aims to gain more information on the genetic structure of modern Italian populations and to shed light on the migration/expansion events that led to their formation. SUBJECTS AND METHODS: High resolution Y-chromosome variation analysis in 817 unrelated males from 10 informative areas of Italy was performed. Haplogroup frequencies and microsatellite haplotypes were used, together with available data from the literature, to evaluate Mediterranean and European inputs and date their arrivals. RESULTS: Fifty-three distinct Y-chromosome lineages were identified. Their distribution is in general agreement with geography, southern populations being more differentiated than northern ones. CONCLUSIONS: A complex genetic structure reflecting the multifaceted peopling pattern of the Peninsula emerged: southern populations show high similarity with those from the Middle East and Southern Balkans, while those from Northern Italy are close to populations of North-Western Europe and the Northern Balkans. Interestingly, the population of Volterra, an ancient town of Etruscan origin in Tuscany, displays a unique Y-chromosomal genetic structure.


Assuntos
Cromossomos Humanos Y/genética , DNA Mitocondrial/genética , Variação Genética , Haplótipos , Repetições de Microssatélites , Humanos , Itália , Masculino
4.
J Am Soc Nephrol ; 29(1): 335-348, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29093028

RESUMO

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

5.
Front Surg ; 4: 40, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28791295

RESUMO

OBJECTIVE: To analyze the ovarian reserve via measurement of follicular density and anti-Müllerian hormone (AMH) in endometriosis patients participating to a clinical program of cortical ovarian cryopreservation. DESIGN: Retrospective analysis of serum AMH levels and prospective investigation of ovarian follicle number. SETTING: University Hospital. PATIENTS: Two hundred and two women with endometriosis and 400 controls. INTERVENTIONS: Blood samples and ovarian biopsies. MAIN OUTCOME MEASURES: Correlation of serum AMH levels and the number of non-growing follicles in the biopsied cortical tissues in endometriosis and control subjects, including age, type of AMH kit, and the laboratory performing the analysis as covariates. RESULTS: AMH levels were shown to decrease with age in untreated endometriosis patients (P < 1.0 × 10-5) but they were significantly lower in endometriosis compared to controls only in patients over 36 years old (P = 2.7 × 10-4). The AMH decrease was faster in endometriosis compared to controls (beta = 0.27, P = 4.0 × 10-4). Primordial follicle number decreased with the reduction of AMH levels in both cases and controls (beta = 0.3; P = 0.04). CONCLUSION: AMH is a reliable marker of ovarian reserve in endometriosis patients, and it can predict follicular density in women undergoing ovarian tissue cryopreservation.

6.
Nat Commun ; 8: 15927, 2017 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-28643794

RESUMO

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.

7.
Blood ; 129(25): 3371-3378, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28424163

RESUMO

Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of, developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 or more mutations, had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and comutation patterns involving TET2, DNMT3A, or ASXL1 had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio = 13.9, P < .001). The predictive values of mutation analysis were confirmed in the independent validation cohort. The findings of this study indicate that mutation analysis on peripheral blood granulocytes may significantly improve the current diagnostic approach to unexplained cytopenia and more generally the diagnostic accuracy of myeloid neoplasms.


Assuntos
Anemia/genética , Neoplasias Hematológicas/genética , Mutação , Pancitopenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Estudos Prospectivos , Adulto Jovem
8.
Brain ; 140(3): 555-567, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28073787

RESUMO

Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target.


Assuntos
Colágeno Tipo VI/genética , Saúde da Família , Variação Genética/genética , Doenças do Sistema Nervoso Periférico/genética , Prurido/genética , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Prurido/complicações , Prurido/patologia , Pele/inervação , Pele/metabolismo , Pele/patologia
9.
J Clin Endocrinol Metab ; 102(2): 576-582, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27802094

RESUMO

Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. Setting: Academic research institution. Participants: All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels. Interventions: None. Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway. Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.


Assuntos
Envelhecimento/genética , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Manutenção de Minicromossomo/genética , Insuficiência Ovariana Primária/genética , Adulto , Feminino , Humanos , Análise de Sequência de DNA
10.
Pflugers Arch ; 469(1): 91-103, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27915449

RESUMO

The nature and importance of genetic factors regulating the differential handling of Ca2+ and Mg2+ by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10-12), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg2+ over Ca2+ in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.


Assuntos
Cálcio/urina , Claudinas/genética , Magnésio/urina , Polimorfismo de Nucleotídeo Único/genética , Urina/química , Animais , Cálcio/metabolismo , Humanos , Túbulos Renais/metabolismo , Magnésio/metabolismo
11.
PLoS One ; 11(11): e0166628, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27846281

RESUMO

Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants.


Assuntos
Predisposição Genética para Doença , Hepcidinas/genética , Inflamação/genética , Ferro/sangue , Eritropoese/genética , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hepcidinas/sangue , Humanos , Inflamação/sangue , Inflamação/patologia , Masculino , Polimorfismo de Nucleotídeo Único
12.
Rev Endocr Metab Disord ; 17(2): 209-19, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27129595

RESUMO

Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 × 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.


Assuntos
Preferências Alimentares/fisiologia , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos
13.
PLoS Genet ; 12(2): e1005874, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26910538

RESUMO

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.


Assuntos
Loci Gênicos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Cromossomos Humanos , Grupo com Ancestrais do Continente Europeu/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Nat Genet ; 47(11): 1272-1281, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26366554

RESUMO

We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.


Assuntos
Biomarcadores/sangue , Variação Genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Lipídeos/sangue , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Efeito Fundador , Frequência do Gene , Genética Populacional , Genótipo , Geografia , Haplótipos , Humanos , Mediadores da Inflamação/sangue , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
15.
Nat Commun ; 6: 7846, 2015 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-26242864

RESUMO

Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination.


Assuntos
Troca Genética , Idade Materna , Recombinação Genética , Aneuploidia , Teorema de Bayes , Estudos de Coortes , Humanos , Modelos Lineares , Modelos Genéticos
17.
Nat Commun ; 6: 5681, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25743335

RESUMO

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.


Assuntos
Sinapsinas/metabolismo , Glândula Tireoide/fisiologia , Tireotropina/metabolismo , Tiroxina/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/genética , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Estudos de Coortes , Metilação de DNA/genética , Estudos de Associação Genética , Genômica/métodos , Humanos , Sinapsinas/genética , Glândula Tireoide/metabolismo , Tireotropina/genética , Tiroxina/genética , Reino Unido
18.
Eur J Hum Genet ; 23(12): 1717-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25758996

RESUMO

Wine is the most popular alcoholic beverage around the world and because of its importance in society has been widely studied. Understanding what drives its flavor has been a quest for decades but much is still unknown and will be determined at least in part by individual taste preferences. Recently studies in the genetics of taste have uncovered the role of different genes in the determination of food preferences giving new insight on its physiology. In this context we have performed a genome-wide association study on red and white wine liking using three isolated populations collected in Italy, and replicated our results on two additional populations coming from the Netherland and Central Asia for a total of 3885 samples. We have found a significant association (P=2.1 × 10(-8)) between white wine liking and rs9276975:C>T a polymorphism in the HLA-DOA gene encoding a non-canonical MHC II molecule, which regulates other MHC II molecules. The same association was also found with red wine liking (P=8.3 × 10(-6)). Sex-separated analysis have also revealed that the effect of HLA-DOA is twice as large in women as compared to men suggesting an interaction between this polymorphism and gender. Our results are one of the first examples of genome-wide association between liking of a commonly consumed food and gene variants. Moreover, our results suggest a role of the MHC system in the determination of food preferences opening new insight in this field in general.


Assuntos
Preferências Alimentares , Antígenos HLA-D/genética , Polimorfismo de Nucleotídeo Único , Vinho , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
PLoS Genet ; 10(4): e1004234, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24743097

RESUMO

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.


Assuntos
Haplótipos/genética , Mapeamento Cromossômico/métodos , Efeito de Coortes , Família , Genótipo , Humanos , Modelos Genéticos , Linhagem , Fenótipo , Recombinação Genética/genética
20.
PLoS One ; 9(3): e92065, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24647340

RESUMO

Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs) variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R) on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.


Assuntos
Café , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Acoplados a Proteínas-G/genética , Paladar/genética , Humanos
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