Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest ...familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome‐wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population‐based case‐control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray‐500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid‐stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.
What's new?
Differentiated thyroid carcinoma (DTC) has a strong genetic component, and Pacific Islanders have a particularly high incidence of the disease. Here, the authors conducted a genome‐wide association study (GWAS) in a mixed population including individuals of European and Pacific Islander ancestry. The study drew from the EPITHYR consortium, a collection of 2000 DTC cases and age‐matched controls. The analysis confirmed 5 previously known susceptibility loci and identified 2 new ones. Three of these loci were more prevalent among Pacific Islanders. More studies are needed to fully account for the rate of DTC in that population.
Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic ...causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.
Background PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds low-density lipoprotein receptor, preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis. The ...PCSK9-rs562556 variant has been reported as a gain-of-function mutation. The aim of this study was to determine whether the PCSK9-low-density lipoprotein receptor-rs562556 axis is associated with carotid artery plaques between 2 visits separated by almost 20 years in a longitudinal population cohort. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort is a longitudinal familial cohort from the Lorraine region of France. Participants attending 2 visits (visit 1 and visit 4) separated by 18.5 years (mean) were included (n=997). Carotid artery plaques were determined with standardized vascular echography. The mean age of the adult population at visit 1 was 42±5 years. At visit 4, 203 (20.4%) participants had arterial plaques. Participants who developed arterial plaques were older (42.7±5.4 versus 41.7±4.7 years), more often male (60% versus 49%), smokers (29% versus 18%), with diabetes mellitus (6% versus 3%), and higher cholesterol levels (low-density lipoprotein cholesterol, 1.6±0.4 versus 1.5±0.3 g/L) (all
<0.05). The independent factors associated with arterial plaques were age, smoking, and low-density lipoprotein cholesterol. Higher PCSK9 levels were associated with arterial plaques on top of the clinical model (odds ratio, 2.14; 95% CI,= 1.28-3.58); the missense mutation coding the single-nucleotide polymorphism rs562556 was associated with both higher PCSK9 concentration and incident carotid arterial plaques. Conclusions Higher PCSK9 concentration was associated with the development of arterial plaques almost 20 years in advance in a healthy middle-aged population. Mutations of the single-nucleotide polymorphism rs562556 associated with both PCSK9 levels and arterial plaques reinforce the potential causality of our findings. PCSK9 inhibitors could be useful for primary cardiovascular prevention.
Background Hyperuricemia is associated with poor cardiovascular outcomes, although it is uncertain whether this relationship is causal in nature. This study aimed to: (1) assess the heritability of ...serum uric acid (SUA) levels, (2) conduct a genome-wide association study on SUA levels, and (3) investigate the association between certain single-nucleotide polymorphisms and target organ damage. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) study cohort is a single-center longitudinal cohort recruited between 1993 and 1995 (visit 1), with a last visit (visit 4 V4) performed ≈20 years apart. Serum lipid profile, SUA, urinary albumin/creatinine ratio, estimated glomerular filtration rate, 24-hour ambulatory blood pressure monitoring, transthoracic echocardiography, pulse wave velocity, and genotyping for each participant were assessed at V4. A total of 1573 participants were included at V4, among whom 1417 had available SUA data at visit 1. Genome-wide association study results highlighted multiple single-nucleotide polymorphisms on the
gene linked to SUA levels. Carriers of the most associated mutated
allele (
) had significantly lower SUA levels. Although SUA level at V4 was highly associated with diabetes, prediabetes, higher body mass index, CRP (C-reactive protein) levels, estimated glomerular filtration rate variation (visit 1-V4), carotid intima-media thickness, and pulse wave velocity,
was only associated with higher carotid intima-media thickness. Conclusions Our findings demonstrate that
, a genetic determinant of SUA levels located on the
gene, is associated with carotid intima-media thickness despite significant associations between SUA levels and several clinical outcomes, thereby lending support to the hypothesis of a link between SUA and cardiovascular disease.
A fundamental shortcoming in the current treatment of schizophrenia is the lack of valid criteria to predict who will respond to antipsychotic treatment. The identification of blood-based biological ...markers of the therapeutic response would enable clinicians to identify the subgroup of patients in whom conventional antipsychotic treatment is ineffective and offer alternative treatments. As part of the Optimisation of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) programme, we conducted an RNA-Seq analysis on 188 subjects with first episode psychosis, all of whom were subsequently treated with amisulpride for 4 weeks. We compared gene expression on total RNA from patients' blood before and after treatment and identified 32 genes for which the expression changed after treatment in good responders only. These findings were replicated in an independent sample of 24 patients with first episode psychosis. Six genes showed a significant difference in expression level between good and poor responders before starting treatment, allowing to predict treatment outcome with a predictive value of 93.8% when combined with clinical features. Collectively, these findings identified new mechanisms to explain symptom improvement after amisulpride medication and highlight the potential of combining gene expression profiling with clinical data to predict treatment response in first episode psychoses.
Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide ...complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
Next-generation sequencing (NGS) studies are becoming routinely used for the detection of novel and clinically actionable DNA variants at a pangenomic scale. Such analyses are now used in the ...clinical practice to enable precision medicine. Formalin-fixed paraffin-embedded (FFPE) tissues are still one of the most abundant source of cancer clinical specimen, unfortunately this method of preparation is known to degrade DNA and therefore compromise subsequent analysis. Some studies have reported that variant detection can be performed on FFPE samples sequenced with NGS techniques, but few or none have done an in-depth coverage analysis and compared the influence of different state-of-the-art FFPE DNA extraction kits on the quality of the variant calling. Here, we generated 42 human whole-exome sequencing data sets from fresh-frozen (FF) and FFPE samples. These samples include normal and tumor tissues from two different organs (liver and colon), that we extracted with three different FFPE extraction kits (QIAamp DNA FFPE Tissue kit and GeneRead DNA FFPE kit from Qiagen, Maxwell™ RSC DNA FFPE Kit from Promega). We determined the rate of concordance of called variants between matched FF and FFPE samples on all common variants (representing at least 86% of the total number of variants for SNVs). The concordance rate is very high between all matched FF / FFPE pairs, with equivalent values for the three kits we analyzed. On the other hand, when looking at the difference between the total number of variants in FF and FFPE, we find a significant variation for the three different FFPE DNA extraction kits. Coverage analysis shows that FFPE samples have less good indicators than FF samples, yet the coverage quality remains above accepted thresholds. We detect limited but statistically significant variations in coverage indicator values between the three FFPE extraction kits. Globally, the GeneRead and QIAamp kits have better variant calling and coverage indicators than the Maxwell kit on the samples used in this study, although this kit performs better on some indicators and has advantages in terms of practical usage. Taken together, our results confirm the potential of FFPE samples analysis for clinical genomic studies, but also indicate that the choice of a FFPE DNA extraction kit should be done with careful testing and analysis beforehand in order to maximize the accuracy of the results.
Aims
Elevated brain natriuretic peptide (BNP) and the N‐terminal fragment of its pro‐hormone (NT‐proBNP) have become established biomarkers for heart failure and are associated with cardiovascular ...morbidity and mortality. Investigating sources of inter‐individual heterogeneity, particularly genetic factors, could help better identify patients at risk of future cardiovascular disease. The aim of this study was to estimate the heritability of circulating NT‐proBNP levels, to perform a genome‐wide association study (GWAS) and gene‐candidate analysis focused on NPPB–NPPA genes on these levels, and to examine their association with cardiovascular or metabolic outcomes.
Methods and results
A total of 1555 individuals from the STANISLAS study were included. The heritability of circulating NT‐proBNP levels was estimated at 15%, with seven single nucleotide polymorphisms (SNPs) reaching the significant threshold in the GWAS. All above SNPs were located on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. NPPA gene expression was also associated with NT‐proBNP levels. Moreover, six other SNPs from NPPA–NPPB genes were associated with diastolic function (lateral e′ on echocardiography) and metabolic features (glycated haemoglobin).
Conclusions
The heritability of natriuretic peptides appears relatively low (15%) and mainly based on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. Natriuretic peptide polymorphisms are associated with natriuretic peptide levels and diastolic function. These results suggest that natriuretic peptide polymorphisms may have an impact in the early stages of cardiovascular and metabolic disease.
Background: High-throughput next generation sequencing (NGS) technologies enable the detection of biomarkers used for tumor classification, disease monitoring and cancer therapy. Whole-transcriptome ...analysis using RNA-seq is important, not only as a means of understanding the mechanisms responsible for complex diseases but also to efficiently identify novel genes/exons, splice isoforms, RNA editing, allele-specific mutations, differential gene expression and fusion-transcripts or chimeric RNA (chRNA).
Methods: We used
Crac, a tool that uses genomic locations and local coverage to classify biological events and directly infer splice and chimeric junctions within a single read. Crac's algorithm extracts transcriptional chimeric events irrespective of annotation with a high sensitivity, and
CracTools was used to aggregate, annotate and filter the chRNA reads. The selected chRNA candidates were validated by real time PCR and sequencing. In order to check the tumor specific expression of chRNA, we analyzed a publicly available dataset using a new tag search approach.
Results: We present data related to acute myeloid leukemia (AML) RNA-seq analysis. We highlight novel biological cases of chRNA, in addition to previously well characterized leukemia chRNA. We have identified and validated 17 chRNAs among 3 AML patients: 10 from an AML patient with a translocation between chromosomes 15 and 17 (AML-t(15;17), 4 from patient with normal karyotype (AML-NK) 3 from a patient with chromosomal 16 inversion (AML-inv16). The new fusion transcripts can be classified into four groups according to the exon organization.
Conclusions: All groups suggest complex but distinct synthesis mechanisms involving either collinear exons of different genes, non-collinear exons, or exons of different chromosomes. Finally, we check tumor-specific expression in a larger RNA-seq AML cohort and identify new AML biomarkers that could improve diagnosis and prognosis of AML.
Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of ...idiopathic membranous nephropathy in a white population.
We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method).
In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2).
An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.
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