A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma.

Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637

Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator

Although many genetic variants are known for obesity, their function remains largely unknown. Here, in a weight-loss intervention cohort, the authors identify protein quantitative trait loci associated with BMI at baseline and after weight loss and find FAM46A to be a regulator of leptin in adipocytes

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis

Compositeurs et réalisateurs en duo. Dix-sept études musico-filmiques

International audienceLes dix-sept études musico-filmiques proposées par l’ouvrage tentent de dégager les traits stylistiques marquants de duos entre réalisateurs et compositeurs par-delà la diversité de leurs œuvres.Les duos de créateurs, particulièrement en ce qui concerne les réalisateurs et les compositeurs, sont souvent l’objet d’une idéalisation, et il est fréquent de trouver des expressions comme « accords parfaits », « relation fusionnelle », tandem, frères, couple… L’ouvrage tente de dépasser ce stade pour travailler la notion de duo en proposant plusieurs stades, de la collaboration « au service de l’émotion collective », où la créativité reste soumise à des impératifs de divertissement et de rentabilité, à « l’alchimie cinémusicale » où le duo est peu à peu amené à élaborer une poétique musico-filmique qui lui est propre

Compositeurs et réalisateurs en duo. Dix-sept études musico-filmiques

International audienceLes dix-sept études musico-filmiques proposées par l’ouvrage tentent de dégager les traits stylistiques marquants de duos entre réalisateurs et compositeurs par-delà la diversité de leurs œuvres.Les duos de créateurs, particulièrement en ce qui concerne les réalisateurs et les compositeurs, sont souvent l’objet d’une idéalisation, et il est fréquent de trouver des expressions comme « accords parfaits », « relation fusionnelle », tandem, frères, couple… L’ouvrage tente de dépasser ce stade pour travailler la notion de duo en proposant plusieurs stades, de la collaboration « au service de l’émotion collective », où la créativité reste soumise à des impératifs de divertissement et de rentabilité, à « l’alchimie cinémusicale » où le duo est peu à peu amené à élaborer une poétique musico-filmique qui lui est propre

Compositeurs et réalisateurs en duo. Dix-sept études musico-filmiques

International audienceLes dix-sept études musico-filmiques proposées par l’ouvrage tentent de dégager les traits stylistiques marquants de duos entre réalisateurs et compositeurs par-delà la diversité de leurs œuvres.Les duos de créateurs, particulièrement en ce qui concerne les réalisateurs et les compositeurs, sont souvent l’objet d’une idéalisation, et il est fréquent de trouver des expressions comme « accords parfaits », « relation fusionnelle », tandem, frères, couple… L’ouvrage tente de dépasser ce stade pour travailler la notion de duo en proposant plusieurs stades, de la collaboration « au service de l’émotion collective », où la créativité reste soumise à des impératifs de divertissement et de rentabilité, à « l’alchimie cinémusicale » où le duo est peu à peu amené à élaborer une poétique musico-filmique qui lui est propre

Estimating penetrance from family data using a retrospective likelihood when ascertainment depends on genotype and age of onset.: Estimating penetrance from family data

International audienceIn diseases caused by deleterious gene mutations, knowledge of age-specific cumulative risks is necessary for medical management of mutation carriers. When pedigrees are ascertained through several affected persons, ascertainment bias can be corrected by using a retrospective likelihood. This likelihood is a function of the genotypes of pedigree members given their phenotypes and provides unbiased estimates of penetrance without modeling the selection process, provided that selection is independent of genotypes. However, since mutation testing is offered only to relatives of mutation carriers, the genotypes of family members are available only in mutated families and selection does depend on genotype. In the present study, we quantified the bias due to selection on genotype using simulations. We found that this bias depended on the true penetrance value: the lower the penetrance, the higher the bias (risk by age 80 estimated to be 46% for a true penetrance value of 20%). When age of onset is added to the selection criteria, as usually done, we showed that the bias was even higher. We modified the conditioning in the retrospective likelihood, what we call "genotype restricted likelihood" (GRL). Using simulations, we show that this method provided unbiased parameter estimates under all the selection designs considered

Autism risk assessment in siblings of affected children using sex-specific genetic scores.

International audienceUNLABELLED: ABSTRACT: BACKGROUND: The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system. METHODS: SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism. RESULTS: We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 × 10-6 and 1.9 × 10-5, respectively). CONCLUSIONS: Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism

Cognitive behavioral therapy combined with physical exercise for depression, anxiety, fatigue and pain in adults with chronic diseases: Systematic review and meta-analysis

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