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Identifying rare recessive variants involved in Differentiated Thyroid Cancer susceptibility
Project: Recessive variants are likely to play an important role in human diseases. Indeed, it has long been known, from mutagenesis studies in many different diploid organisms, that the majority (over 90%) of variations are recessive to the wild type . Disease predisposing genes affected by recessive pathogenic alleles are also less conserved than those affected by dominant variants and this could probably be due to the fact that recessive pathogenic alleles could remain hidden from selection while at the heterozygous state . The power of association tests to detect the effect of recessive alleles is however limited as these tests usually assume an additive model that performs especially poorly for low-frequency recessive causal alleles .
In a proof of concept article , we have proposed a new strategy (HBD-GWAS) that focuses on inbred individuals in large genome-wide association study (GWAS) projects in order to identify rare recessive variants involved in complex traits. We showed by simulation that it has a higher power than the affected sib-pair approach when there exists a strong allelic heterogeneity. The HBD-GWAS approach was illustrated on WTCCC1 Type-2 diabetes and it identified a region where a 45-kb deletion and rare causing alleles had been previously associated with obesity . The strength of the approach is that it directly works on genotypes of haplotypes, i.e. the regions of the genome that are detected homozygous-by-descent (HBD) by the approach. It can hence capture the effect of multiple rare variants acting recessively in a genomic region.
In this project, we would like to study Differentiated Thyroid Cancer (DTC) susceptibility with the HBD-GWAS approach to identify new variants acting recessively in such pathology. The method will be compared with Runs of Homozygosity (ROH) approaches that have been previously used in DTC .
The multi-ethnic sample is composed of 2,522 cases and 3,458 controls from the EPITHYR international network (Metropolitan France, Polynesia, New Caledonia, Cuba, Belarus) and from the European cohort EPIC (France, Italy, Spain, UK, Netherlands, Germany, Sweden, Denmark, Norway). Individuals have been genotyped with the Illumina OncoArray chip (~500,000 SNPs).
The intern will be in charge of the quality control and analyses of the data. The work will be done in collaboration with Fabienne Lesueur (Inserm U900, Curie Institute) and a Ph.D. student for the ROH comparison.
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 Génin E, Sahbatou M, Gazal S, Babron MC, Perdry H, Leutenegger AL. Could inbred cases identified in GWAS data succeed in detecting rare recessive variants where affected sib-pairs have failed? Hum Hered. 2012;74(3-4):142-52.
 Willer CJ, Speliotes EK, Loos RJ, et al: Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25–34.
 Thomsen H, Chen B, Figlioli G, Elisei R, Romei C, Cipollini M, Cristaudo A, Bambi F, Hoffmann P, Herms S, Landi S, Hemminki K, Gemignani F, Försti A. Runs of homozygosity and inbreeding in thyroid cancer. BMC Cancer. 2016 Mar 16;16:227
Qualifications: internship for master or engineering school students in genetic epidemiology, biostatistics, bioinformatics or other quantitative fields. Strong interest in genetics. Knowledge in a computer language such as R or Perl. UNIX environments.
Contact : send CV and cover letter to Anne-Louise Leutenegger, email@example.com (Inserm U946 Genetic Variation and Human Diseases Lab, Paris), and Thérèse Truong, firstname.lastname@example.org (Inserm U1018, CESP -Centre de Recherche en Épidémiologie et Santé des Populations, Villejuif).
Location: the intern will be located at CESP in Paul Brousse Hospital (Villejuif) with regular meetings at Inserm U946 in Robert Debré Hospital (Paris).
Start date: Any time in 2021 for a minimum of 5 months