Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis

Gilles de la Tourette Sydrome (TS) is a childhood onset neurodevelopmental disorder, characterized phenotypically by the presence of multiple motor and vocal tics. It is often accompanied by multiple psychiatric comorbidities, with Attention Deficit/Hyperactivity Disorder (ADHD) among the most common. The extensive co-occurrence of the two disorders suggests a shared genetic background. A major step toward the elucidation of the genetic architecture of TS was undertaken by the first TS Genome-wide Association Study (GWAS) reporting 552 SNPs that were moderately associated with TS (p < 1E-3). Similarly, initial ADHD GWAS attempts and meta-analysis were not able to produce genome-wide significant findings, but have provided insight to the genetic basis of the disorder. Here, we examine the common genetic background of the two neuropsychiatric phenotypes, by meta-analyzing the 552 top hits in the TS GWAS with the results of ADHD first GWASs. We identify 19 significant SNPs, with the top four implicated genes being TBC1D7, GUCY1A3, RAP1GDS1, and CHST11. TBCD17 harbors the top scoring SNP, rs1866863 (p:3.23E-07), located in a regulatory region downstream of the gene, and the third best-scoring SNP, rs2458304 (p:2.54E-06), located within an intron of the gene. Both variants were in linkage disequilibrium with eQTL rs499818, indicating a role in the expression levels of the gene. TBC1D7 is the third subunit of the TSC1/TSC2 complex, an inhibitor of the mTOR signaling pathway, with a central role in cell growth and autophagy. The top genes implicated by our study indicate a complex and intricate interplay between them, warranting further investigation into a possibly shared etiological mechanism for TS and ADHD

Maritime route of colonization of Europe

The Neolithic populations, which colonized Europe approximately 9,000 y ago, presumably migrated from Near East to Anatolia and from there to Central Europe through Thrace and the Balkans. An alternative route would have been island hopping across the Southern European coast. To test this hypothesis, we analyzed genome-wide DNA polymorphisms on populations bordering the Mediterranean coast and from Anatolia and mainland Europe. We observe a striking structure correlating genes with geography around the Mediterranean Sea with characteristic east to west clines of gene flow. Using population network analysis, we also find that the gene flow from Anatolia to Europe was through Dodecanese, Crete, and the Southern European coast, compatible with the hypothesis that a maritime coastal route was mainly used for the migration of Neolithic farmers to Europe

Υπολογιστικές μέθοδοι ανάλυσης γονιδιακής έκφρασης και ποικιλότητας σε επίπεδο γονιδιώματος

My PhD thesis focuses on the computational methods and pipelines to analyse data of different types of genomic, transcriptomic and epigenomic data with applications to understand the aetiology of Gilles de la Tourette Syndrome (GTS), a psychiatric disorder of complex background. Advancements in microarray technologies have made possible the genomewide analysis of large patient cohorts producing vast amounts of data. The analysis of big data from microarray technologies has to tackle a wide-range of problems; from basic quality control to complex association models. Analysis of such big data are subjected to rigorous quality filters at variant and sample levels to remove technical problems which reduces the false positive results in the association. Here we put forward the computational methods and pipelines to address genomewide gene expression, Single Nucleotide Polymorphisms (SNPs), Copy Number Variants (CNVs) and DNA Methylation marker studies. Our applications on GTS shed light into the aetiology of the disorder, implicating several candidate susceptibility genes that warrant further investigation.Η διδακτορική μου διατριβή επικεντρώνεται στις υπολογιστικές μεθόδους και τα σύνολα εντολών για την ανάλυση διαφορετικών τύπων γονιδιωματικών, μεταγραφικών και επιγονιδιωματικών δεδομένων με στόχο την κατανόηση της αιτιολογίας του συνδρόμου Gilles de la Tourette (GTS), μιας ψυχιατρικής διαταραχής πολύπλοκου υποβάθρου. Οι εξελίξεις στις τεχνολογίες μικροσυστοιχιών έχουν καταστήσει δυνατή την ανάλυση του γονιδιώματος μεγάλων ομάδων ασθενών παράγοντας τεράστιο όγκο δεδομένων. Η ανάλυση του μεγάλου όγκου δεδομένων από τις τεχνολογίες μικροσυστοιχιών πρέπει να αντιμετωπίσει ένα ευρύ φάσμα προβλημάτων, που εκτείνονται από το βασικό έλεγχο ποιότητας έως τα πολύπλοκα μοντέλα συσχέτισης. Η ανάλυση τέτοιων δεδομένων μεγάλου όγκου υποβάλλονται σε αυστηρό ποιοτικό έλεγχο τόσο σε επίπεδο παραλλαγών όσο και επίπεδο δειγμάτων για την εξάλειψη τεχνικών προβλημάτων που μειώνουν τα ψευδώς θετικά αποτελέσματα της συσχέτισης. Εδώ παρουσιάζουμε τις υπολογιστικές μεθόδους και τα σύνολα εντολών που χρησιμοποιούνται για την ανάλυση της γονιδιακής έκφρασης σε επίπεδο ολόκληρου του γονιδιώματος, των μονονουκλεοτιδικών πολυμορφισμών (SNPs), των παραλλαγών αριθμού αντιγράφων (CNVs) και των μελετών δεικτών μεθυλίωσης DNA. Η εφαρμογή των παραπάνω μεθόδων στο GTS ρίχνουν φως στην αιτιολογία της διαταραχής, εμπλέκοντας πολλά υποψήφια γονίδια προδιάθεσης που δικαιολογούν περαιτέρω διερεύνηση

Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.Peer reviewe