Visa genoma asociācijas pētījumā identificēti četri riska polimorfismi un izveidots poligēnā riska modelis 2. tipa diabēta pacientiem Latvijas populācijā
Date
2020
Authors
Reščenko, Raimonds
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Journal ISSN
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Publisher
Latvijas Universitāte
Abstract
Maģistra darbs veltīts 2. tipa cukura diabēta ģenētisko cēloņu izpētei Latvijas populācijā, kā arī automatizētas visa genoma asociācijas pētījumu darbplūsmas programmas izveidei. Darba ietvaros noskaidroti četri Latvijā bieži sastopami viena nukleotīda polimorfismi, kas būtiski asociēti ar 2. tipa cukura diabēta risku. Trīs no tiem atrodas gēnos LOC105370658, STK39 un BTNL2, kas ekspresējas un ir nozīmīgi aizkuņģa dziedzera insulīnu sekretējošo beta šūnu darbībā. Apvienojot 41 polimorfismu poligēnā riska modelī (PRS), izskaidroti 11% no slimības variācijas ar AUC 0.69. Cilvēkiem ar augstāko noteikto PRS ir 2.8 reizes palielināts 2. tipa diabēta risks, salīdzinot ar vidējo. Papildus tam, Latvijas populācijā fiksēta būtiska stratifikācija starp etniskās un reģionālās piederības grupu ģenētisko fonu, kas turpmāk jāņem vērā visa genoma asociāciju pētījumos. Visu augstāk minēto datu analīzes posmu automatizēšanai izveidota programmatūra, kas publicēta GitHub repozitorijā. Darbs izstrādāts Latvijas Biomedicīnas pētījumu un studiju centra Cilvēka ģenētikas un molekulārās medicīnas grupas ietvaros no 2018. gada aprīļa līdz 2020. gada maijam.
Whole genome association study of type 2 diabetes mellitus identifies four risk polymorphisms and develops polygenic risk model in Latvian population Masters thesis was devoted to investigation of genetic causes of type 2 diabetes mellitus in population of Latvia, as well as creation of automatic pipeline software for whole genome association studies. In this work we discover four genome wide significant associations with type 2 diabetes risk. These variants function in relation to pancreatic beta cells. Incorporating 41 independed loci variants, we propose a poligenic risk score. It explains 11% of disease variation in Latvian population and shows factor of 2.8 increase in risk for highest quartile, compared to average. Employing UMAP PCA transformation method, we discover significant population stratification between different ethnic and regional groups. Future genome wide studies will have to take this effect into account. In order to automate above tasks for future research, full analysis software was published in GitHub repository. Study was conducted in Human genetics and disease pathogenesis resaerch group in Latvian Biomedical Research and Study Centre. Key words Type 2 diabetes, SNP, GWAS, PRS, population stratification, GWAS analysis software
Whole genome association study of type 2 diabetes mellitus identifies four risk polymorphisms and develops polygenic risk model in Latvian population Masters thesis was devoted to investigation of genetic causes of type 2 diabetes mellitus in population of Latvia, as well as creation of automatic pipeline software for whole genome association studies. In this work we discover four genome wide significant associations with type 2 diabetes risk. These variants function in relation to pancreatic beta cells. Incorporating 41 independed loci variants, we propose a poligenic risk score. It explains 11% of disease variation in Latvian population and shows factor of 2.8 increase in risk for highest quartile, compared to average. Employing UMAP PCA transformation method, we discover significant population stratification between different ethnic and regional groups. Future genome wide studies will have to take this effect into account. In order to automate above tasks for future research, full analysis software was published in GitHub repository. Study was conducted in Human genetics and disease pathogenesis resaerch group in Latvian Biomedical Research and Study Centre. Key words Type 2 diabetes, SNP, GWAS, PRS, population stratification, GWAS analysis software
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Keywords
Bioloģija , 2. tipa cukura diabēts , SNP , GWAS , PRS , Populācijas stratifikācija