Decoding genetic associations of female reproductive health traits
Date
2024-05-15
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Abstract
Geneetiline varieeruvus, eriti üksiku nukleotiidi polümorfismid, mõjutavad erinevate komplekshaiguste eelsoodumust. Ülegenoomsed seoseuuringud (GWAS) on leidnud tuhandeid seoseid erinevate geneetiliste variantide ja haiguste vahel. Samas on teadmised naiste reproduktiivtervise tunnuste geneetilise eelsoodumuse osas piiratud, kuna vaid väike osa kõigist GWAS uuringutest keskendub sellele valdkonnale. Populatsioonipõhised biopangad, nagu Eesti geenivaramu, ning rahvastikupõhised sünnikohordid, nagu Northern Finland Birth Cohort 1966, pakuvad väärtuslikku raamistikku selle valdkonna uuringuteks. Tänu metoodika arengule saab GWAS tulemuste põhjal haigusega seotud geneetilistest variantidest liikuda edasi potentsiaalselt mõjutatud geenide, valkude, bioloogiliste radade ja kudedeni. Seega on GWAS uuringud aluseks uutele hüpoteesidele, mida saab kinnitada funktsionaalsete eksperimentide abil. Tunnuste geneetilise komponendi mõistmine on oluline, kuna see võib anda ülevaate haiguse etioloogiast, ja pakkuda uusi võimalusi haigusriskide ennustamiseks ja uuteks ravimsihtmärkideks. GWAS tulemuste põhjal saab koostada ka polügeenseid riskiskoore (PRS), mis annavad kokkuvõtliku hinnangu indiviidi geneetilisele eelsoodumusele teatud tunnuse osas. PRSi abil saab hinnata haigusriske ja lisaks saab seda kasutada vahendina haiguse bioloogia täiendavaks uurimiseks, näiteks seoses kaasuvate haigustega. PRS-id on kesksel kohal nn personaalmeditsiini poole püüdlemisel. Käesoleva doktoritöö eesmärk on dešifreerida naiste reproduktiivtervise teatud tunnuste geneetilisi aluseid ülegenoomsete seoseuuringute abil ning kasutadaa PRS-i nii riskide stratifitseerimisel kui ka tunnuste bioloogia uurimisel. Minu teadustöö ühendab genoomika ja naiste reproduktiivtervise ning loob uusi teadmisi, kasutades selleks suuri genoomikaandmestikke, mida täiendavad elektroonsed terviseandmed ja bioloogilised mõõtmised.
Genetic variation, particularly single-nucleotide polymorphisms, has shown to influence health and disease susceptibility for multiple complex diseases. This has been supported by many genome-wide association studies (GWAS) which have unravelled thousands of genetic variants in association with health traits. However, studies of genetic variation underlying female reproductive health traits remain limited, with only a small proportion of all GWAS focusing on this area. Currently, the availability of population-based biobanks, such as the Estonian Biobank, and population-based birth cohorts such as the Northern Finland Birth Cohort 1966, provide a valuable framework for studies in this field. Additionally, GWAS set the ground to move from genetic variations to potentially affected genes, proteins, biological pathways and tissues, serving as a foundation for forming hypotheses that can be validated through functional experiments. Understanding the genetic variation that is associated with a trait is important as it can provide insights into disease aetiology, prediction, and potential treatments. Another notable outcome of GWAS is the construction of polygenic risk scores (PRS), which provide a summary of an individual's genetic predisposition for a certain trait. PRS has the potential to predict disease susceptibility and serve as a tool to further explore disease biology, for example, relationships with a certain trait’s comorbidities. PRS have attracted massive attention in the pursuit of the so-called personalised medicine. This thesis aims to decode the genetic underpinnings of selected female reproductive health traits through GWAS and explores PRS as a tool for both risk stratification and for informing a trait’s biology. In conclusion, this research, placed at the intersection of genomics and female reproductive health, is poised to address a knowledge gap in both national and international research systems through the availability of large genomic datasets coupled with electronic health records and biological measurements.
Genetic variation, particularly single-nucleotide polymorphisms, has shown to influence health and disease susceptibility for multiple complex diseases. This has been supported by many genome-wide association studies (GWAS) which have unravelled thousands of genetic variants in association with health traits. However, studies of genetic variation underlying female reproductive health traits remain limited, with only a small proportion of all GWAS focusing on this area. Currently, the availability of population-based biobanks, such as the Estonian Biobank, and population-based birth cohorts such as the Northern Finland Birth Cohort 1966, provide a valuable framework for studies in this field. Additionally, GWAS set the ground to move from genetic variations to potentially affected genes, proteins, biological pathways and tissues, serving as a foundation for forming hypotheses that can be validated through functional experiments. Understanding the genetic variation that is associated with a trait is important as it can provide insights into disease aetiology, prediction, and potential treatments. Another notable outcome of GWAS is the construction of polygenic risk scores (PRS), which provide a summary of an individual's genetic predisposition for a certain trait. PRS has the potential to predict disease susceptibility and serve as a tool to further explore disease biology, for example, relationships with a certain trait’s comorbidities. PRS have attracted massive attention in the pursuit of the so-called personalised medicine. This thesis aims to decode the genetic underpinnings of selected female reproductive health traits through GWAS and explores PRS as a tool for both risk stratification and for informing a trait’s biology. In conclusion, this research, placed at the intersection of genomics and female reproductive health, is poised to address a knowledge gap in both national and international research systems through the availability of large genomic datasets coupled with electronic health records and biological measurements.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone
Keywords
women, reproductive health, genomics, candidate gene association study