Using large-scale cohorts to identify genetic backgrounds of complex traits
Most cases of diseases with heritable components are not explained by single-gene variants following Mendelian inheritance. The majority of such heritable traits result from the combined contributions of many genes, environmental factors, and chance. These are called complex traits, and include phen...
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Format: | Doctoral or Postdoctoral Thesis |
Language: | English |
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Helsingin yliopisto
2022
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Online Access: | http://hdl.handle.net/10138/338666 |
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ftunivhelsihelda:oai:helda.helsinki.fi:10138/338666 |
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Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
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English |
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lääketiede Saarentaus, Elmo Using large-scale cohorts to identify genetic backgrounds of complex traits |
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Most cases of diseases with heritable components are not explained by single-gene variants following Mendelian inheritance. The majority of such heritable traits result from the combined contributions of many genes, environmental factors, and chance. These are called complex traits, and include phenotypes such as intelligence, neuropsychiatric disorders, and susceptibility to infection. In this thesis, I investigate how the genetic component of complex traits can be explained using rare and common variation. The first study investigated the genetic etiology of rare idiopathic intellectual disability and syndromic comorbidities in an extreme population isolate in Northern Finland affected by several genetic bottlenecks. Here, I found that there is a significant common variant component in ID, in addition to the rare variant burden expected by nature of the phenotype and study design. I then sought to improve our understanding of general differences in rare variant burden. I analyzed the phenotypes of rare disease-associated copy number variants (CNVs) among patients with epilepsy and comorbid features from several neurology specialist clinics in Europe and the US. Pathogenic CNVs were detected in 10.9% of cases and associated with non-neurological but not neurological phenotypes. The results indicate that in syndromic epilepsy, rare CNV impact associates with other organ systems instead of along neurological disease severity. Next, to investigate the impact rare pathogenic CNVs have on general quality of life in unaffected carriers, I analyzed the impact on general health and socioeconomic factors in two Finnish population cohorts. I found that in the unaffected population, there is an average socioeconomic impact of high-risk CNVs, although one that is less than the impact of polygenic risk scores (PRSs) for educational attainment and intelligence. Finally, to improve understanding of chronic and complicated infections of the upper respiratory tract, I performed a genome-wide association study (GWAS) of these ... |
author2 |
Fall, Tove University of Helsinki, Faculty of Medicine, Institute for Molecular Medicine Finland (FIMM) Doctoral Program in Population Health Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA Helsingin yliopisto, lääketieteellinen tiedekunta Väestön terveyden tohtoriohjelma Helsingfors universitet, medicinska fakulteten Doktorandprogrammet i befolkningshälsan Palotie, Aarno Pietiläinen, Olli Kurki, Mitja |
format |
Doctoral or Postdoctoral Thesis |
author |
Saarentaus, Elmo |
author_facet |
Saarentaus, Elmo |
author_sort |
Saarentaus, Elmo |
title |
Using large-scale cohorts to identify genetic backgrounds of complex traits |
title_short |
Using large-scale cohorts to identify genetic backgrounds of complex traits |
title_full |
Using large-scale cohorts to identify genetic backgrounds of complex traits |
title_fullStr |
Using large-scale cohorts to identify genetic backgrounds of complex traits |
title_full_unstemmed |
Using large-scale cohorts to identify genetic backgrounds of complex traits |
title_sort |
using large-scale cohorts to identify genetic backgrounds of complex traits |
publisher |
Helsingin yliopisto |
publishDate |
2022 |
url |
http://hdl.handle.net/10138/338666 |
genre |
Northern Finland |
genre_facet |
Northern Finland |
op_relation |
URN:ISBN:978-951-51-7827-5 Turenki: Hansaprint, 2022, Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis. 2342-3161 Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis URN:ISSN:2342-317X http://hdl.handle.net/10138/338666 URN:ISBN:978-951-51-7828-2 |
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Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty. This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited. Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden. |
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ftunivhelsihelda:oai:helda.helsinki.fi:10138/338666 2023-08-20T04:08:44+02:00 Using large-scale cohorts to identify genetic backgrounds of complex traits Saarentaus, Elmo Fall, Tove University of Helsinki, Faculty of Medicine, Institute for Molecular Medicine Finland (FIMM) Doctoral Program in Population Health Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA Helsingin yliopisto, lääketieteellinen tiedekunta Väestön terveyden tohtoriohjelma Helsingfors universitet, medicinska fakulteten Doktorandprogrammet i befolkningshälsan Palotie, Aarno Pietiläinen, Olli Kurki, Mitja 2022-01-17T05:52:11Z application/pdf http://hdl.handle.net/10138/338666 eng eng Helsingin yliopisto Helsingfors universitet University of Helsinki URN:ISBN:978-951-51-7827-5 Turenki: Hansaprint, 2022, Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis. 2342-3161 Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis URN:ISSN:2342-317X http://hdl.handle.net/10138/338666 URN:ISBN:978-951-51-7828-2 Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty. This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited. Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden. lääketiede Text 1184 Genetiikka, kehitysbiologia, fysiologia 3111 Biolääketieteet 3124 Neurologia ja psykiatria 3125 Korva-, nenä- ja kurkkutaudit, silmätaudit 3142 Kansanterveystiede, ympäristö ja työterveys 1184 Genetik, utvecklingsbiologi, fysiologi 3111 Biomedicinska vetenskaper 3124 Neurologi och psykiatri 3125 Öron-, näs- och halssjukdomar, ögonsjukdomar 3142 Folkhälsovetenskap, miljö och arbetshälsa 1184 Genetics, developmental biology, physiology 3111 Biomedicine 3124 Neurology and psychiatry 3125 Otorhinolaryngology, ophthalmology 3142 Public health care science, environmental and occupational health Doctoral dissertation (article-based) Artikkeliväitöskirja Artikelavhandling doctoralThesis 2022 ftunivhelsihelda 2023-07-28T06:06:16Z Most cases of diseases with heritable components are not explained by single-gene variants following Mendelian inheritance. The majority of such heritable traits result from the combined contributions of many genes, environmental factors, and chance. These are called complex traits, and include phenotypes such as intelligence, neuropsychiatric disorders, and susceptibility to infection. In this thesis, I investigate how the genetic component of complex traits can be explained using rare and common variation. The first study investigated the genetic etiology of rare idiopathic intellectual disability and syndromic comorbidities in an extreme population isolate in Northern Finland affected by several genetic bottlenecks. Here, I found that there is a significant common variant component in ID, in addition to the rare variant burden expected by nature of the phenotype and study design. I then sought to improve our understanding of general differences in rare variant burden. I analyzed the phenotypes of rare disease-associated copy number variants (CNVs) among patients with epilepsy and comorbid features from several neurology specialist clinics in Europe and the US. Pathogenic CNVs were detected in 10.9% of cases and associated with non-neurological but not neurological phenotypes. The results indicate that in syndromic epilepsy, rare CNV impact associates with other organ systems instead of along neurological disease severity. Next, to investigate the impact rare pathogenic CNVs have on general quality of life in unaffected carriers, I analyzed the impact on general health and socioeconomic factors in two Finnish population cohorts. I found that in the unaffected population, there is an average socioeconomic impact of high-risk CNVs, although one that is less than the impact of polygenic risk scores (PRSs) for educational attainment and intelligence. Finally, to improve understanding of chronic and complicated infections of the upper respiratory tract, I performed a genome-wide association study (GWAS) of these ... Doctoral or Postdoctoral Thesis Northern Finland Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |