Beyond GWAS: Novel Methods and Resources for Genetic Epidemiology

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Schmitz, Daniel,1995-Uppsala universitet,Genomik och neurobiologi (författare)

Beyond GWAS : Novel Methods and Resources for Genetic Epidemiology

BokEngelska2024

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Uppsala :Acta Universitatis Upsaliensis,2024
52 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:uu-517196
ISBN:9789151319865
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-517196URI

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Språk:engelska
Sammanfattning på:engelska &language:-1_t

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Serie

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;2001

Anmärkningar

Since the first human genome assembly’s release, our knowledge of the genetic architecture of complex traits and diseases has grown steadily. Genome-wide association studies (GWAS) played a major role but are limited to common traits and single-nucleotide polymorphisms (SNPs). Technologies and resources like next-generation sequencing, Mendelian Randomization (MR), long-read sequencing and improved reference genomes enable the investigation of variants inaccessible to GWAS, such as copy number variations (CNVs), rare variants and variants in previously unresolved regions.In project I, we performed a GWAS of estradiol measurements using data from UK Biobank and quantified estradiol’s effect on bone mineral density (BMD) using MR. 14 loci were associated with estradiol levels in males, of which one was also significant in females and an additional female-specific locus. We found a significant effect of estradiol on BMD, confirming previous research of estrogen’s importance for skeletal health.In project II, we used the GWAS results from project I to investigate the effect of endogenous estradiol on breast, endometrial and ovarian cancer using MR. Estradiol was associated with ovarian cancer and nominally associated with estrogen receptor-positive breast cancer, demonstrating the effect of endogenous estrogen on cancer risk. In project III, we quantified the effect of 184,182 CNVs on 438 blood plasma proteins using whole-genome sequencing (WGS) data from a Northern Swedish cohort and validated our findings using long-read sequencing in a subcohort. 15 CNVs were associated with 16 proteins of which four could be validated using long reads and three more were more complex variation. Our findings show the effects of CNVs on the plasma proteome and highlight the application different sequencing technologies for CNV detection.In project IV, we evaluated the use of T2T-CHM13 as reference for the SweGen cohort. Compared to GRCh38, mapping quality improved and we identified 9.8 million more variants. Sensitivity for rare, singleton and functionally relevant variants was higher. These findings show how research and clinical applications benefit from T2T-CHM13 by improving detection of previously unknown functionally relevant variation.This thesis demonstrates the application of novel technologies and resources in genomics to detect variation and study its impact on quantitative traits. By using genotyping and WGS variants from short and long reads, I showed how we can leverage these technologies for research beyond GWAS.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
NATURVETENSKAP Data- och informationsvetenskap Bioinformatik hsv//swe
NATURAL SCIENCES Computer and Information Sciences Bioinformatics hsv//eng
GWAS
NGS
long-read sequencing
mendelian randomization
WGS
CNVs

Biuppslag (personer, institutioner, konferenser, titlar ...)

Johansson, ÅsaUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Science for Life Laboratory, SciLifeLab,Genomik och neurobiologi(Swepub:uu)asjoh108 (preses)
Lappalainen, Tuuli,ProfessorNew York Genome Center. Department of Systems Biology, Columbia University, New York, NY, USA. Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden (opponent)
Uppsala universitetGenomik och neurobiologi (creator_code:org_t)

Internetlänk

https://uu-se.zoom.us/j/66605810809Online defence:
https://uu.diva-portal.org/smash/get/diva2:1817383/FULLTEXT01.pdffulltext
https://uu.diva-portal.org/smash/get/diva2:1817383/PREVIEW01.jpgpreview image
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-517196

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Av författaren/redakt...: Schmitz, Daniel, ...; Johansson, Åsa; Lappalainen, Tuu ...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Medicinsk geneti ...

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