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- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Martin, Alicia R, et al.
(författare)
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Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 102:5, s. 760-775
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Tidskriftsartikel (refereegranskat)abstract
- Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.
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| 3. |
- Solovieva, Svetlana, et al.
(författare)
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Association between the aggrecan gene variable number of tandem repeats polymorphism and intervertebral disc degeneration
- 2007
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Ingår i: Spine. - 0362-2436 .- 1528-1159. ; 32:16, s. 1700-1705
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine the association between an aggrecan variable number of tandem repeats (VNTR) polymorphism and intervertebral disc degeneration in middle-aged Finnish men. SUMMARY OF BACKGROUND DATA: An association between the aggrecan VNTR polymorphism and multilevel disc degeneration has been previously reported in young Japanese women. METHODS: Lumbar discs of 132 men representing 3 occupations (carpenters, machine drivers, and office workers) were evaluated on magnetic resonance imaging, using decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height as signs of degeneration. The aggrecan gene VNTR region was analyzed by Southern hybridization. RESULTS: The allele A26 with 26 repeats was statistically significantly overrepresented among the persons with dark nucleus pulposus. Carrying 2 copies of the A26 allele increased the risk of dark nucleus pulposus (odds ratio = 2.77; 95% confidence interval, 1.24-6.16). Carrying the alleles with either less or more than 26 repeats decreased the risk of dark nucleus pulposus. The carpenters and machine drivers with the A26 allele had a statistically significantly higher risk of disc bulge and decreased disc height than the office workers without the allele. CONCLUSION: The findings provide additional support for the role of the aggrecan gene VNTR polymorphism in intervertebral disc degeneration.
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