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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0003-3423-2021
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.ORCID iD: 0000-0001-5894-0351
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.ORCID iD: 0000-0003-2256-6972
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Number of Authors: 3902019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 452-469Article in journal (Refereed) Published
Abstract [en]

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Place, publisher, year, edition, pages
2019. Vol. 51, no 3, p. 452-469
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Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-379344DOI: 10.1038/s41588-018-0334-2ISI: 000459947200014PubMedID: 30778226OAI: oai:DiVA.org:uu-379344DiVA, id: diva2:1296424
Funder
NIH (National Institute of Health), 1K99HL130580NIH (National Institute of Health), R01-DK089256NIH (National Institute of Health), 2R01HD057194NIH (National Institute of Health), U01HG007416NIH (National Institute of Health), R01DK101855NIH (National Institute of Health), T32 HL007055NIH (National Institute of Health), KL2TR001109
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-018-0334-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved

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Giedraitis, VilmantasGustafsson, StefanIngelsson, ErikLind, LarsWallentin, Lars

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