Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

T2D-Genes Consortium, The MAGIC Investigators, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)452-469
Number of pages18
JournalNature Genetics
Volume51
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Body Fat Distribution
Homeostasis
Lipids
Fats
Genes
Exome
White Adipose Tissue
Proteins
Waist-Hip Ratio
Bone Development
Adiponectin
RNA Interference
Gene Frequency
Drosophila
Triglycerides
Body Mass Index
Health

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

T2D-Genes Consortium, The MAGIC Investigators, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, ... ReproGen Consortium (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), 452-469. https://doi.org/10.1038/s41588-018-0334-2
T2D-Genes Consortium ; The MAGIC Investigators ; CHD Exome+ Consortium ; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ; EPIC-CVD Consortium ; ExomeBP Consortium ; Global Lipids Genetic Consortium ; GoT2D Genes Consortium ; InterAct ; ReproGen Consortium. / Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. In: Nature Genetics. 2019 ; Vol. 51, No. 3. pp. 452-469.
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abstract = "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.",
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T2D-Genes Consortium, The MAGIC Investigators, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct & ReproGen Consortium 2019, 'Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution', Nature Genetics, vol. 51, no. 3, pp. 452-469. https://doi.org/10.1038/s41588-018-0334-2

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. / T2D-Genes Consortium; The MAGIC Investigators; CHD Exome+ Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetic Consortium; GoT2D Genes Consortium; InterAct; ReproGen Consortium.

In: Nature Genetics, Vol. 51, No. 3, 01.03.2019, p. 452-469.

Research output: Contribution to journalArticle

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AU - T2D-Genes Consortium

AU - The MAGIC Investigators

AU - CHD Exome+ Consortium

AU - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

AU - EPIC-CVD Consortium

AU - ExomeBP Consortium

AU - Global Lipids Genetic Consortium

AU - GoT2D Genes Consortium

AU - InterAct

AU - ReproGen Consortium

AU - Justice, Anne E.

AU - Karaderi, Tugce

AU - Highland, Heather M.

AU - Young, Kristin L.

AU - Graff, Mariaelisa

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AU - Turcot, Valérie

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AU - Fine, Rebecca S.

AU - Guo, Xiuqing

AU - Schurmann, Claudia

AU - Lempradl, Adelheid

AU - Marouli, Eirini

AU - Mahajan, Anubha

AU - Winkler, Thomas W.

AU - Locke, Adam E.

AU - Medina-Gomez, Carolina

AU - Esko, Tõnu

AU - Vedantam, Sailaja

AU - Giri, Ayush

AU - Lo, Ken Sin

AU - Alfred, Tamuno

AU - Mudgal, Poorva

AU - Ng, Maggie C.Y.

AU - Heard-Costa, Nancy L.

AU - Feitosa, Mary F.

AU - Manning, Alisa K.

AU - Willems, Sara M.

AU - Sivapalaratnam, Suthesh

AU - Abecasis, Goncalo

AU - Alam, Dewan S.

AU - Allison, Matthew

AU - Amouyel, Philippe

AU - Arzumanyan, Zorayr

AU - Balkau, Beverley

AU - Bastarache, Lisa

AU - Bergmann, Sven

AU - Bielak, Lawrence F.

AU - Blüher, Matthias

AU - Boehnke, Michael

AU - Boeing, Heiner

AU - Boerwinkle, Eric

AU - Böger, Carsten A.

AU - Bork-Jensen, Jette

AU - Bottinger, Erwin P.

AU - Bowden, Donald W.

AU - Brandslund, Ivan

AU - Broer, Linda

AU - Burt, Amber A.

AU - Butterworth, Adam S.

PY - 2019/3/1

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N2 - 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.

AB - 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.

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T2D-Genes Consortium, The MAGIC Investigators, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics. 2019 Mar 1;51(3):452-469. https://doi.org/10.1038/s41588-018-0334-2