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

CHD Exome Consortium, Cohorts For Heart Aging Res Genomi, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2G Genes Consortium, MAGIC Investigators

Research output: Contribution to journalArticle

5 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
Pages (from-to)452-+
Number of pages21
JournalNature Genetics
Volume51
Issue number3
DOIs
Publication statusPublished - Mar 2019

Cite this

CHD Exome Consortium, Cohorts For Heart Aging Res Genomi, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, ... MAGIC Investigators (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), 452-+. https://doi.org/10.1038/s41588-018-0334-2
CHD Exome Consortium ; Cohorts For Heart Aging Res Genomi ; EPIC-CVD Consortium ; ExomeBP Consortium ; Global Lipids Genetic Consortium ; GoT2D Genes Consortium ; InterAct ; ReproGen Consortium ; T2G Genes Consortium ; MAGIC Investigators. / 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-+.
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CHD Exome Consortium, Cohorts For Heart Aging Res Genomi, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2G Genes Consortium & MAGIC Investigators 2019, 'Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution' Nature Genetics, vol. 51, no. 3, pp. 452-+. https://doi.org/10.1038/s41588-018-0334-2

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. / CHD Exome Consortium; Cohorts For Heart Aging Res Genomi; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetic Consortium; GoT2D Genes Consortium; InterAct; ReproGen Consortium; T2G Genes Consortium; MAGIC Investigators.

In: Nature Genetics, Vol. 51, No. 3, 03.2019, p. 452-+.

Research output: Contribution to journalArticle

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AU - CHD Exome Consortium

AU - Cohorts For Heart Aging Res Genomi

AU - EPIC-CVD Consortium

AU - ExomeBP Consortium

AU - Global Lipids Genetic Consortium

AU - GoT2D Genes Consortium

AU - InterAct

AU - ReproGen Consortium

AU - T2G Genes Consortium

AU - MAGIC Investigators

AU - Justice, Anne E.

AU - Karaderi, Tugce

AU - Highland, Heather M.

AU - Young, Kristin L.

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AU - Lu, Yingchang

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AU - Winkler, Thomas W.

AU - Locke, Adam E.

AU - Medina-Gomez, Carolina

AU - Esko, Tonu

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.

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AU - Abecasis, Goncalo

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AU - Wang, Carol A.

AU - Wang, Shuai

AU - Wareham, N. Icholas J.

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AU - Zhou, Wei

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PY - 2019/3

Y1 - 2019/3

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.

KW - GENOME-WIDE ASSOCIATION

KW - TYPE-2 DIABETES SUSCEPTIBILITY

KW - ADIPOSE-TISSUE

KW - KINASE 7

KW - ADIPOCYTE DIFFERENTIATION

KW - RS11209026 POLYMORPHISM

KW - ABDOMINAL ADIPOSITY

KW - WAIST CIRCUMFERENCE

KW - INSULIN-RESISTANCE

KW - RECEPTOR ALK7

U2 - 10.1038/s41588-018-0334-2

DO - 10.1038/s41588-018-0334-2

M3 - Article

VL - 51

SP - 452-+

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -

CHD Exome Consortium, Cohorts For Heart Aging Res Genomi, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics. 2019 Mar;51(3):452-+. https://doi.org/10.1038/s41588-018-0334-2