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

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@article{7821cf9fcbfe42b8a1999f1e5cd96b78,
title = "Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution",
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.",
author = "{CHD Exome+ Consortium} and Justice, {Anne E} and Tugce Karaderi and Highland, {Heather M} and Young, {Kristin L} and Mariaelisa Graff and Yingchang Lu and Val{\'e}rie Turcot and Auer, {Paul L} and Fine, {Rebecca S} and Xiuqing Guo and Claudia Schurmann and Adelheid Lempradl and Eirini Marouli and Anubha Mahajan and Winkler, {Thomas W} and Locke, {Adam E} and Carolina Medina-Gomez and T{\~o}nu Esko and Sailaja Vedantam and Ayush Giri and Lo, {Ken Sin} and Tamuno Alfred and Poorva Mudgal and Ng, {Maggie C Y} and Heard-Costa, {Nancy L} and Feitosa, {Mary F} and Manning, {Alisa K} and Willems, {Sara M} and Suthesh Sivapalaratnam and Goncalo Abecasis and Alam, {Dewan S} and Matthew Allison and Philippe Amouyel and Zorayr Arzumanyan and Beverley Balkau and Lisa Bastarache and Sven Bergmann and Bielak, {Lawrence F} and Matthias Bl{\"u}her and Michael Boehnke and Heiner Boeing and Eric Boerwinkle and Jette Bork-Jensen and Nele Friedrich and Torben Hansen and Torben J{\o}rgensen and Allan Linneberg and Pers, {Tune H} and Thuesen, {Betina H} and Henrik Vestergaard",
year = "2019",
month = "3",
day = "1",
doi = "10.1038/s41588-018-0334-2",
language = "English",
volume = "51",
pages = "452--469",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",

}

RIS

TY - JOUR

T1 - Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

AU - CHD Exome+ Consortium

AU - Justice, Anne E

AU - Karaderi, Tugce

AU - Highland, Heather M

AU - Young, Kristin L

AU - Graff, Mariaelisa

AU - Lu, Yingchang

AU - Turcot, Valérie

AU - Auer, Paul L

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 - Bork-Jensen, Jette

AU - Friedrich, Nele

AU - Hansen, Torben

AU - Jørgensen, Torben

AU - Linneberg, Allan

AU - Pers, Tune H

AU - Thuesen, Betina H

AU - Vestergaard, Henrik

PY - 2019/3/1

Y1 - 2019/3/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85061697378&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0334-2

DO - 10.1038/s41588-018-0334-2

M3 - Journal article

VL - 51

SP - 452

EP - 469

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -

ID: 56600479