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

CHD Exome+ Consortium

doi:10.1038/s41588-018-0334-2

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

CHD Exome+ Consortium

Division of Musculoskeletal & Dermatological Sciences (L5)

Geisinger Health System
Eastern Mediterranean University
University of Texas Health Science Center at Houston (UTHealth Houston)
The University of North Carolina at Chapel Hill
Icahn School of Medicine at Mount Sinai
Universite de Montreal
University of Wisconsin - Milwaukee
Boston Children's Hospital
Los Angeles Biomedical Research Institute at Harbor-UCLA
Max-Planck-Institute for Immunobiology
Queen Mary University of London
Wellcome Centre for Human Genetics
Universitat Regensburg
Washington University School of Medicine
Erasmus MC
University of Tartu
Vanderbilt University
Wake Forest School of Medicine
National Heart, Lung & Blood Institute (NHBLI)
Massachusetts General Hospital
MRC Epidemiology Unit, University of Cambridge
University of Cambridge
University of Michigan
York University
University of California,San Diego
University of Lille I (Universite des Sciences et Techniques de Lille Flandres Artois)
INSERM U1018, Centre de Recherche en Épidémiologie et Santé des Populations (CESP)
Swiss Institute of Bioinformatics
Universitat Leipzig
German Institute of Human Nutrition
Baylor College of Medicine
University Hospital Regensburg
University of Copenhagen
University of Southern Denmark (SYDDANSK UNIVERISTET)
University of Washington

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	452-469
Number of pages	18
Journal	Nature Genetics
Volume	51
Issue number	3
Early online date	18 Feb 2019
DOIs	https://doi.org/10.1038/s41588-018-0334-2
Publication status	Published - 1 Mar 2019

Keywords

Animals
Body Fat Distribution/methods
Body Mass Index
Case-Control Studies
Drosophila/genetics
Exome/genetics
Female
Gene Frequency/genetics
Genetic Predisposition to Disease/genetics
Genetic Variation/genetics
Genome-Wide Association Study/methods
Homeostasis/genetics
Humans
Lipids/genetics
Male
Proteins/genetics
Risk Factors
Waist-Hip Ratio/methods

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10.1038/s41588-018-0334-2

Giantexomewaist_maintext_Revision_FINAL_07162018Accepted author manuscript, 1.1 MB

Cite this

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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.",

keywords = "Animals, Body Fat Distribution/methods, Body Mass Index, Case-Control Studies, Drosophila/genetics, Exome/genetics, Female, Gene Frequency/genetics, Genetic Predisposition to Disease/genetics, Genetic Variation/genetics, Genome-Wide Association Study/methods, Homeostasis/genetics, Humans, Lipids/genetics, Male, Proteins/genetics, Risk Factors, Waist-Hip Ratio/methods",

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 B{\"o}ger, \{Carsten A\} and Jette Bork-Jensen and Bottinger, \{Erwin P\} and Bowden, \{Donald W\} and Ivan Brandslund and Linda Broer and Burt, \{Amber A\} and Morris, \{Andrew P\}",

year = "2019",

month = mar,

day = "1",

doi = "10.1038/s41588-018-0334-2",

language = "English",

volume = "51",

pages = "452--469",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

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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 - 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 - Morris, Andrew P

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.

KW - Animals

KW - Body Fat Distribution/methods

KW - Body Mass Index

KW - Case-Control Studies

KW - Drosophila/genetics

KW - Exome/genetics

KW - Female

KW - Gene Frequency/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Genetic Variation/genetics

KW - Genome-Wide Association Study/methods

KW - Homeostasis/genetics

KW - Humans

KW - Lipids/genetics

KW - Male

KW - Proteins/genetics

KW - Risk Factors

KW - Waist-Hip Ratio/methods

UR - https://livrepository.liverpool.ac.uk/3033843/

UR - https://www.scopus.com/pages/publications/85061697378

U2 - 10.1038/s41588-018-0334-2

DO - 10.1038/s41588-018-0334-2

M3 - Article

C2 - 30778226

SN - 1061-4036

VL - 51

SP - 452

EP - 469

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

Abstract

Keywords

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