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

CHD Exome+ Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind51
Udgave nummer3
Sider (fra-til)452-469
ISSN1061-4036
DOI
StatusUdgivet - mar. 2019

Fingeraftryk

Homeostasis
Lipids
Fats
Exome
White Adipose Tissue
Proteins
Adiponectin
RNA Interference
Body Mass Index
Health

Citer dette

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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 = "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 Cramer Christensen and Torben Hansen and Thuesen, {Betina H} and {CHD Exome+ Consortium}",
year = "2019",
month = "3",
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",

}

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. / CHD Exome+ Consortium.

I: Nature Genetics, Bind 51, Nr. 3, 03.2019, s. 452-469.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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

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 - Christensen, Cramer

AU - Hansen, Torben

AU - Thuesen, Betina H

AU - CHD Exome+ Consortium

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 - 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

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 -