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 - Bork-Jensen, Jette

AU - Grarup, Niels

AU - Hansen, Torben

AU - Jørgensen, Torben

AU - Justesen, Johanne M.

AU - Karpe, Fredrik

AU - Kovacs, Peter

AU - Li, Jin

AU - Lind, Lars

AU - Linneberg, Allan

AU - Pedersen, Oluf

AU - Pers, Tune H

AU - Vestergaard, Henrik

AU - Zhao, Jing Hua

AU - Loos, Ruth J. F.

AU - CHD Exome+ Consortium

PY - 2019

Y1 - 2019

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.

U2 - 10.1038/s41588-018-0334-2

DO - 10.1038/s41588-018-0334-2

M3 - Journal article

C2 - 30778226

VL - 51

SP - 452

EP - 469

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -