TY - JOUR
T1 - Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
AU - T2D-Genes Consortium
AU - The MAGIC Investigators
AU - CHD Exome+ Consortium
AU - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
AU - EPIC-CVD Consortium
AU - ExomeBP Consortium
AU - Global Lipids Genetic Consortium
AU - GoT2D Genes Consortium
AU - InterAct
AU - ReproGen 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 - Jia, Yucheng
AU - Stefansson, Kari
AU - Thorsteinsdottir, Unnur
N1 - Funding Information:
This work was primarily supported through funding from the National Institute of Health (NIH): 1K99HL130580, R01-DK089256, 2R01HD057194, U01HG007416, R01DK101855, T32 HL007055, KL2TR001109; and the American Heart Association (AHA): 13POST16500011 and 13GRNT16490017. Co-author Y. Jia recently passed away while this work was in process. This study was completed as part of the Genetic Investigation of ANtropometric Traits (GIANT) Consortium. This research has been conducted using the UK Biobank resource. A full list of acknowledgements is provided in the Supplementary Data 18.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
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 - Article
C2 - 30778226
AN - SCOPUS:85061697378
SN - 1061-4036
VL - 51
SP - 452
EP - 469
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -