@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 = "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 and {CHD Exome+ Consortium}",
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",
}