Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
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
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
17
11
2017
accepted:
17
12
2018
pubmed:
20
2
2019
medline:
25
4
2019
entrez:
20
2
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30778226
doi: 10.1038/s41588-018-0334-2
pii: 10.1038/s41588-018-0334-2
pmc: PMC6560635
mid: NIHMS1016010
doi:
Substances chimiques
Lipids
0
Proteins
0
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
452-469Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL130580
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK106621
Pays : United States
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK110113
Pays : United States
Organisme : Medical Research Council
ID : MR/S003746/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G9521010
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : P30 DK056336
Pays : United States
Organisme : NHLBI NIH HHS
ID : R21 HL121422
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_14089
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK093757
Pays : United States
Organisme : British Heart Foundation
ID : FS/12/82/29736
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U01 HG007417
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007416
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM126479
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12015/1
Pays : United Kingdom
Organisme : NIDA NIH HHS
ID : R21 DA040177
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001109
Pays : United States
Organisme : Medical Research Council
ID : MC_EX_MR/M009203/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK072193
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL130580
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107786
Pays : United States
Organisme : Medical Research Council
ID : MR/L01341X/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK075787
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL119443
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062370
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12015/2
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : R01 HG008983
Pays : United States
Organisme : British Heart Foundation
ID : RG/08/014/24067
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/14/5/30893
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L01632X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M009203/1
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : K12 HD043483
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : U01 DK062370
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107904
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK089256
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD057194
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007055
Pays : United States
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom
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