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

Simple item page
dc.contributor.authorJustice, Anne E.
dc.contributor.authorKaraderi, Tugce
dc.contributor.authorHighland, Heather M.
dc.contributor.authorYoung, Kristin L.
dc.contributor.authorGraff, Mariaelisa
dc.contributor.authorLu, Yingchang
dc.contributor.authorMcCarthy, Mark, I
dc.date.accessioned2026-02-06T18:43:38Z
dc.date.issued2019
dc.departmentDoğu Akdeniz Üniversitesi
dc.description.abstractBody-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.
dc.description.sponsorshipNational Institute of Health (NIH) [1K99HL130580, R01-DK089256, 2R01HD057194, U01HG007416, R01DK101855, T32 HL007055, KL2TR001109]; American Heart Association (AHA) [13POST16500011, 13GRNT16490017]; British Heart Foundation [RG/18/13/33946, FS/12/82/29736, RG/14/5/30893, RG/13/13/30194, RG/08/014/24067] Funding Source: researchfish; Cancer Research UK [16565, 16563] Funding Source: researchfish; Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish; Medical Research Council [MR/S003746/1, G9521010, MC_UU_00007/10, MC_UU_12015/1, MC_UU_12015/2, MR/R023484/1, MC_PC_14089, MC_PC_13048, HDR-9004, MC_EX_MR/M009203/1, MR/L01341X/1, MR/L01632X/1, MC_PC_13046, MR/M009203/1, HDR-2002] Funding Source: researchfish; National Institute for Health Research [NF-SI-0514-10027, NF-SI-0507-10228, NF-SI-0611-10170, NF-SI-0617-10113, NF-SI-0611-10219, NF-SI-0611-10099, NF-SI-0617-10149, NF-SI-0512-10113, NF-SI-0616-10080, ACF-2016-19-005, NF-SI-0617-10154] Funding Source: researchfish; NNF Center for Basic Metabolic Research [Pers Group, Hansen Group] Funding Source: researchfish; Novo Nordisk Fonden [NNF16OC0021496] Funding Source: researchfish; Steno Diabetes Center Copenhagen (SDCC) [SDCC 3.F CMP] Funding Source: researchfish; Wellcome Trust [098395/Z/12/Z] Funding Source: researchfish; American Heart Association (AHA) [13POST16500011, 13GRNT16490017] Funding Source: American Heart Association (AHA); National Heart Lung and Blood Institute [T32HL007055] Funding Source: NIH RePORTER; National Human Genome Research Institute [ZIAHG000024] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK062370, R01DK072193, P30DK056336, P30DK079626, U01DK062370, R01DK075787, R01DK093757, P30DK020572] Funding Source: NIH RePORTER; MRC [MR/S003746/1, MR/M009203/1, MR/R023484/1, MC_UU_12015/1, MR/L01632X/1, MR/L01341X/1, MC_UU_12015/2, MC_UU_00007/10, G9521010, MC_EX_MR/M009203/1, MC_PC_14089, MC_PC_13048, MC_PC_13046] Funding Source: UKRI
dc.description.sponsorshipThis 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.
dc.identifier.doi10.1038/s41588-018-0334-2
dc.identifier.endpage+
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.issue3
dc.identifier.orcid0000-0001-9763-8139
dc.identifier.orcid0000-0003-3793-5910
dc.identifier.orcid0000-0002-3097-0230
dc.identifier.orcid0000-0001-6225-8240
dc.identifier.orcid0000-0002-1233-7642
dc.identifier.orcid0000-0002-9920-6257
dc.identifier.orcid0000-0003-3196-2491
dc.identifier.pmid30778226
dc.identifier.scopus2-s2.0-85061697378
dc.identifier.scopusqualityQ1
dc.identifier.startpage452
dc.identifier.urihttps://doi.org/10.1038/s41588-018-0334-2
dc.identifier.urihttps://hdl.handle.net/11129/13676
dc.identifier.volume51
dc.identifier.wosWOS:000459947200014
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.indekslendigikaynakScopus
dc.language.isoen
dc.publisherNature Portfolio
dc.relation.ispartofNature Genetics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WoS_20260204
dc.subjectGenome-Wide Association
dc.subjectType-2 Diabetes Susceptibility
dc.subjectAdipose-Tissue
dc.subjectKinase 7
dc.subjectAdipocyte Differentiation
dc.subjectRs11209026 Polymorphism
dc.subjectAbdominal Adiposity
dc.subjectWaist Circumference
dc.subjectInsulin-Resistance
dc.subjectReceptor Alk7
dc.titleProtein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
dc.typeArticle

Files

Collections

WoS Indexed Publications Collection
PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu