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.
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Data availability
Summary statistics of all analyses are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files.
Change history
07 March 2019
In the HTML version of the article originally published, the link for Supplementary Data 5 returned the file for Supplementary Data 7. The error has been corrected in the HTML version of the article.
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Acknowledgements
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.
Author information
Authors and Affiliations
Consortia
Contributions
Writing Group: L.A.C., R.S.F., T.M.F., M. Graff, H.M.H., J.N.H., A.E.J., T.K., Z.K., C.M.L., R.J.F.L., Y.L., K.E.N., V.T., K.L.Y.
Data preparation group: T.A., I.B.B., T.E., S.F., M. Graff, H.M.H., A.E.J., T.K., D.J.L., K.S.L., A.E.L., R.J.F.L., Y.L., E. Marouli, N.G.D.M., C.M.-G, P.M., M.C.Y.N., M.A.R., S.S., C.S., K. Stirrups, V.T., S.V., S.M.W., T.W.W., K.L.Y., X.Z.
WHR meta-analyses: P.L.A., H.M.H., A.E.J., T.K., M. Graff, C.M.L., R.J.F.L., K.E.N., V.T., K.L.Y.
Pleiotropy working group: G.A., M. Boehnke, J.P.C., P.D., F.D., J.C.F., H.M.H., H.K., H.M.H., A.E.J., C.M.L., D.J.L., R.J.F.L., A. Mahajan, E. Marouli, G.M., M.I.M., P.B.M., G.M.P., J.R.B.P., K.S.R., X.S., S.W., J.W., C.J.W.
Phenome-wide association studies: L. Bastarache, J.C.D., A.G., A. Mahajan, M.I.M.
Gene-set enrichment analyses: S.B., R.S.F., J.N.H., Z.K., D.L., T.H.P., T.F.V.
eQTL analyses: C.K.R., Y.L., K.L.M.
Monogenic and syndromic gene enrichment analyses: H.M.H., A.K.M.
Fly Obesity Screen: A. Lempradl, J.A. Pospisilik.
Overseeing of contributing studies and consortia: (1958 Birth Cohort) P.D.; (Airwave) P.E.; (AMC PAS) G.K.H.; (Amish) J.R.O.; (ARIC) E.B.; (ARIC, Add Health) K.E.N.; (BRAVE) E.D.A., R.C.; (BRIGHT) P.B.M.; (CARDIA) M.F., P.J.S.; (Cebu Longitudinal Health and Nutrition Survey) K.L.M.; (CHD Exome + Consortium) A.S.B., J.M.M.H., D.F.R., J.D.; (CHES) R.V.; (Clear/eMERGE (Seattle)) G.P.J.; (CROATIA_Korcula) V.V., O. Polasek, I.R.; (deCODE) K. Stefansson, U.T.; (DHS) D.W.B.; (DIACORE) C.A.B.; (DPS) J.T., J. Lindström, M.U.; (DRSEXTRA) T.A.L., R.R.; (EFSOCH) A.T.H., T.M.F.; (EGCUT) T.E.; (eMERGE (Seattle)) E.B.L.; (EPIC-Potsdam) M.B.S., H.B.; (EpiHealth) E.I., P.W.F.; (EXTEND) A.T.H., T.M.F.; (Family Heart Study) I.B.B.; (Fenland, EPIC) R.A.S.; (Fenland, EPIC, InterAct) N.J.W., C.L.; (FINRISK) S. Männistö; (FINRISK 2007 (T2D)) P.J., V. Salomaa; (Framingham Heart Study) L.A.C.; (FUSION) M. Boehnke, F.S.C.; (FVG) P.G.; (Generation Scotland) C.H., B.H.S.; (Genetic Epidemiology Network of Arteriopathy (GENOA)) S.L.R.K.; (GRAPHIC) N.J.S.; (GSK-STABILITY) D.M.W., L.W., H.D.W.; (Health) A. Linneberg; (HELIC MANOLIS) E.Z., G.D.; (HELIC Pomak) E.Z., G.D.; (HUNT-MI) K.H., C.J.W.; (Inter99) T.H., T.J.; (IRASFS) L.E.W., E.K.S.; (Jackson Heart Study (JHS)) J.G.W.; (KORA S4) K. Strauch, I.M.H.; (Leipzig-Adults) M. Blüher, P. Kovacs.; (LOLIPOP-Exome) J.C.C., J.S.K.; (LOLIPOP-OmniEE) J.C.C., J.S.K.; (MESA) J.I.R., X.G.; (METSIM) J.K., M.L.; (MONICA-Brianza) G.C.; (Montreal Heart Institute Biobank (MHIBB)) M.P.D., G.L., S.d.D., J.C.T.; (MORGAM Central Laboratory) M.P.; (MORGAM Data Centre) K.K.; (OBB) F. Karpe; (PCOS) A.P.M., C.M.L.; (PIVUS) C.M.L., L.L.; (PRIME—Belfast) F. Kee; (PRIME—Lille) P.A.; (PRIME—Strasbourg) M.M.; (PRIME—Toulouse) J.F.; (PROMIS) D.S.; (quality control) M.A.R.; (RISC) B.B., E.F., M.W.; (Rotterdam Study I) A.G.U., M.A.I.; (SEARCH) A.M.D.; (SHIP/SHIP-Trend) M.D.; (SIBS) D.F.E.; (SOLID TIMI-52) D.M.W.; (SORBS) A.P.M., M.S., A. Tönjes; (The Mount Sinai BioMe Biobank) E.P.B., R.J.F.L.; (The NEO Study) D.O.M.K.; (The NHAPC Study, The GBTDS Study) X.L.; (The Western Australian Pregnancy Cohort (Raine) Study) C.E.P., S. Macgregor; (TwinsUK) T.D.S.; (ULSAM) A.P.M.; (Vejle Biobank) I.B., C.C., O. Pedersen; (WGHS) D.I.C., P.M.R.; (Women’s Health Initiative) P.L.A.; (WTCCC-UKT2D) M.I.M., K.R.O.; (YFS) T.L., O.T.R.
Genotyping of contributing studies and consortia: (1958 Birth Cohort) K.E.S.; (Airwave) E.E., M.S.L.; (AMC PAS) S.S.; (Amish) L.M.Y.A., J.A. Perry; (ARIC) E.W.D., M.L.G.; (BBMRI-NL) S.H.V., L. Broer, C.M.v.D., P.I.W.d.B.; (BRAVE) E.D.A.; (Cambridge Cancer Studies) J.G.D.; (CARDIA) M.F.; (CHD Exome + Consortium) A.S.B., J.M.M.H., D.F.R., J.D., R.Y.; (Clear/eMERGE (Seattle)) G.P.J.; (CROATIA_Korcula) V.V.; (DIACORE) C.A.B., M. Gorski; (DPS) A.U.J., J. Lindström; (DRSEXTRA) P. Komulainen; (EGCUT) T.E.; (EPIC-Potsdam) M.B.S., K.M.; (EpiHealth) E.I., P.W.F.; (Family Heart Study) K.D.T.; (Fenland, EPIC) R.A.S.; (Fenland, EPIC, InterAct) N.J.W., C.L.; (FUSION) N.N.; (FVG) I.G., A. Morgan; (Generation Scotland) C.H.; (Genetic Epidemiology Network of Arteriopathy (GENOA)) S.L.R.K., J.A.S.; (GRAPHIC) N.J.S.; (GSK-STABILITY) D.M.W.; (Health) J.B.J.; (HELIC MANOLIS) L. Southam; (HELIC Pomak) L. Southam; (Inter99) T.H., N.G.; (KORA) M.M.N.; (KORA S4) K. Strauch, H.G.; (Leipzig-Adults) A. Mahajan; (LOLIPOP-Exome) J.C.C., J.S.K.; (LOLIPOP-OmniEE) J.C.C., J.S.K.; (MESA) J.I.R., Y.D.I.C., K.D.T.; (METSIM) J.K., M.L.; (Montreal Heart Institute Biobank (MHIBB)) M.P.D.; (OBB) F. Karpe; (PCOS) A.P.M.; (PIVUS) C.M.L.; (Rotterdam Study I) A.G.U., C.M.G., F.R.; (SDC) J.M.J., H.V.; (SEARCH) A.M.D.; (SOLID TIMI-52) D.M.W.; (SORBS) A.P.M.; (The Mount Sinai BioMe Biobank) E.P.B., R.J.F.L., Y.L., C.S.; (The NEO Study) R.L.G.; (The NHAPC study, The GBTDS study) X.L., H.L., Y.H.; (The Western Australian Pregnancy Cohort (Raine) Study) C.E.P., S. Macgregor; (TUDR) Z.A.; (TwinsUK) A.P.M.; (ULSAM) A.P.M.; (WGHS) D.I.C., A.Y.C.; (Women’s Health Initiative) A.P.R.; (WTCCC-UKT2D) M.I.M.; (YFS) T.L., L.P.L.
Phenotyping of contributing studies and consortia: (Airwave) E.E.; (AMC PAS) S.S.; (Amish) L.M.Y.A.; (ARIC) E.W.D.; (ARIC, Add Health) K.E.N.; (BBMRI-NL) S.H.V.; (BRAVE) E.D.A.; (BRIGHT) M.J.C.; (CARL) A. Robino, G.G.; (Cebu Longitudinal Health and Nutrition Survey) N.R.L.; (CHES) R.V., M.T.; (Clear/eMERGE (Seattle)) G.P.J., A.A.B.; (CROATIA_Korcula) O. Polasek, I.R.; (DIACORE) C.A.B., B.K.K.; (DPS) A.U.J., J. Lindström; (EFSOCH) A.T.H.; (EGCUT) E. Mihailov; (EPIC-Potsdam) H.B.; (EpiHealth) E.I.; (EXTEND) A.T.H.; (Family Heart Study) M.F.F.; (Fenland, EPIC, InterAct) N.J.W.; (FIN-D2D 2007) L.M., M.V.; (FINRISK) S. Männistö; (FINRISK 2007 (T2D)) P.J., H.M.S.; (Framingham Heart Study) C.S.F.; (Generation Scotland) C.H., B.H.S.; (Genetic Epidemiology Network of Arteriopathy (GENOA)) S.L.R.K., J.A.S.; (GRAPHIC) N.J.S.; (GSK-STABILITY) L.W., H.D.W.; (Health) A. Linneberg, B.H.T.; (HELIC MANOLIS) L. Southam, A.E.F., E.T.; (HELIC Pomak) L. Southam, A.E.F., M.K.; (HUNT-MI) K.H., O.L.H.; (Inter99) T.J., N.G.; (IRASFS) L.E.W., B.K.; (KORA) M.M.N.; (BBMRI-NL) K.M.A.S.; (Leipzig-Adults) M. Blüher, P. Kovacs; (LOLIPOP-Exome) J.C.C., J.S.K.; (LOLIPOP-OmniEE) J.C.C., J.S.K.; (MESA) M.A.; (Montreal Heart Institute Biobank (MHIBB)) G.L., K.S.L., V.T.; (MORGAM Data Centre) K.K.; (OBB) F. Karpe, M.N.; (PCOS) C.M.L.; (PIVUS) L.L.; (PRIME—Belfast) F. Kee; (PRIME—Lille) P.A.; (PRIME—Strasbourg) M.M.; (PRIME—Toulouse) J.F.; (RISC) B.B., E.F.; (Rotterdam Study I) M.A.I., C.M.G., F.R., M.C.Z.; (SHIP/SHIP-Trend) N.F.; (SORBS) M.S., A. Tönjes; (The Mount Sinai BioMe Biobank) E.P.B., Y.L., C.S.; (The NEO Study) R.d.M.; (The NHAPC study, The GBTDS study) X.L., H.L., L. Sun, F.W.; (The Western Australian Pregnancy Cohort (Raine) Study) C.E.P.; (TUDR) Y.J.H., W.J.L.; (TwinsUK) T.D.S., K.S.S.; (ULSAM) V.G.; (WGHS) D.I.C., P.M.R.; (Women’s Health Initiative) A.P.R.; (WTCCC-UKT2D) M.I.M., K.R.O.; (YFS) T.L., O.T.R.
Data analysis of contributing studies and consortia: (1958 Birth Cohort) K.E.S., I.N.; (Airwave) E.E., M.S.L.; (AMC PAS) S.S.; (Amish) J.R.O., L.M.Y.A., J.A. Perry; (ARIC, Add Health) K.E.N., K.L.Y., M. Graff; (BBMRI-NL) L. Broer; (BRAVE) R.C., D.S.A.; (BRIGHT) H.R.W.; (Cambridge Cancer Studies) J.G.D., A.E., D.J.T.; (CARDIA) C.E.L, M.F., L.-A.L.; (CARL) A. Robino, D.V.; (Cebu Longitudinal Health and Nutrition Survey) Y.W.; (CHD Exome + Consortium) A.S.B., J.M.M.H., D.F.R., R.Y., P.S.; (CHES) Y.J.; (CROATIA_Korcula) V.V.; (deCODE) V. Steinthorsdottir, G.T.; (DHS) A.J.C., P.M., M.C.Y.N.; (DIACORE) C.A.B., M. Gorski; (EFSOCH) H.Y.; (EGCUT) T.E., R.M.; (eMERGE (Seattle)) D.S.C.; (ENDO) T.K.; (EPIC) J.H.Z.; (EPIC-Potsdam) K.M.; (EpiHealth) S.G.; (EXTEND) H.Y.; (Family Heart Study) M.F.F.; (Fenland) J.Luan.; (Fenland, EPIC) R.A.S.; (Fenland, InterAct) S.M.W.; (FIN-D2D 2007) M.V., L.M.; (Finrisk Extremes and quality control) S.V.; (Framingham Heart Study) C.T.L., N.L.H.C.; (FVG) I.G.; (Generation Scotland) C.H., J.M.; (Genetic Epidemiology Network of Arteriopathy (GENOA)) L.F.B.; (GIANT-Analyst) A.E.J.; (GRAPHIC) N.J.S., N.G.D.M., C.P.N.; (GSK-STABILITY) D.M.W., A.J.S.; (Health) J.B.J.; (HELIC MANOLIS) L. Southam; (HELIC Pomak) L. Southam; (HUNT-MI) W. Zhou; (Inter99) N.G.; (IRASFS) B.K.; (Jackson Heart Study (JHS)) L.A.L., J. Li; (KORA S4) T.W.W.; (BBMRI-NL) K.M.A.S.; (Leipzig-Adults) A. Mahajan; (LOLIPOP-Exome) J.C.C., J.S.K., W. Zhang; (LOLIPOP-OmniEE) J.C.C., J.S.K., Weihua Zhang; (MESA) J.I.R., X.G., J.Y.; (METSIM) X.S.; (Montreal Heart Institute Biobank (MHIBB)) J.C.T., G.L., K.S.L., V.T.; (OBB) A. Mahajan; (PCOS) A.P.M., T.K.; (PIVUS) N.R.R.; (PROMIS) A. Rasheed, W. Zhao; (quality control GoT2D/T2D-GENES (FUSION, METSIM and so on)) A.E.L.; (RISC) H.Y.; (Rotterdam Study I) C.M.G., F.R.; (SHIP/SHIP-Trend) A. Teumer; (SOLID TIMI-52) D.M.W., A.J.S.; (SORBS) A.P.M; (The Mount Sinai BioMe Biobank) Y.L., C.S.; (The NEO Study) R.L.G.; (The NHAPC study, The GBTDS study) X.L., H.L., Y.H., H.Z.; (The Western Australian Pregnancy Cohort (Raine) Study) C.A.W.; (UK Biobank) A.R.W.; (ULSAM) A.P.M., A. Mahajan; (WGHS) D.I.C., A.Y.C.; (Women’s Health Initiative) P.L.A., J.H.; (WTCCC-UKT2D) W.G.; (YFS) L.P.L.
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Competing interests
The authors declare the following competing interests: A.S.B. holds interest in AstraZeneca, Biogen, Bioverativ, Merck, Novartis and Pfizer. A.S.C. and C.S.F. are current employees of Merck. Authors affiliated with deCODE (V.St., G.T., U.T. and K.S.) are employed by deCODE Genetics/Amgen, Inc. H.D.W. has the following financial and non-financial competing interests to declare: research grants: Sanofi Aventis; Eli Lilly; NIH; Omthera Pharmaceuticals, Pfizer, Elsai Inc. AstraZeneca; DalCor and Services; lecture fees: Sanofi Aventis; advisory boards: Acetelion, Sirtex, CSL Boehring. J.D. has received grants from AstraZeneca, Biogen, Merck, Novartis and Pfizer. L.M.Y.A. and R.A.S. are employee stock holders of GlaxoSmithKline. M.P.D. received honoraria and holds minor equity in Dalcor. V.S. has participated in a conference trip sponsored by Novo Nordisk.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–24, Supplementary Tables 1–10 and Supplementary Note
Supplementary Data 1
Study design, number of individuals and sample quality control for ExomeChip study cohorts.
Supplementary Data 2
Information on genotyping methods, quality control of SNPs, imputation, and statistical analysis for ExomeChip study cohorts.
Supplementary Data 3
Study-specific descriptive statistics for anthropometric measurements in men and women of the ExomeChip cohorts.
Supplementary Data 4
Sex combined stage 1 and stage 2 results for all variants with initial stage 1 results that met P value
Supplementary Data 5
Male-Specific stage 1 and stage 2 results for all variants with initial stage 1 results that met P value
Supplementary Data 6
Female-Specific stage 1 and stage 2 results for all variants with initial stage 1 results that met P value
Supplementary Data 7
Conditional analysis and reciprocal
Supplementary Data 8
ExomeChip Data-driven ExpressionPrioritized Integration for Complex Traits (EC-DEPICT) results when including all variants associated WHRadjBMI with P value
Supplementary Data 9
ExomeChip Data-driven ExpressionPrioritized Integration for Complex Traits (EC-DEPICT) results when including all variants associated with WHRadjBMI with P value
Supplementary Data 10
Results from PASCAL (Pathway scoring algorithm) for Exomechip coding variants and genome-wide coding and regulatory variants associated with WHRadjBMI. Pascal (Pathway scoring algorithm) details and software are available at https://www2.unil.ch/cbg/index.php?title=Pascal
Supplementary Data 11
Associations between the WHRadjBMI that
Supplementary Data 12
Previously-reported associations with other traits in the GWAS Catalog for significant WHRadjBMI variants from the current study. This table lists all previously reported associations within 1 MB (+/- 500 kb) and in high LD (r2 >0.2) with our lead novel SNPs along with relevant annotation (for example miRNA target binding site, variant location relevant to nearest gene) reported in the GWAS Catalog.
Supplementary Data 13
Genes that have been linked to monogenic and syndromic obesity.
Supplementary Data 14
Exome variant - expression quantitative trait loci (eQTL) gene associations at false discovery rate
Supplementary Data 15
Detailed description for each of the variants that met array-wide significance in the stage 1 plus stage 2 sex-combined analyses, men only analyses, or women only analyses (see also Tables 1 and 2).
Supplementary Data 16
Exome variant - expression quantitative trait loci (eQTL) gene associations at false discovery rate <5% identified in the Genotype-Tissue Expression (GTEx) database. The results were extracted from the GTEx project (version 6):
Supplementary Data 17
Variant Effect Predictor (VEP) annotation
Supplementary Data 18
Detailed acknowledgements by study and/or contributing author(s).
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Justice, A.E., Karaderi, T., Highland, H.M. et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nat Genet 51, 452–469 (2019). https://doi.org/10.1038/s41588-018-0334-2
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DOI: https://doi.org/10.1038/s41588-018-0334-2
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