Genome-wide association study of neck circumference identifies sex-specific loci independent of generalized adiposity.
Journal
International journal of obesity (2005)
ISSN: 1476-5497
Titre abrégé: Int J Obes (Lond)
Pays: England
ID NLM: 101256108
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
01
10
2020
accepted:
09
04
2021
revised:
06
03
2021
pubmed:
29
4
2021
medline:
27
1
2022
entrez:
28
4
2021
Statut:
ppublish
Résumé
Neck circumference, an index of upper airway fat, has been suggested to be an important measure of body-fat distribution with unique associations with health outcomes such as obstructive sleep apnea and metabolic disease. This study aims to study the genetic bases of neck circumference. We conducted a multi-ethnic genome-wide association study of neck circumference, adjusted and unadjusted for BMI, in up to 15,090 European Ancestry (EA) and African American (AA) individuals. Because sexually dimorphic associations have been observed for anthropometric traits, we conducted both sex-combined and sex-specific analysis. We identified rs227724 near the Noggin (NOG) gene as a possible quantitative locus for neck circumference in men (N = 8831, P = 1.74 × 10 Our study suggests that neck circumference may have unique genetic basis independent of BMI.
Sections du résumé
BACKGROUND/OBJECTIVES
Neck circumference, an index of upper airway fat, has been suggested to be an important measure of body-fat distribution with unique associations with health outcomes such as obstructive sleep apnea and metabolic disease. This study aims to study the genetic bases of neck circumference.
METHODS
We conducted a multi-ethnic genome-wide association study of neck circumference, adjusted and unadjusted for BMI, in up to 15,090 European Ancestry (EA) and African American (AA) individuals. Because sexually dimorphic associations have been observed for anthropometric traits, we conducted both sex-combined and sex-specific analysis.
RESULTS
We identified rs227724 near the Noggin (NOG) gene as a possible quantitative locus for neck circumference in men (N = 8831, P = 1.74 × 10
CONCLUSIONS
Our study suggests that neck circumference may have unique genetic basis independent of BMI.
Identifiants
pubmed: 33907307
doi: 10.1038/s41366-021-00817-2
pii: 10.1038/s41366-021-00817-2
pmc: PMC8236408
mid: NIHMS1692847
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1532-1541Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL046380
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL063463
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL113338
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135818
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL070839
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL154284
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL110068
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL135405
Pays : United States
Références
Björntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991;14:1132–43.
pubmed: 1773700
doi: 10.2337/diacare.14.12.1132
Björntorp P. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition. 1997;13:795–803.
pubmed: 9290093
doi: 10.1016/S0899-9007(97)00191-3
Patel P, Abate N. Body fat distribution and insulin resistance. Nutrients. 2013;5:2019–27.
pubmed: 23739143
pmcid: 3725490
doi: 10.3390/nu5062019
Meisinger C, Döring A, Thorand B, Heier M, Löwel H. Body fat distribution and risk of type 2 diabetes in the general population: are there differences between men and women? The MONICA/KORA Augsburg Cohort Study. Am J Clin Nutr. 2006;84:483–9.
pubmed: 16960160
doi: 10.1093/ajcn/84.3.483
Després J-P. Body fat distribution and risk of cardiovascular disease: an update. Circulation. 2012;126:1301–13.
pubmed: 22949540
doi: 10.1161/CIRCULATIONAHA.111.067264
Millman RP, Carlisle CC, McGarvey ST, Eveloff SE, Levinson PD. Body fat distribution and sleep apnea severity in women. Chest. 1995;107:362–6.
pubmed: 7842762
doi: 10.1378/chest.107.2.362
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197.
pubmed: 25673413
pmcid: 4382211
doi: 10.1038/nature14177
Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in ~ 700,000 individuals of European ancestry. bioRxiv. 2018:274654.
Komaroff M. For researchers on obesity: historical review of extra body weight definitions. J Obes. 2016;2016:2460285.
pubmed: 27313875
pmcid: 4904092
doi: 10.1155/2016/2460285
Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187.
pubmed: 25673412
pmcid: 4338562
doi: 10.1038/nature14132
Ebbert JO, Jensen MD. Fat depots, free fatty acids, and dyslipidemia. Nutrients. 2013;5:498–508.
pubmed: 23434905
pmcid: 3635208
doi: 10.3390/nu5020498
Randall JC, Winkler TW, Kutalik Z, Berndt SI, Jackson AU, Monda KL, et al. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS Genet. 2013;9:e1003500.
pubmed: 23754948
pmcid: 3674993
doi: 10.1371/journal.pgen.1003500
Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, et al. The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLoS Genet. 2015;11:e1005378.
pubmed: 26426971
pmcid: 4591371
doi: 10.1371/journal.pgen.1005378
Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010;42:949.
pubmed: 20935629
pmcid: 3000924
doi: 10.1038/ng.685
White UA, Tchoukalova YD. Sex dimorphism and depot differences in adipose tissue function. Biochim Biophys Acta (BBA)-Mol Basis Dis. 2014;1842:377–92.
doi: 10.1016/j.bbadis.2013.05.006
Whitaker KM, Choh AC, Lee M, Towne B, Czerwinski SA, Demerath EW. Sex differences in the rate of abdominal adipose accrual during adulthood: the Fels Longitudinal Study. Int J Obes. 2016;40:1278–85.
doi: 10.1038/ijo.2016.48
Preis SR, Massaro JM, Hoffmann U, D’Agostino RB Sr, Levy D, Robins SJ, et al. Neck circumference as a novel measure of cardiometabolic risk: the Framingham Heart study. J Clin Endocrinol Metab. 2010;95:3701–10.
pubmed: 20484490
pmcid: 2913042
doi: 10.1210/jc.2009-1779
Chang S-H, Beason TS, Hunleth JM, Colditz GA. A systematic review of body fat distribution and mortality in older people. Maturitas. 2012;72:175–91.
pubmed: 22595204
pmcid: 3367099
doi: 10.1016/j.maturitas.2012.04.004
Nafiu OO, Burke C, Lee J, Voepel-Lewis T, Malviya S, Tremper KK. Neck circumference as a screening measure for identifying children with high body mass index. Pediatrics. 2010. https://doi.org/10.1542/peds.2010-0242 .
Preis SR, Pencina MJ, D’agostino RB, Meigs JB, Vasan RS, Fox CS. Neck circumference and the development of cardiovascular disease risk factors in the Framingham Heart Study. Diabetes Care. 2013;36:e3.
pubmed: 23264305
doi: 10.2337/dc12-0738
Ben‐Noun L, Laor A. Relationship of neck circumference to cardiovascular risk factors. Obes Res. 2003;11:226–31.
pubmed: 12582218
doi: 10.1038/oby.2003.35
Onat A, Hergenç G, Yüksel H, Can G, Ayhan E, Kaya Z, et al. Neck circumference as a measure of central obesity: associations with metabolic syndrome and obstructive sleep apnea syndrome beyond waist circumference. Clin Nutr. 2009;28:46–51.
pubmed: 19010573
doi: 10.1016/j.clnu.2008.10.006
Mortimore I, Marshall I, Wraith P, Sellar R, Douglas N. Neck and total body fat deposition in nonobese and obese patients with sleep apnea compared with that in control subjects. Am J Respir Crit Care Med. 1998;157:280–3.
pubmed: 9445310
doi: 10.1164/ajrccm.157.1.9703018
McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48:1279–83.
pubmed: 27548312
pmcid: 5388176
doi: 10.1038/ng.3643
Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44:821.
pubmed: 22706312
pmcid: 3386377
doi: 10.1038/ng.2310
Therneau TM, Therneau MTM. Package ‘coxme’. Mixed effects cox models R package version. 2015;2.
Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.
pubmed: 20616382
pmcid: 2922887
doi: 10.1093/bioinformatics/btq340
Campos AI, García-Marín LM, Byrne EM, Martin NG, Cuéllar-Partida G, Rentería ME. Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank. Nat Commun. 2020;11:817.
pubmed: 32060260
pmcid: 7021827
doi: 10.1038/s41467-020-14625-1
Beck T, Hastings RK, Gollapudi S, Free RC, Brookes AJ. GWAS Central: a comprehensive resource for the comparison and interrogation of genome-wide association studies. Eur J Hum Genet. 2014;22:949–52.
pubmed: 24301061
doi: 10.1038/ejhg.2013.274
Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10:e1004383.
pubmed: 24830394
pmcid: 4022491
doi: 10.1371/journal.pgen.1004383
Allen HL, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467:832.
doi: 10.1038/nature09410
Van Setten J, Brody JA, Jamshidi Y, Swenson BR, Butler AM, Campbell H, et al. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. Nat Commun. 2018;9:2904.
Taira M, Imamura M, Takahashi A, Kamatani Y, Yamauchi T, Araki S-i, et al. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes. PloS ONE. 2018;13:e0208654.
pubmed: 30566433
pmcid: 6300288
doi: 10.1371/journal.pone.0208654
Sofer T, Heller R, Bogomolov M, Avery CL, Graff M, North KE, et al. A powerful statistical framework for generalization testing in GWAS, with application to the HCHS/SOL. Genet Epidemiol. 2017;41:251–8.
pubmed: 28090672
pmcid: 5340573
doi: 10.1002/gepi.22029
Loos RJ, Yeo GS. The bigger picture of FTO—the first GWAS-identified obesity gene. Nat Rev Endocrinol. 2014;10:51.
pubmed: 24247219
doi: 10.1038/nrendo.2013.227
Roberts AB, McCune BK, Sporn MB. TGF-β: regulation of extracellular matrix. Kidney Int. 1992;41:557–9.
pubmed: 1573828
doi: 10.1038/ki.1992.81
Lin D, Chun T-H, Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem Pharmacol. 2016;119:8–16.
pubmed: 27179976
pmcid: 5061598
doi: 10.1016/j.bcp.2016.05.005
Chen C, Lin J, Li L, Zhu T, Gao L, Wu W, et al. The role of the BMP4/Smad1 signaling pathway in mesangial cell proliferation: a possible mechanism of diabetic nephropathy. Life Sci. 2019;220:106–16.
pubmed: 30708099
doi: 10.1016/j.lfs.2019.01.049
Blázquez-Medela AM, Jumabay M, Rajbhandari P, Sallam T, Guo Y, Yao J, et al. Noggin depletion in adipocytes promotes obesity in mice. Mol Metab. 2019;25:50–63.
pubmed: 31027994
pmcid: 6600080
doi: 10.1016/j.molmet.2019.04.004
Wijgerde M, Karp S, McMahon J, McMahon AP. Noggin antagonism of BMP4 signaling controls development of the axial skeleton in the mouse. Dev Biol. 2005;286:149–57.
pubmed: 16122729
doi: 10.1016/j.ydbio.2005.07.016
Gustafson B, Smith U. The WNT inhibitor Dickkopf 1 and bone morphogenetic protein 4 rescue adipogenesis in hypertrophic obesity in humans. Diabetes. 2012;61:1217–24.
pubmed: 22447857
pmcid: 3331742
doi: 10.2337/db11-1419
Gustafson B, Hammarstedt A, Hedjazifar S, Hoffmann JM, Svensson P-A, Grimsby J, et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes. 2015;64:1670–81.
pubmed: 25605802
doi: 10.2337/db14-1127
Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry. Hum Mol Genet. 2018;27:3641–9.
pubmed: 30124842
pmcid: 6488973
doi: 10.1093/hmg/ddy271
Lai FY, Nath M, Hamby SE, Thompson JR, Nelson CP, Samani NJ. Adult height and risk of 50 diseases: a combined epidemiological and genetic analysis. BMC Med. 2018;16:187.
pubmed: 30355295
pmcid: 6201543
doi: 10.1186/s12916-018-1175-7
Honda T, Yamamoto H, Ishii A, Inui M. PDZRN3 negatively regulates BMP-2–induced osteoblast differentiation through inhibition of Wnt signaling. Mol Biol Cell. 2010;21:3269–77.
pubmed: 20668165
pmcid: 2938391
doi: 10.1091/mbc.e10-02-0117
Honda T, Ishii A, Inui M. Regulation of adipocyte differentiation of 3T3-L1 cells by PDZRN3. Am J Physiol-Cell Physiol. 2013;304:C1091–7.
pubmed: 23576576
doi: 10.1152/ajpcell.00343.2012
Sewduth RN, Kovacic H, Jaspard-Vinassa B, Jecko V, Wavasseur T, Fritsch N, et al. PDZRN3 destabilizes endothelial cell-cell junctions through a PKCζ-containing polarity complex to increase vascular permeability. Sci Signal. 2017;10:eaag3209.
pubmed: 28143902
doi: 10.1126/scisignal.aag3209
Nielsen JB, Pietersen A, Graff C, Lind B, Struijk JJ, Olesen MS, et al. Risk of atrial fibrillation as a function of the electrocardiographic PR interval: results from the Copenhagen ECG Study. Heart Rhythm. 2013;10:1249–56.
pubmed: 23608590
doi: 10.1016/j.hrthm.2013.04.012
Rasmussen PV, Nielsen JB, Skov MW, Pietersen A, Graff C, Lind B, et al. Electrocardiographic PR interval duration and cardiovascular risk: results from the Copenhagen ECG study. Can J Cardiol. 2017;33:674–81.
pubmed: 28449838
doi: 10.1016/j.cjca.2017.02.015
Claussnitzer M, Dankel SN, Kim K-H, Quon G, Meuleman W, Haugen C, et al. FTO obesity variant circuitry and adipocyte browning in humans. N Engl J Med. 2015;373:895–907.
pubmed: 26287746
pmcid: 4959911
doi: 10.1056/NEJMoa1502214
Mannarino MR, Di Filippo F, Pirro M. Obstructive sleep apnea syndrome. Eur J Intern Med. 2012;23:586–93.
pubmed: 22939801
doi: 10.1016/j.ejim.2012.05.013
Roca GQ, Redline S, Claggett B, Bello N, Ballantyne CM, Solomon SD, et al. Sex-specific association of sleep apnea severity with subclinical myocardial injury, ventricular hypertrophy, and heart failure risk in a community-dwelling cohort: the atherosclerosis risk in Communities–Sleep Heart Health Study. Circulation. 2015;132:1329–37.
pubmed: 26316620
pmcid: 4596785
doi: 10.1161/CIRCULATIONAHA.115.016985
Wang SH, Keenan BT, Wiemken A, Zang Y, Staley B, Sarwer DB, et al. Effect of weight loss on upper airway anatomy and the apnea–hypopnea index. The importance of tongue fat. Am J Respir Crit Care Med. 2020;201:718–27.
pubmed: 31918559
pmcid: 7068828
doi: 10.1164/rccm.201903-0692OC
Huang T, Lin BM, Stampfer MJ, Tworoger SS, Hu FB, Redline S. A population-based study of the bidirectional association between obstructive sleep apnea and type 2 diabetes in three prospective US cohorts. Diabetes Care. 2018;41:2111–9.
pubmed: 30072403
pmcid: 6150434
doi: 10.2337/dc18-0675
Fox CS, Liu Y, White CC, Feitosa M, Smith AV, Heard-Costa N, et al. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS Genet. 2012;8:e1002695.
pubmed: 22589738
pmcid: 3349734
doi: 10.1371/journal.pgen.1002695
Rask-Andersen M, Karlsson T, Ek WE, Johansson Å. Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects. Nat Commun. 2019;10:339.
pubmed: 30664634
pmcid: 6341104
doi: 10.1038/s41467-018-08000-4
Tekola-Ayele F, Doumatey AP, Shriner D, Bentley AR, Chen G, Zhou J, et al. Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome. Mol Genet Metab. 2015;116:305–13.
pubmed: 26507551
pmcid: 5292212
doi: 10.1016/j.ymgme.2015.10.008
Chen G, Doumatey AP, Zhou J, Lei L, Bentley AR, Tekola-Ayele F, et al. Genome-wide analysis identifies an african-specific variant in SEMA4D associated with body mass index. Obesity. 2017;25:794–800.
pubmed: 28296344
doi: 10.1002/oby.21804
Carroll JF, Chiapa AL, Rodriquez M, Phelps DR, Cardarelli KM, Vishwanatha JK, et al. Visceral fat, waist circumference, and BMI: impact of race/ethnicity. Obesity. 2008;16:600–7.
pubmed: 18239557
doi: 10.1038/oby.2007.92
Araneta MRG, Barrett-Connor E. Ethnic differences in visceral adipose tissue and type 2 diabetes: Filipino, African-American, and White Women. Obes Res. 2005;13:1458–65.
pubmed: 16129729
doi: 10.1038/oby.2005.176